AU2001264889A1 - Human receptor proteins; related reagents and methods - Google Patents

Description

HUMAN RECEPTOR PROTEINS; RELATED REAGENTS AND METHODS

FIELD OF THE INVENTION

The present invention relates to compositions and methods for affecting mammalian physiology, including morphogenesis or immune system function. In particular, it provides nucleic acids, proteins, and antibodies which regulate development and/or the immune system. Diagnostic and therapeutic uses of these materials are also disclosed.

BACKGROUND OF THE INVENTION

Recombinant DNA technology refers generally to techniques of integrating genetic information from a donor source into vectors for subsequent processing, such as through introduction into a host, whereby the transferred genetic information is copied and/or expressed in the new environment. Commonly, the genetic information exists in the form of complementary DNA (cDNA) derived from messenger RNA (mRNA) coding for a desired protein product . The carrier is frequently a plasmid having the capacity to incorporate cDNA for later replication in a host and, in some cases, actually to control expression of the cDNA and thereby direct synthesis of the encoded product in the host . For some time, it has been known that the mammalian immune response is based on a series of complex cellular interactions, called the "immune network". Recent research has provided new insights into the inner workings of this network. While it remains clear that much of the immune response does, in fact, revolve around the networklike interactions of lymphocytes, macrophages, granulocytes, and other cells, im unologists now generally hold the opinion that soluble proteins, known as lymphokines, cytokines, or monokines, play critical roles in controlling these cellular interactions. Thus, there is considerable interest in the isolation, characterization, and mechanisms of action of cell modulatory factors, an understanding of which will lead to significant advancements in the diagnosis and therapy of numerous medical abnormalities, e.g., immune system disorders .

Lymphokines apparently mediate cellular activities in a variety of ways. They have been shown to support the proliferation, growth, and/or differentiation of pluripotential hematopoietic stem cells into vast numbers of progenitors comprising diverse cellular lineages which make up a complex immune system. Proper and balanced interactions between the cellular components are necessary for a healthy immune response. The different cellular lineages often respond in a different manner when lymphokines are administered in conjunction with other agents .

Cell lineages especially important to the immune response include two classes of lymphocytes: B-cells, which can produce and secrete immunoglobulins (proteins with the capability of recognizing and binding to foreign matter to effect its removal) , and T-cells of various subsets that secrete lymphokines and induce or suppress the B-cells and various other cells (including other T- cells) making up the immune network. These lymphocytes interact with many other cell types.

Another important cell lineage .is the mast cell (which has not been positively identified in all mammalian species) , which is a granule-containing connective tissue cell located proximal to capillaries throughout the body. These cells are found in especially high concentrations in the lungs, skin, and gastrointestinal and genitourinary tracts. Mast cells play a central role in allergy-related disorders, particularly anaphylaxis as follows: when selected antigens crosslink one class of immunoglobulins bound to receptors on the mast cell surface, the mast cell degranulates and releases mediators, e.g., histamine, serotonin, heparin, and prostaglandins, which cause allergic reactions, e.g., anaphylaxis.

Research to better understand and treat various immune disorders has been hampered by the general inability to maintain cells of the immune system in vitro. Immunologists have discovered that culturing many of these cells can be accomplished through the use of T-cell and other cell supernatants, which contain various growth factors, including many of the lymphokines.

The interleukin-1 family of proteins includes the IL-lα, the IL-lβ, the IL-1RA, and recently the IL-lγ (also designated Interferon-Gamma Inducing Factor, IGIF) . This related family of genes have been implicated in a broad range of biological functions. See Dinarello (1994) FASEB ^ 8:1314-1325; Dinarello (1991) Blood 77:1627-1652; and Okamura, et al. (1995) Nature 378:88-91. In addition, various growth and regulatory factors exist which modulate morphogenetic development. This includes, e.g., the Toll ligands, which signal through binding to receptors which share structural, and mechanistic, features characteristic of the IL-1 receptors. See, e.g., Lemaitre, et al. (1996) Cell 86:973-983; and Belvin and Anderson (1996) Ann. Rev. Cell & Devel. Biol. 12:393-416.

From the foregoing, it is evident that the discovery and development of new soluble proteins and their receptors, including ones similar to lymphokines, should contribute to new therapies for a wide range of degenerative or abnormal conditions which directly or indirectly involve development, differentiation, or function, e.g., of the immune system and/or hematopoietic cells. In particular, the discovery and understanding of novel receptors for lymphokine-like molecules which enhance or potentiate the beneficial activities of other lymphokines would be highly advantageous. The present invention provides new receptors for ligands exhibiting similarity to interleukin-1 like compositions and related compounds, and methods for their use.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a schematic comparison of the protein architectures of Drosophila, Caenorabditis, and human DTLRs, and their relationship to vertebrate IL-1 receptors and plant disease resistance proteins. Three Drosophila (Dm) DTLRs (Toll, 18w, and the Mst ORF fragment) (Morisato and Anderson (1995) Ann. Rev. Genet. 29:371-399; Chiang and Beachy (1994) Mech. Develop. 47:225-239; Mitcham, et al. (1996) J. Biol. Chem. 271:5777-5783; and Eldon, et al. (1994) Develop. 120:885-899) are arrayed beside four complete (DTLRs 1-4) and one partial (DTLR5) human (Hu) receptors. Individual LRRs in the receptor ectodomains that are flagged by PRINTS (Attwood, et al. (1997) Nucleic Acids Res. 25:212-217) are explicitly noted by boxes; 'top' and 'bottom¹ Cys-rich clusters that flank the C- or N-terminal ends of LRR arrays are respectively drawn by opposed half-circles. The loss of the internal Cys-rich region in DTLRs 1-5 largely accounts for their smaller ectodomains (558, 570, 690, and 652 aa, respectively) when compared to the 784 and 977 aa extensions of Toll and 18w. The incomplete chains of DmMst and HuDTLR5 (about 519 and 153 aa ectodomains, respectively) are represented by dashed lines. The intracellular signaling module common to DTLRs, IL-1-type receptors (IL-lRs), the intracellular protein Myd88, and the tobacco disease resistance gene N product (DRgN) is indicated below the membrane. See, e.g., Hardiman, et al. (1996) Qncogene 13:2467-2475; and Rock, et al. (1998) Proc. Nat ' 1 Acad. Sci. USA 95:588-. Additional domains include the trio of Ig-like modules in IL-lRs (disulfide-linked loops) ; the DRgN protein features an NTPase domain (box) and Myd88 has a death domain (black oval) .

Figures 2A-2C show conserved structural patterns in the signaling domains of Toll- and IL-1-like cytokine receptors, and two divergent modular proteins. Figures 2A-2B show a sequence alignment of the common TH domain. DTLRs are labeled as in Figure 1; the human (Hu) or mouse (Mo) IL-1 family receptors (IL-1R1-6) are sequentially numbered as earlier proposed (Hardiman, et al. (1996) Oncogene 13:2467-2475); Myd88 and the sequences from tobacco (To) and flax, L. usitatissimum (Lu) , represent C- and N-terminal domains, respectively, of larger, multidomain molecules. Ungapped blocks of sequence (numbered 1-10) are boxed. ^' Triangles indicate deleterious mutations, while truncations N-terminal of the arrow eliminate bioactivity in human IL-1R1 (Heguy, et al. (1992) J. Biol. Chem. 267:2605-2609). PHD (Rost and Sander (1994) Proteins 19:55-72) and DSC (King and Sternberg (1996) Protein Sci. 5:2298-2310) secondary structure predictions of α-helix (H) , β-strand (E) , or coil (L) are marked. The amino acid shading scheme depicts chemically similar residues: hydrophobic, acidic, basic, Cys, aromatic, structure-breaking, and tiny. Diagnostic sequence patterns for IL-lRs, DTLRs, and full alignment (ALL) were derived by Consensus at a stringency of 75%. Symbols for amino acid subsets are (see internet site for detail) : o, alcohol; 1, aliphatic; . , any amino acid; a, aromatic; c, charged; h, hydrophobic; -, negative; p, polar; +, positive; s, small; u, tiny; t, turnlike. Figure 2C shows a topology diagram of the proposed TH β/α domain fold. The parallel β-sheet (with β-strands A-E as yellow triangles) is seen at its C- terminal end; α-helices (circles labeled 1-5) link the β- strands; chain connections are to the front (visible) or back (hidden) . Conserved, charged residues at the C-end of the β-sheet are noted in gray (Asp) or as a lone black (Arg) residue (see text) .

Figure 3 shows evolution of a signaling domain superfa ily. The multiple TH module alignment of Figures 2A-2B was used to derive a phylogenetic tree by the Neighbor-Joining method (Thompson, et al. (1994) Nucleic Acids Res. 22:4673-4680) . Proteins labeled as in the alignment; the tree was rendered with TreeView.

Figures 4A-4D depict FISH chromosomal mapping of human DTLR genes. Denatured chromosomes from synchronous cultures of human lymphocytes were hybridized to biotinylated DTΪ.R cDNA probes for localization. The assignment of the FISH mapping data (left, Figures 4A, DTLR2; 4B, DTLR3; 4C, DTLR ; D, DTLR5) with chromosomal bands was achieved by superimposing FISH signals with DAPI banded chromosomes (center panels) . Heng and Tsui (1994) Meth. Molec. Biol. 33:109-122. Analyses are summarized in the form of human chromosome ideograms (right panels) . Figures 5A-5F depict mRNA blot analyses of Human DTLRs. Human multiple tissue blots (He, heart; Br, brain; PI, placenta; Lu, lung; Li, liver; Mu, muscle; Ki, kidney; Pn, Pancreas; Sp, spleen; Th, thymus; Pr, prostate; Te, testis; Ov, ovary, SI, small intestine; Co, colon; PBL, peripheral blood lymphocytes) and cancer cell line (promyelocytic leukemia, HL60; cervical cancer, HELAS3; chronic myelogenous leukemia, K562; lymphoblastic leukemia, Molt4; colorectal adenocarcinoma, SW480; melanoma, G361; Burkitt ' s Lymphoma Raji, Burkitt's; colorectal adenocarcinoma, SW480; lung carcinoma, A549) containing approximately 2 μg of poly (A) ⁺ RNA per lane were probed with radiolabeled cDNAs encoding DTLR1

(Figures 5A-5C) , DTLR2 (Figure 5D) , DTLR3 (Figure 5E) , and DTLR4 (Figure 5F) as described. Blots were exposed to X- ray film for 2 days (Figures 5A-5C) or one week (Figure 5D-5F) at -70° C with intensifying screens. An anomalous 0.3 kB species appears in some lanes; hybridization experiments exclude a message encoding a DTLR cytoplasmic fragment. SUMMARY OF THE INVENTION The present invention is directed to nine novel related mammalian receptors, e.g., primate, human, DNAX Toll receptor like molecular structures, designated DTLR2, DTLR3, DTLR4, DTLR5, DTLR7, DTLR8 , DTLR9, and DTLR10, and their biological activities. It includes nucleic acids coding for the polypeptides themselves and methods for their production and use. The nucleic acids of the invention are characterized, in part, by their homology to cloned complementary DNA (cDNA) sequences enclosed herein.

In certain embodiments, the invention provides a composition of matter selected from the group of: a substantially pure or recombinant DTLR2 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 4; a natural sequence DTLR2 of SEQ ID NO: 4; a fusion protein comprising DTLR2 sequence; a substantially pure or recombinant DTLR3 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 6; a natural sequence DTLR3 of SEQ ID NO: 6; a fusion protein comprising DTLR3 sequence; a substantially pure or recombinant DTLR4 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 26; a natural sequence DTLR4 of SEQ ID NO: 26; a fusion protein comprising DTLR4 sequence; a substantially pure or recombinant DTLR5 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 10; a natural sequence DTLR5 of SEQ ID NO: 10; a fusion protein comprising DTLR5 sequence; a substantially pure or recombinant DTLR6 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 12, 28, or 30; a natural sequence DTLR6 of SEQ ID NO: 12, 28, or 30; a fusion protein comprising DTLR6 sequence; a substantially pure or recombinant DTLR7 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 16, 18, or 37; a natural sequence DTLR7 of SEQ ID NO: 16, 18, or 37; a fusion protein comprising DTLR7 sequence; a substantially pure or recombinant DTLR8 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 32 or 39; a natural sequence DTLR8 of SEQ ID NO: 32 or 39; a fusion protein comprising DTLR8 sequence; a substantially pure or recombinant DTLR9 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 22 or 41; a natural sequence DTLR9 of SEQ ID NO: 22 or 41; a fusion protein comprising DTLR9 sequence; a substantially pure or recombinant DTLR10 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 34, 43, or 45; a natural sequence DTLR10 of SEQ ID NO: 34, 43, or 45; and a fusion protein comprising DTLR10 sequence. Preferably, the substantially pure or isolated protein comprises a segment exhibiting sequence identity to a corresponding portion of a DTLR2, DTLR3, DTLR4 ,

DTLR5, DTLR6, DTLR7 , DTLR8 , DTLR9, or DTLR10, wherein said identity is over at least about 15 amino acids; preferably about 19 amino acids; or more preferably about 25 amino acids. In specific embodiments, the composition of matter: is DTLR2, which comprises a mature sequence of Table 2; or lacks a post-translational modification; is DTLR3, which comprises a mature sequence of Table 3; or ~ lacks a post-translational modification; is DTLR4, which: comprises a mature sequence of Table 4; or lacks a post- translational modification; is DTLR5, which: comprises the complete sequence of Table 5; or lacks a post- translational; is DTLR6, which comprises a mature sequence of Table 6; or lacks a post-translational modification; is DTLR7, which comprises a mature sequence of Table 7; or lacks a post-translational modification; is DTLR8, which: comprises a mature sequence of Table 8; or lacks a post- translational modification; is DTLR9, which: comprises the complete sequence of Table 9; or lacks a post- translational; is DTLRIO, which comprises a mature sequence of Table 10; or la'cks a post-translational modification; or the composition of matter may be a protein or peptide which: is from a warm blooded animal selected from a mammal, including a primate, such as a human; comprises at least one polypeptide segment of SEQ ID NO: 4, 6, 26, 10, 12, 28, 30, 16, 18, 32, 22, or 34; exhibits a plurality of portions exhibiting said identity; is a natural allelic variant of DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7 , DTLR8, DTLR9, or DTLRIO; has a length, at least about 30 amino acids; exhibits at least two non- overlapping epitopes which are specific for a primate DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO; exhibits sequence identity over a length of at least about 35 amino acids to a primate DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7 , DTLR8, DTLR9. or DTLRIO; further exhibits at least two non-overlapping epitopes which are specific for a primate DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO; exhibits identity over a length of at least about 20 amino acids to a rodent DTLR6; is glycosylated; has a molecular weight of at least 100 kD with natural glycosylation; is a synthetic polypeptide; is attached to a solid substrate; is conjugated to another chemical moiety; is a 5-fold or less substitution from natural sequence; or is a deletion or insertion variant from a natural sequence.

Other embodiments include a composition comprising: a sterile DTLR2 protein or peptide; or the DTLR2 protein or peptide and a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLR3 protein or peptide; or the DTLR3 protein or peptide and a carrier, wherein the carrier is: an aqueous compound,_, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLR4 protein or peptide; or the DTLR4 protein or peptide and a carrier, wherein the carrier is: an ^''aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLR5 protein or peptide; or the DTLR5 protein or peptide arid a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLR6 protein or peptide; or the DTLR6 protein or peptide and a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLR7 protein or peptide; or the DTLR7 protein or peptide and a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLR8 protein or peptide; or the DTLR8 protein or peptide and a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLR9 protein or peptide; or the DTLR9 protein or peptide and a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration; a sterile DTLRIO protein or peptide; or the DTLRIO protein or peptide and a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration . In certain fusion protein embodiments, the invention provides a fusion protein comprising: mature protein sequence of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; a detection or purification tag, including a FLAG, His6, or Ig sequence; or sequence of another receptor protein.

Various kit embodiments include a kit comprising a DTLR protein or polypeptide, and: a compartment comprising the protein or polypeptide; and/or instructions for use or disposal of reagents in the kit.

Binding compound embodiments include those comprising an antigen binding site from an antibody, which specifically binds to a natural DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7 , DTLR8 , DTLR9, or DTLRIO protein, wherein: the protein is a primate protein; the binding compound is an Fv, Fab, or Fab2 fragment; the binding compound is conjugated to another chemical moiety; or the antibody: is raised against a peptide sequence of a mature polypeptide of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; is raised against a mature DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO; is raised to a purified human DTLR2, DTLR3, DTLR , DTLR5, DTLR6, DTLR7 , DTLR8, DTLR9, or DTLRIO; is i munoselected; is a polyclonal antibody; binds to a denatured DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO; exhibits a Kd to antigen of at least 30 μM; is attached to a solid substrate, including a bead or plastic membrane; is in a sterile composition; or is detectably labeled, including a radioactive or fluorescent label. A binding composition kit often comprises the binding compound, and: a compartment comprising said binding compound; and/or instructions for use or disposal of reagents in the kit. Often the kit is capable of making a qualitative or quantitative analysis.

Methods are provided, e.g., of making an antibody, comprising immunizing an immune system with an immunogenic amount of a primate DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO, thereby causing said antibody to be produced; or producing an antigen: antibody complex, comprising contacting such an antibody with a mammalian DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7, DTLR8 , DTLR9, or DTLRIO protein or peptide, thereby allowing said complex to form. Other compositions include a composition comprising: a sterile binding compound, or the binding compound and a carrier, wherein the carrier is: an aqueous compound, including water, saline, and/or buffer; and/or formulated for oral, rectal, nasal, topical, or parenteral administration.

Nucleic acid embodiments include an isolated or recombinant nucleic acid encoding a DTLR2-10 protein or peptide or fusion protein, wherein: the DTLR is from a mammal; or the nucleic acid: encodes an antigenic peptide sequence of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; encodes a plurality of antigenic peptide sequences of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; comprises at least 17 contiguous nucleotides from Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; exhibits at least about 80% identity to a natural cDNA encoding said segment; is an expression vector; further comprises an origin of replication; is from a natural source; comprises a detectable label; comprises synthetic nucleotide sequence; is less than 6 kb, preferably less than 3 kb; is from a mammal, including a primate; comprises a natural full length coding sequence; is a hybridization probe for a gene encoding said DTLR; or is a PCR primer, PCR product, or mutagenesis primer. A cell, tissue, or organ comprising such a recombinant nucleic acid is also provided. Preferably, the cell is: a prokaryotic cell; a eukaryotic cell; a bacterial cell; a yeast cell; an insect cell; a mammalian cell; a mouse cell; a primate cell; or a human cell. Kits are provided comprising such nucleic acids, and: a compartment comprising said nucleic acid; a compartment further comprising a primate DTLR2, DTLR3, DTLR4, or DTLR5 protein or polypeptide; and/or instructions for use or disposal of reagents in the kit. Often, the kit is capable of making a qualitative or quantitative analysis.

Other embodiments include a nucleic acid which: hybridizes under wash conditions of 30° C and less than 2M salt to SEQ ID NO: 3; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 5; hybridizes under wash conditions of 30° C and less than 2M salt to SEQ ID NO: 7; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 9; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 11, 13, 27, or 29; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 15, 17, or 36; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 19, 31, or 38; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 21 or 40; hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 23, 33, 42, or 44; exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to- a primate DTLR2; exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLR3; exhibits at least about 85% identity over a stretch of at least about 30 -- nucleotides to a primate DTLR4; or exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLR5. Preferably, such nucleic acid will have such properties, wherein: wash conditions are at 45° C and/or 500 mM salt; or the identity is at least 90% and/or the stretch is at least 55 nucleotides. More preferably, the wash conditions are at 55° C and/or 150 M salt; or the identity is at least 95% and/or the stretch is at least 75 nucleotides.

Also provided are methods of producing a ■ ligand: receptor complex, comprising contacting a substantially pure primate DTLR2, DTLR3, DTLR4 , DTLR5, . DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO, including a recombinant or synthetically produced protein, with candidate Toll ligand; thereby allowing said complex to form.

The invention also provides a method of modulating physiology or development of a cell or tissue culture cells comprising contacting the cell with an agonist or antagonist of a ^"mammalian DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8 , DTLR9, or DTLRIO. Preferably, the cell is a pDC2 cell with the agonist or antagonist of DTLRIO.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

OUTLINE

I. General II. Activities

III. Nucleic acids

A. encoding fragments, sequence, probes

B. mutations, chimeras, fusions

C. making nucleic acids D. vectors, cells comprising

IV. Proteins, Peptides

A. fragments, sequence, immunogens, antigens

B. muteins

C. agonists/antagonists, functional equivalents D. making proteins

V. Making nucleic acids, proteins

A. synthetic

B. recombinant

C. natural sources VI. Antibodies

A. polyclonals

B. monoclonal

C. fragments; Kd

D. an^'ti-idiotypic antibodies E. hybridoma cell lines

VII. Kits and Methods to quantify DTLRs 2-10

A. ELISA

B. assay mRNA encoding

C. qualitative/quantitative D. kits

VIII. Therapeutic compositions, methods

A. combination compositions

B. unit dose

C. administration IX. Ligands

I. General

The present invention provides the amino acid sequence and DNA sequence of mammalian, herein primate DNAX Toll like receptor molecules (DTLR) having particular defined properties, both structural and biological. These have been designated herein as DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8 , DTLR9, and DTLRIO, respectively, and increase the number of members of the human Toll like receptor family from 1 to 10. Various cDNAs encoding these molecules were obtained from primate, e.g., human, cDNA sequence libraries. Other primate or other mammalian counterparts would also be desired. Some of the standard methods applicable are described or referenced, e.g., in Maniatis, et al. (1982) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Press; Sambrook, et al . (1989) Molecular Cloning: A Laboratory Manual, (2d ed. ) , vols. 1-3, CSH Press, NY; Ausubel, et al., Biology, Greene Publishing Associates, Brooklyn, NY; or Ausubel, et al. (1987 and periodic supplements) Current Protocols in Molecular Biology, Greene/Wiley, New York; each of which is incorporated herein by reference. A complete nucleotide (SEQ ID NO: 1) and corresponding amino acid sequence (SEQ ID NO: 2) of a human DTLR1 coding segment is shown in Table 1. See also Nomura, et al. (1994) DNA Res. 1:27-35. A complete nucleotide (SEQ ID NO: 3) and corresponding amino acid sequence (SEQ ID NO: 4) of a human DTLR2 coding segment is shown in Table 2. A complete nucleotide (SEQ ID NO: 5) and corresponding amino acid sequence (SEQ ID NO: 6) of a human DTLR3 coding segment is shown in Table 3. A complete nucleotide (SEQ ID NO: 7) and corresponding amino acid sequence (SEQ ID NO: 8) of a human DTLR4 coding segment is shown in Table 4; see also SEQ ID NO: 25 and 26. A partial nucleotide (SEQ ID NO: 9) and corresponding amino acid sequence (SEQ ID NO: 10) of a human DTLR5 coding segment is shown in Table 5. A complete nucleotide (SEQ ID NO: 11) and corresponding amino acid sequence (SEQ ID NO: 12) of a human DTLR6 coding segment is shown in Table 6, along with partial sequence of a mouse DTLR6 (SEQ ID NO: 13, 14, 27, 28, 29, and 30). Partial nucleotide (SEQ ID NO: 15 and 17) and corresponding amino acid sequence (SEQ ID NO: 16 and 18) of a human DTLR7 coding segment is shown in Table 7; full length sequence is provided in SEQ ID NO: 36 and 37. Partial nucleotide (SEQ ID NO: 19) and corresponding amino acid sequence (SEQ ID NO: 20) of a human DTLR8 coding segment is shown in Table 8, with supplementary sequence (SEQ ^'ID NO: 31, 32, 38, and 39). Partial nucleotide (SEQ ID NO: 21) and corresponding amino acid sequence (SEQ ID NO: 22) of a human DTLR9 coding segment is shown in Table 9; see also SEQ ID NO: 40 and 41. Partial nucleotide (SEQ ID NO: 23) and corresponding amino acid sequence (SEQ ID NO: 24) of a human DTLRIO coding segment is shown in Table 10, along with supplementary sequence (SEQ ID NO: 33, 34, 42, and 43) and rodent, e.g., mouse, sequence (SEQ ID NO: 35, 44, and 45) .

Table 1: Nucleotide and amino acid sequences (see SEQ ID NO: 1 and 2) of a primate, e.g., human, DNAX Toll like receptor 1 (DTLR1) .

ATG ACT AGC ATC TTC CAT TTT GCC ATT ATC TTC ATG TTA ATA CTT CAG 48 Met Thr Ser lie Phe His Phe Ala He He Phe Met Leu He Leu Gin

-22 -20 -15 ^" -10

ATC AGA ATA CAA TTA TCT GAA GAA AGT GAA TTT TTA GTT GAT AGG TCA 96 He Arg He Gin Leu^' Ser Glu Glu Ser Glu Phe Leu Val Asp Arg Ser -5 1 5 10

AAA AAC GGT CTC ATC CAC GTT CCT AAA GAC CTA TCC CAG AAA ACA ACA 144

Lys Asn Gly Leu He His Val Pro Lys Asp Leu Ser Gin Lys Thr Thr

15 20 25

ATC TTA AAT ATA TCG CAA AAT TAT ATA TCT GAG CTT TGG ACT TCT GAC 192

He Leu Asn He Ser Gin Asn Tyr He Ser Glu Leu Trp Thr Ser Asp

30 35 40 ATC TTA TCA CTG TCA AAA CTG AGG ATT TTG ATA ATT TCT CAT AAT AGA 240

He Leu Ser Leu Ser Lys Leu Arg He Leu He He Ser His Asn Arg

45 50 55

ATC CAG TAT CTT GAT ATC AGT GTT TTC AAA TTC AAC CAG GAA TTG GAA 288 He Gin Tyr Leu Asp He Ser Val Phe Lys Phe Asn Gin Glu Leu Glu

60 65 70

TAC TTG GAT TTG TCC CAC AAC AAG TTG GTG AAG ATT TCT TGC CAC CCT 336

Tyr Leu Asp Leu Ser His Asn Lys Leu Val Lys He Ser Cys His Pro 75 80 85 90

ACT GTG AAC CTC AAG CAC TTG GAC CTG TCA TTT AAT GCA TTT GAT GCC 384

Thr Val Asn Leu Lys His Leu Asp Leu Ser Phe Asn Ala Phe Asp Ala -«-

95 100 105

CTG CCT ATA TGC AAA GAG TTT GGC AAT ATG TCT CAA CTA AAA TTT CTG 432

Leu Pro He Cys Lys Glu Phe Gly Asn Met Ser Gin Leu Lys Phe Leu

110 115 120 GGG TTG AGC ACC ACA CAC TTA GAA AAA TCT AGT GTG CTG CCA ATT GCT .480

Gly Leu Ser Thr Thr His Leu Glu Lys Ser Ser Val Leu Pro He Ala

125 130 135

CAT TTG AAT ATC AGC AAG GTC TTG CTG GTC TTA GGA GAG ACT TAT GGG 528 His Leu Asn He Ser Lys Val Leu Leu Val Leu Gly Glu Thr Tyr Gly

140 145 150

GAA AAA GAA GAC CCT GAG GGC CTT CAA GAC TTT AAC ACT GAG AGT CTG 576

Glu Lys Glu Asp Pro Glu Gly Leu Gin Asp Phe Asn Thr Glu Ser Leu 155 160 165 170

CAC ATT GTG TTC CCC ACA AAC AAA GAA TTC CAT TTT ATT TTG GAT GTG 624

His He Val Phe Pro Thr Asn Lys Glu Phe His Phe He Leu Asp Val

175 - 180 185 TCA GTC AAG ACT GTA GCA AAT CTG GAA CTA TCT AAT ATC AAA TGT GTG 672

Ser Val Lys Thr Val Ala Asn Leu Glu Leu Ser Asn He Lys Cys Val 190 195 200 CTA GAA GAT AAC AAA TGT TCT TAC TTC CTA AGT ■^•ATT CTG GCG AAA CTT 720

Leu Glu Asp Asn Lys Cys Ser Tyr Phe Leu Ser He Leu Ala Lys Leu 205 210_. ^• 215

CAA ACA AAT CCA AAG TTA TCA AGT CTT ACC TTA AAC AAC ATT GAA ACA 768 Gin Thr Asn Pro Lys Leu Ser Ser Leu Thr Leu Asn Asn He Glu Thr 220 225 230

ACT TGG AAT TCT TTC ATT AGG ATC CTC CAA CTA GTT TGG CAT ACA ACT 816

Thr Trp Asn Ser Phe He Arg He Leu Gin Leu Val Trp His Thr Thr 235 240 245 250

GTA TGG TAT TTC TCA ATT TCA AAC GTG AAG CTA CAG GGT CAG CTG GAC 864

Val Trp Tyr Phe Ser He Ser Asn Val Lys Leu Gin Gly Gin Leu Asp 255 260 265

TTC AGA GAT TTT GAT TAT TCT GGC ACT TCC TTG AAG GCC TTG TCT ATA 912

Phe Arg Asp Phe Asp Tyr Ser Gly Thr Ser Leu Lys Ala Leu Ser He 270 275 280 CAC CAA GTT GTC AGC GAT GTG TTC GGT TTT CCG CAA AGT TAT ATC TAT 960

His Gin Val Val Ser Asp Val Phe Gly Phe Pro Gin Ser Tyr He Tyr 285 290 295

GAA ATC TTT TCG AAT ATG AAC ATC AAA AAT TTC ACA GTG TCT GGT ACA 1008 Glu He Phe Ser Asn Met Asn He Lys Asn Phe Thr Val Ser Gly Thr 300 305 310

CGC ATG GTC CAC ATG CTT TGC CCA TCC AAA ATT AGC CCG TTC CTG CAT 1056

Arg Met Val His Met Leu Cys Pro Ser Lys He Ser Pro Phe Leu His 315 320 325 330

TTG GAT TTT TCC AAT AAT CTC TTA ACA GAC ACG GTT TTT GAA AAT TGT 110

Leu Asp Phe Ser Asn Asn Leu Leu Thr Asp Thr Val Phe Glu Asn Cys 335 340 345

GGG CAC CTT ACT GAG TTG GAG ACA CTT ATT TTA CAA ATG AAT CAA TTA 1152

Gly His Leu Thr Glu Leu Glu Thr Leu He Leu Gin Met Asn Gin Leu 350 355 360 AAA GAA CTT TCA AAA ATA GCT GAA ATG ACT ACA CAG ATG AAG TCT CTG 120(

Lys Glu Leu Ser Lys He Ala Glu Met Thr Thr Gin Met Lys Ser Leu 365 370 375

CAA CAA TTG GAT ATT AGC CAG AAT TCT GTA AGC TAT GAT GAA AAG AAA 124 Gin Gin Leu Asp He Ser Gin Asn Ser Val Ser Tyr Asp Glu Lys Lys 380 385 390

GGA GAC TGT TCT TGG ACT AAA AGT TTA TTA AGT TTA AAT ATG TCT TCA 129

Gly Asp Cys Ser Trp Thr Lys Ser Leu Leu Ser Leu Asn Met Ser Ser 395 400 405 410 AAT ATA CTT ACT GAC ACT ATT TTC AGA TGT TTA CCT CCC AGG ATC AAG 1344

Asn He Leu Thr Asp Thr He Phe Arg Cys Leu Pro Pro Arg He Lys

415 420 425

GTA CTT GAT CTT CAC AGC AAT AAA ATA AAG AGC ATT CCT AAA CAA GTC 1392

Val Leu Asp Leu His Ser Asn Lys He Lys Ser He Pro Lys Gin Val

430 435 440 GTA AAA CTG GAA GCT TTG CAA GAA CTC AAT GTT GCT TTC AAT TCT TTA 1440

Val Lys Leu Glu Ala Leu Gin Glu Leu Asn Val Ala Phe Asn Ser Leu

445 450 ^" 455

ACT GAC CTT CCT GGA TGT GGC AGC TTT AGC AGC CTT TCT GTA TTG ATC 1488 Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser Ser Leu Ser Val Leu He 460 465 470

ATT GAT CAC AAT TCA GTT TCC CAC CCA TCA GCT GAT TTC TTC CAG AGC 1536

He Asp His Asn Ser Val Ser His Pro Ser Ala Asp Phe Phe Gin Ser 475 480 485 490

TGC CAG AAG ATG AGG TCA ATA AAA GCA GGG GAC AAT CCA TTC CAA TGT 1584

Cys Gin Lys Met Arg Ser He Lys Ala Gly Asp Asn Pro Phe Gin Cys

495 500 505

ACC TGT GAG CTC GGA GAA TTT GTC AAA AAT ATA GAC CAA GTA TCA AGT 1632

Thr Cys Glu Leu Gly Glu Phe Val Lys Asn He Asp Gin Val Ser Ser

510 515 520 GAA GTG TTA GAG GGC TGG CCT GAT TCT TAT AAG TGT GAC TAC CCG GAA 1680

Glu Val Leu Glu Gly Trp Pro Asp Ser Tyr Lys Cys Asp Tyr Pro Glu

525 530 535

AGT TAT AGA GGA ACC CTA CTA AAG GAC TTT CAC ATG TCT GAA TTA TCC 1728 Ser Tyr Arg Gly Thr Leu Leu Lys Asp Phe His Met Ser Glu Leu Ser 540 545 550

TGC AAC ATA ACT CTG CTG ATC GTC ACC ATC GTT GCC ACC ATG CTG GTG 1776

Cys Asn He Thr Leu Leu He Val Thr He Val Ala Thr Met Leu Val 555 560 565 570

TTG GCT GTG ACT GTG ACC TCC CTC TGC ATC TAC TTG GAT CTG CCC TGG 1824

Leu Ala Val Thr Val Thr Ser Leu Cys He Tyr Leu Asp Leu Pro Trp

575 580 585

TAT CTC AGG ATG GTG TGC CAG TGG ACC CAG ACC CGG CGC AGG GCC AGG 1872

Tyr Leu Arg Met Val Cys Gin Trp Thr Gin Thr Arg Arg Arg Ala Arg

590 595 600 AAC ATA CCC TTA GAA GAA CTC CAA AGA AAT CTC CAG TTT CAT GCA TTT 1920

Asn He Pro Leu Glu Glu Leu Gin Arg Asn Leu Gin Phe His Ala Phe

605 610 615 ATT TCA TAT AGT GGG CAC GAT TCT TTC TGG GTG AAG AAT GAA TTA TTG 1968 He Ser Tyr Ser Gly His Asp Ser Phe Trp Val Lys Asn Glu Leu Leu 620 625 630 CCA AAC CTA GAG AAA GAA GGT ATG CAG ATT TGC. CTT CAT GAG AGA AAC 2016 Pro Asn Leu Glu Lys Glu Gly Met Gin He Cys Leu His Glu Arg Asn 635 640 645 650

TTT GTT CCT GGC AAG AGC ATT GTG GAA AAT ATC ATC ACC TGC ATT GAG 2064 Phe Val Pro Gly Lys Ser He Val Glu Asn He He Thr Cys He Glu

655 660 665

AAG AGT TAC AAG TCC ATC TTT GTT TTG TCT CCC AAC TTT GTC CAG AGT 2112 Lys Ser Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Ser 670 675 680

GAA TGG TGC CAT TAT GAA CTC TAC TTT GCC CAT CAC AAT CTC TTT CAT 2160

Glu Trp Cys His Tyr Glu Leu Tyr Phe Ala His His Asn Leu Phe His

685 690 695

GAA GGA TCT AAT AGC TTA ATC CTG ATC TTG CTG GAA CCC ATT CCG CAG 2208

Glu Gly Ser Asn Ser Leu He Leu He Leu Leu Glu Pro He Pro Gin

700 705 710 TAC TCC ATT CCT AGC AGT TAT CAC AAG CTC AAA AGT CTC ATG GCC AGG 2256 Tyr Ser He Pro Ser Ser Tyr His Lys Leu Lys Ser Leu Met Ala Arg 715 720 725 730

AGG ACT TAT TTG GAA TGG CCC AAG GAA AAG AGC AAA CGT GGC CTT TTT 2304 Arg Thr Tyr Leu Glu Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe

735 740 745

TGG GCT AAC TTA AGG GCA GCC ATT AAT ATT AAG CTG ACA GAG CAA GCA 2352 Trp Ala Asn Leu Arg Ala Ala He Asn He Lys Leu Thr Glu Gin Ala 750 755 760

AAG AAA TAGTCTAGA 2367

Lys Lys

MTSIFHFAIIFMLILQIRIQLSEESEFLVDRSKNGLIHVPKD SQKTTILNISQNYISEL TSDILS SKLRILI ISHNRIQYLDISVFKFNQELEYLDLSHNKLVKISCHPTVNLKHLDLSFNAFDALPICKEFGNMSQLKFLGLSTTH LEKSSVLPIAHLNISKVLLVLGΞTYGEKEDPEGLQDFNTESLHIVFPTNKEFHFILDVSVKTVANLEIiSNIKCVL ΞDNKCSYFLSILAKLQTNPKLSSLTLNNIETTWNSFIRILQLVWHTTVWYFSISNVKLQGQLDFRDFDYSGTSLK ALSIHQWSDVFGFPQSYIYEIFSNMNIKNFTVSGTRMVHMLCPSKISPFLHLDFSNNLLTDTVFENCGH TELE TLILQMNQLKELSKIAEMTTQMKSLQQLD1SQNSVSYDEKKGDCS TKSLLSLNMSSNILTDTIFRCLPPRIKVL DLHSNKIKSIPKQWKLEALQELNVAFNSLTDLPGCGSFSSLSVLIIDHNSVSHPSADFFQSCQKMRSIKAGDNP FQCTCELGEFVKNIDQVSSEVLEG PDSYKCDYPESYRGTLLKDFHMSELSCNITLLIVTIVATMLVLAVTVTSL CIYLDLPWY RMVCQWTQTRRRARNIPLEELQRNLQFHAFISYSGHDSFWVK ELLPNLEKEGMQICLHERNFVP GKSIVENIITCIEKSYKSIFVLSPNFVQSEWCHYΞLYFAHHNLFHEGSNSLI ILLEPIPQYSIPSSYHKLKSLM ARRTYLE PKEKSKRGLF ANLRAAINIKLTEQAKK Table 2: Nucleotide and amino acid sequences (see SEQ ID NO: 3 and 4) of a primate, e.g., human, DNAX Toll like Receptor 2 (DTLR2) .

ATG CCA CAT ACT TTG TGG ATG GTG TGG GTC TTG GGG GTC ATC ATC AGC 48 Met Pro His Thr Leu Trp Met Val Trp Val Leu Gly Val He He Ser -22 -20 -15 ^' -10

CTC TCC AAG GAA GAA TCC TCC AAT CAG GCT TCT CTG TCT TGT GAC CGC 96 Leu Ser Lys Glu Glu Ser Ser Asn Gin Ala Ser Leu Ser Cys Asp Arg -5 1 5 10

AAT GGT ATC TGC AAG GGC AGC TCA GGA TCT TTA AAC TCC ATT CCC TCA 144

Asn Gly He Cys Lys Gly Ser Ser Gly Ser Leu Asn Ser He Pro Ser 15 20 25

GGG CTC ACA GAA GCT GTA AAA AGC CTT GAC CTG TCC AAC AAC AGG ATC 192

Gly Leu Thr Glu Ala Val Lys Ser Leu Asp Leu Ser Asn Asn Arg He 30 35 40 ACC TAC ATT AGC AAC AGT GAC CTA CAG AGG TGT GTG AAC CTC CAG GCT 240 Thr Tyr He Ser Asn Ser Asp Leu Gin Arg Cys Val Asn Leu Gin Ala 45 50 55

CTG GTG CTG ACA TCC AAT GGA ATT AAC ACA ATA GAG GAA GAT TCT TTT 288 Leu Val Leu Thr Ser Asn Gly He Asn Thr He Glu Glu Asp Ser Phe 60 65 70

TCT TCC CTG GGC AGT CTT GAA CAT TTA GAC TTA TCC TAT AAT TAC TTA 336 Ser Ser Leu Gly Ser Leu Glu His Leu Asp Leu Ser Tyr Asn Tyr Leu 75 80 85 90

TCT AAT TTA TCG TCT TCC TGG TTC AAG CCC CTT TCT TCT TTA ACA TTC 384

Ser Asn Leu Ser Ser Ser Trp Phe Lys Pro Leu Ser Ser Leu Thr Phe 95 100 105

TTA AAC TTA CTG GGA AAT CCT TAC AAA ACC CTA GGG GAA ACA TCT CTT 432

Leu Asn Leu Leu Gly Asn Pro Tyr Lys Thr Leu Gly Glu Thr Ser Leu

110 115 120 TTT TCT CAT CTC ACA AAA TTG CAA ATC CTG AGA GTG GGA AAT ATG GAC 480 Phe Ser His Leu Thr Lys Leu Gin He Leu Arg Val Gly Asn Met Asp 125 130 135

ACC TTC ACT AAG ATT CAA AGA AAA GAT TTT GCT GGA CTT ACC TTC CTT 528 Thr Phe Thr Lys He Gin Arg Lys Asp Phe Ala Gly Leu Thr Phe Leu 140 145 150

GAG GAA CTT GAG ATT GAT GCT TCA GAT CTA CAG AGC TAT GAG CCA AAA 576 Glu Glu Leu Glu He Asp Ala Ser Asp Leu Gin Ser Tyr Glu Pro Lys 155 160 165 170

AGT TTG AAG TCA ATT CAG AAC GTA AGT CAT CTG ATC CTT CAT ATG AAG 624

Ser Leu Lys Ser He Gin Asn Val Ser His Leu He Leu His Met Lys 175 180 185 CAG CAT ATT TTA CTG CTG GAG ATT TTT GTA GAT GTT ACA AGT TCC GTG 672

Gin His He Leu Leu Leu Glu He Phe Val Asp Val Thr Ser Ser Val 190 195 200

GAA TGT TTG GAA CTG CGA GAT ACT GAT TTG GAC ACT TTC CAT TTT TCA 720

Glu Cys Leu Glu Leu Arg Asp Thr Asp Leu Asp Thr Phe His Phe Ser 205 210 215

GAA CTA TCC ACT GGT^' GAA ACA AAT TCA TTG ATT AAA AAG TTT ACA TTT 768

Glu Leu Ser Thr Gly Glu Thr Asn Ser Leu He Lys Lys Phe Thr Phe 220 225 230

AGA AAT GTG AAA ATC ACC GAT GAA AGT TTG TTT CAG GTT ATG AAA CTT 816

Arg Asn Val Lys He Thr Asp Glu Ser Leu Phe Gin Val Met Lys Leu

235 240 245 250

TTG AAT CAG ATT CT GGA TTG TTA GAA TTA GAG TTT GAT GAC TGT ACC 864

Leu Asn Gin He Ser Gly Leu Leu Glu Leu Glu Phe Asp Asp Cys Thr 255 260 265

CTT AAT GGA GTT GGT AAT TTT AGA GCA TCT GAT AAT GAC AGA GTT ATA 912

Leu Asn Gly Val Gly Asn Phe Arg Ala Ser Asp Asn Asp Arg Val He 270 275 280

GAT CCA GGT AAA GTG GAA ACG TTA ACA ATC CGG AGG CTG CAT ATT CCA 960

Asp Pro Gly Lys Val Glu Thr Leu Thr He Arg Arg Leu His He Pro

285 290 295

AGG TTT TAC TTA TTT TAT GAT CTG AGC ACT TTA TAT TCA CTT ACA GAA 1008

Arg Phe Tyr Leu Phe Tyr Asp Leu Ser Thr Leu Tyr Ser Leu Thr Glu 300 305 310

AGA GTT AAA AGA ATC ACA GTA GAA AAC AGT AAA GTT TTT CTG GTT CCT 1056

Arg Val Lys Arg He Thr Val Glu Asn Ser Lys Val Phe Leu Val Pro

315 320 325 330

TGT TTA CTT TCA CAA CAT TTA AAA TCA TTA GAA TAC TTG GAT CTC AGT 1104

Cys Leu Leu Ser Gin His Leu Lys Ser Leu Glu Tyr Leu Asp Leu Ser 335 340 345

GAA AAT TTG ATG GTT GAA GAA TAC TTG AAA AAT TCA GCC TGT GAG GAT 1152

Glu Asn Leu Met Val Glu Glu Tyr Leu Lys Asn Ser Ala Cys Glu Asp 350 355 360

GCC TGG CCC TCT CTA CAA ACT TTA ATT TTA AGG CAA AAT CAT TTG GCA 1200

Ala Trp Pro Ser Leu Gin Thr Leu He Leu Arg Gin Asn His Leu Ala 365 370 375

TCA TTG GAA AAA ACC GGA GAG ACT TTG CTC ACT CTG AAA AAC TTG ACT 1248

Ser Leu Glu Lys Thr Gly Glu Thr Leu Leu Thr Leu Lys Asn Leu Thr 380 385 390

AAC ATT GAT ATC AGT AAG AAT AGT TTT CAT TCT ATG CCT GAA ACT TGT 1296

Asn He Asp He Ser Lys Asn ^'Ser Phe His Ser Met Pro Glu Thr Cys

395 400 405 410 CAG TGG CCA GAA AAG ATG AAA TAT TTG AAC TTA TCC AGC ACA CGA ATA 1344

Gin Trp Pro Glu Lys Met Lys Tyr Leu Asn Leu Ser Ser Thr Arg He

415 420 425

CAC AGT GTA ACA GGC TGC ATT CCC "AAG ACA CTG GAA ATT TTA GAT GTT 1392

His Ser Val Thr Gly Cys He Pro Lys Thr Leu Glu He Leu Asp Val

430 435 440 AGC AAC AAC AAT CTC AAT TTA TTT TCT TTG AAT TTG CCG CAA CTC AAA 1440

Ser Asn Asn Asn Leu Asn Leu Phe Ser Leu Asn Leu Pro Gin Leu Lys 445 450 455

GAA CTT TAT ATT TCC AGA AAT AAG TTG ATG ACT CTA CCA GAT GCC TCC 1488 Glu Leu Tyr He Ser Arg Asn Lys Leu Met Thr Leu Pro Asp Ala Ser 460 465 470

CTC TTA CCC ATG TTA CTA GTA TTG AAA ATC AGT AGG AAT GCA ATA ACT 1536

Leu Leu Pro Met Leu Leu Val Leu Lys He Ser Arg Asn Ala He Thr 475 480 485 490

ACG TTT TCT AAG GAG CAA CTT GAC TCA TTT CAC ACA CTG AAG ACT TTG 1584

Thr Phe Ser Lys Glu Gin Leu Asp Ser Phe His Thr Leu Lys Thr Leu

495 500 505

GAA GCT GGT GGC AAT AAC TTC ATT TGC TCC TGT GAA TTC CTC TCC TTC 1632

Glu Ala Gly Gly Asn Asn Phe He Cys Ser Cys Glu Phe Leu Ser Phe

510 515 520 ACT CAG GAG CAG CAA GCA CTG GCC AAA GTC TTG ATT GAT TGG CCA GCA 1680

Thr Gin Glu Gin Gin Ala Leu Ala Lys Val Leu He Asp Trp Pro Ala 525 530 535

AAT TAC CTG TGT GAC TCT CCA TCC CAT GTG CGT GGC CAG CAG GTT CAG 1728 Asn Tyr Leu Cys Asp Ser Pro Ser His Val Arg Gly Gin Gin Val Gin 540 545 550

GAT GTC CGC CTC TCG GTG TCG GAA TGT CAC AGG ACA GCA CTG GTG TCT 1776

Asp Val Arg Leu Ser Val Ser Glu Cys His Arg Thr Ala Leu Val Ser 555 560 565 570

GGC ATG TGC TGT GCT CTG TTC CTG CTG ATC CTG CTC ACG GGG GTC CTG 1824

Gly Met Cys Cys Ala Leu Phe Leu Leu He Leu Leu Thr Gly Val Leu

575 580 585

TGC CAC CGT TTC CAT GGC CTG TGG TAT ATG AAA ATG ATG TGG GCC TGG 1872

Cys His Arg Phe His Gly Leu Trp Tyr Met Lys Met Met Trp Ala Trp

590 ^■ 595 600 CTC CAG GCC AAA AGG AAG CCC AGG AAA GCT CCC AGC AGG AAC ATC TGC 1920

Leu Gin Ala Lys Arg Lys Pro Arg Lys Ala Pro Ser Arg Asn He Cys 605 610 615 TAT GAT GCA TTT GTT TCT TAC AGT GAG CGG GAT GCC TAC TGG GTG GAG 1968 Tyr Asp Ala Phe Val Ser Tyr Ser Glu Arg Asp Ala Tyr Trp Val Glu 620 625 630 AAC CTT ATG GTC CAG GAG CTG GAG AAC TTC AAT 'CCC CCC TTC AAG TTG 2016 Asn Leu Met Val Gin Glu Leu Glu Asn Phe Asn Pro Pro Phe Lys Leu 635 640 645 650

TGT CTT CAT AAG CGG GAC TTC ATT CCT GGC AAG TGG ATC ATT GAC AAT 2064 Cys Leu His Lys Arg Asp Phe He Pro Gly Lys Trp He He Asp Asn

655 660 665

ATC ATT GAC TCC ATT GAA AAG AGC CAC AAA ACT GTC TTT GTG CTT TCT 2112 He He Asp Ser He Glu Lys Ser His Lys Thr Val Phe Val Leu Ser 670 675 680

GAA AAC TTT GTG AAG AGT GAG TGG TGC AAG TAT GAA CTG GAC TTC TCC 2160 Glu Asn Phe Val Lys Ser Glu Trp Cys Lys Tyr Glu Leu Asp Phe Ser 685 690 695

CAT TTC CGT CTT TTT GAA GAG AAC AAT GAT GCT GCC ATT CTC ATT CTT 2208 His Phe Arg Leu Phe Glu Glu Asn Asn Asp Ala Ala He Leu He Leu 700 705 710 CTG GAG CCC ATT GAG AAA AAA GCC ATT CCC CAG CGC TTC TGC AAG CTG 2256 Leu Glu Pro He Glu Lys Lys Ala lie Pro Gin Arg Phe Cys Lys Leu 715 720 725 730

CGG AAG ATA ATG AAC ACC AAG ACC TAC CTG GAG TGG CCC ATG GAC GAG 2304 Arg Lys He Met Asn Thr Lys Thr Tyr Leu Glu Trp Pro Met Asp Glu

735 740 745

GCT CAG CGG GAA GGA TTT TGG GTA AAT CTG AGA GCT GCG ATA AAG TCC 2352 Ala Gin Arg Glu Gly Phe Trp Val Asn Leu Arg Ala Ala lie Lys Ser 750 755 760

TAG 2355 PHTLVmVWVLGVIISLSKEESSNQAS ΞCDRNGICKGSSGS WSIPSGLTEAVKSLDLΞtOTRITYISNSDLQRC W QALVLTSNGINTIEEDSFSSLGSLEHLDLSYNYLSNLSSSWF PLSSLTFLNLLGNPYKT GETSLFSHLTK QILRVGNMDTFTKIQRKDFAGLTF EELEIDASDLQSYEPKSLKSIQNVSHLILHMKQHILLLEIFVDVTSSVE CLE RDTDLDTFHFSELSTGETNSLI KFTFRNVKITDESLFQVMKL NQISGLLELEFDDCTLNGVGNFRASDN DRVIDPG VETLTIRRLHIPRFY FYDLSTLYSLTERVKRITVENSKVFLVPCL SQHLKSLEYLDLSENLMVEE YLK SACEDA PSLQTLILRQNHLASLEKTGETLLT KNLTNIDISK SFHS PETCQ PEKMKYLN SSTRIHS VTGCIPKTLEILDVSNNN NLFSLNLPQLKELYISRNKLM LPDASLLPMLLVLKISRNAITTFΞKEQLDSFHTL KTLEAGG NFICSCEF SFTQEQQALAKVIID PANYLCDSPSHVRGQQVQDVRLSVSECHRTALVSGMCCALF LIIJ TGVLCHRFHGLWYMKMM A QAKRKPRKAPSRNICYDAFVSYSERDAYWVENLMVQELENFNPPFKLCLH KRDFIPGK IIDNIIDSIEKSHRTVFVLSENFVKSEWCKYELDFSHFRLFEENNDAAILILLEPIEK AIPQRFC KLRKIMNTKTYLEWPKDEAQREGFWV LRAAIKS Table 3: Nucleotide and amino acid sequences (see SEQ ID NO: 5 and 6) of a mammalian, e.g., human, Toll like Receptor 3 (DTLR3) .

ATG AGA CAG ACT TTG CCT TGT ATC TAC TTT TGG GGG GGC CTT TTG CCC 48 Met Arg Gin Thr Leu Pro Cys He Tyr Phe Trp ly Gly Leu Leu Pro

-21 -20 -15 ^'' -10

TTT GGG ATG CTG TGT GCA TCC TCC ACC ACC AAG TGC ACT GTT AGC CAT 96

Phe Gly Met Leu Cys^' Ala Ser Ser Thr Thr Lys Cys Thr Val Ser His -5 1 5 10

GAA GTT GCT GAC TGC AGC CAC CTG AAG TTG ACT CAG GTA CCC GAT GAT 144

Glu Val Ala Asp Cys Ser His Leu Lys Leu Thr Gin Val Pro Asp Asp

15 20 25

CTA CCC ACA AAC ATA ACA GTG TTG AAC CTT ACC CAT AAT CAA CTC AGA 192

Leu Pro Thr Asn He Thr Val Leu Asn Leu Thr His Asn Gin Leu Arg

30 35 40 AGA TTA CCA GCC GCC AAC TTC ACA AGG TAT AGC CAG CTA ACT AGC TTG 240

Arg Leu Pro Ala Ala Asn Phe Thr Arg Tyr Ser Gin Leu Thr Ser Leu

45 50 55

GAT GTA GGA TTT AAC ACC ATC TCA AAA CTG GAG CCA GAA TTG TGC CAG 288 Asp Val Gly Phe Asn Thr He Ser Lys Leu Glu Pro Glu Leu Cys Gin

60 65 70 75

AAA CTT CCC ATG TTA AAA GTT TTG AAC CTC CAG CAC AAT GAG CTA TCT 336

Lys Leu Pro Met Leu Lys Val Leu Asn Leu Gin His Asn Glu Leu Ser 80 85 90

CAA CTT TCT GAT AAA ACC TTT GCC TTC TGC ACG AAT TTG ACT GAA CTC 384

Gin Leu Ser Asp Lys Thr Phe Ala Phe Cys Thr Asn Leu Thr Glu Leu

95 100 105

CAT CTC ATG TCC AAC TCA ATC CAG AAA ATT AAA AAT AAT CCC TTT GTC 432

His Leu Met Ser Asn Ser He Gin Lys He Lys Asn Asn Pro Phe Val

110 115 120 AAG CAG AAG AAT TTA ATC ACA TTA GAT CTG TCT CAT AAT GGC TTG TCA 480

Lys Gin Lys Asn Leu He Thr Leu Asp Leu Ser His Asn Gly Leu Ser

125 130 135

TCT ACA AAA TTA GGA ACT CAG GTT CAG CTG GAA AAT CTC CAA GAG CTT 528 Ser Thr Lys Leu Gly Thr Gin Val Gin Leu Glu Asn Leu Gin Glu Leu

140 145 150 155

CTA TTA TCA AAC AAT AAA ATT . CAA GCG CTA AAA AGT GAA GAA CTG GAT 576

Leu Leu Ser Asn Asn Lys He Gin Ala Leu Lys Ser Glu Glu Leu Asp 160 165 170

ATC TTT GCC AAT TCA TCT TTA AAA AAA TTA GAG TTG TCA TCG AAT CAA 624

He Phe Ala Asn Ser Ser Leu Lys Lys Leu Glu Leu Ser Ser Asn Gin

175 180 185 ATT AAA GAG TTT TCT CCA GGG TGT TTT CAC GCA ATT GGA AGA TTA TTT 672

He Lys Glu Phe Ser Pro Gly Cys Phe His Ala He Gly Arg Leu Phe 190 195 200

GGC CTC TTT CTG AAC AAT GTC CAG CTG GGT CCC ^•AGC CTT ACA GAG AAG 720

Gly Leu Phe Leu Asn Asn Val Gin Leu Gly Pro Ser Leu Thr Glu Lys 205 210 215

CTA TGT TTG GAA TTA GCA AAC ACA AGC ATT CGG AAT CTG TCT CTG AGT 768

Leu Cys Leu Glu Leu Ala Asn Thr Ser He Arg Asn Leu Ser Leu Ser

220 225 230 235

AAC AGC CAG CTG TCC ACC ACC AGC AAT ACA ACT TTC TTG GGA CTA AAG 816

Asn Ser Gin Leu Ser Thr Thr Ser Asn Thr Thr Phe Leu Gly Leu Lys 240 245 250

TGG ACA AAT CTC ACT ATG CTC GAT CTT TCC TAC AAC AAC TTA AAT GTG 864

Trp Thr Asn Leu Thr Met Leu Asp Leu Ser Tyr Asn Asn Leu Asn Val 255 260 265

GTT GGT AAC GAT CC TT GCT TGG CTT CCA CAA CTA GAA TAT TTC TTC 912

Val Gly Asn Asp Ser Phe Ala Trp Leu Pro Gin Leu Glu Tyr Phe Phe 270 275 280

CTA GAG TAT AAT AAT ATA CAG CAT TTG TTT TCT CAC TCT TTG CAC GGG 960

Leu Glu Tyr Asn Asn He Gin His Leu Phe Ser His Ser Leu His Gly 285 290 295

CTT TTC AAT GTG AGG TAC CTG AAT TTG AAA CGG TCT TTT ACT AAA CAA 1008

Leu Phe Asn Val Arg Tyr Leu Asn Leu Lys Arg Ser Phe Thr Lys Gin

300 305 310 315

AGT ATT TCC CTT GCC TCA CTC CCC AAG ATT GAT GAT TTT TCT TTT CAG 1056

Ser He Ser Leu Ala Ser Leu Pro Lys He Asp Asp Phe Ser Phe Gin 320 325 330

TGG CTA AAA TGT TTG GAG CAC CTT AAC ATG GAA GAT AAT GAT ATT CCA 1104

Trp Leu Lys Cys Leu Glu His Leu Asn Met Glu Asp Asn Asp He Pro 335 340 345

GGC ATA AAA AGC AAT ATG TTC ACA GGA TTG ATA AAC CTG AAA TAC TTA 1152

Gly He Lys Ser Asn Met Phe Thr Gly Leu He Asn Leu Lys Tyr Leu 350 355 360

AGT CTA TCC AAC TCC TTT ACA AGT TTG CGA ACT TTG ACA AAT GAA ACA 1200

Ser Leu Ser Asn Ser Phe Thr Ser Leu Arg Thr Leu Thr Asn Glu Thr 365 370 375

TTT GTA TCA CTT GCT CAT TCT CCC TTA CAC ATA CTC AAC CTA ACC AAG 1248

Phe Val Ser Leu Ala His Ser Pro Leu His He Leu Asn Leu Thr Lys

380 385 390 395

AAT AAA ATC TCA AAA ATA GAG AGT GAT GCT TTC TCT TGG TTG GGC CAC 1296

Asn Lys He Ser Lys He Glu Ser Asp Ala Phe Ser Trp Leu Gly His 400 405 410 CTA GAA GTA CTT GAC CTG GGC CTT AAT GAA ATT GGG CAA GAA CTC ACA 134 4

Leu Glu Val Leu Asp Leu Gly Leu Asn Glu He Gly Gin Glu Leu Thr 415 420 425

GGC CAG GAA TGG AGA GGT CTA GAA AAT ATT TTC GAA ATC TAT CTT TCC 1392

Gly Gin Glu Trp Arg Gly Leu Glu Asn He Phe Glu He Tyr Leu Ser 430 435 440

TAC AAC AAG TAC CTG CAG CTG ACT AGG AAC CC TTT GCC TTG GTC CCA 14 40

Tyr Asn Lys Tyr Leu Gin Leu Thr Arg Asn Ser Phe Ala Leu Val Pro 445 450 455

AGC CTT CAA CGA CTG ATG CTC CGA AGG GTG GCC CTT AAA AAT GTG GAT 1488

Ser Leu Gin Arg Leu Met Leu Arg Arg Val Ala Leu Lys Asn Val Asp

460 465 470 475

AGC TCT CCT TCA CCA TTC CAG CCT CTT CGT AAC TTG ACC ATT CTG GAT 1536

Ser Ser Pro Ser Pro Phe Gin Pro Leu Arg Asn Leu Thr He Leu Asp 480 485 490

CTA AGC AAC AAC AAC ATA GCC AAC ATA AAT GAT GAC ATG TTG GAG GGT 1584

Leu Ser Asn Asn Asn He Ala Asn He Asn Asp Asp Met Leu Glu Gly 495 500 505

CTT GAG AAA CTA GAA ATT CTC GAT TTG CAG CAT AAC AAC TTA GCA CGG 1632

Leu Glu Lys Leu Glu He Leu Asp Leu Gin His Asn Asn Leu Ala Arg 510 515 520

CTC TGG AAA CAC GCA AAC CCT GGT GGT CCC ATT TAT TTC CTA AAG GGT 1680

Leu Trp Lys His Ala Asn Pro Gly Gly Pro He Tyr Phe Leu Lys Gly 525 530 535

CTG TCT CAC CTC CAC ATC CTT AAC TTG GAG TCC AAC GGC TTT GAC GAG 1728

Leu Ser His Leu His He Leu Asn Leu Glu Ser Asn Gly Phe Asp Glu

540 545 550 555

ATC CCA GTT GAG GTC TC AAG GAT TTA TT GAA CTA AAG ATC ATC GAT 1776

He Pro Val Glu Val Phe Lys Asp Leu Phe Glu ^•Leu Lys He He Asp 560 565 570

TTA GGA TTG AAT AAT TTA AAC ACA CTT CCA GCA TCT GTC TTT AAT AAT 1824

Leu Gly Leu Asn Asn Leu Asn Thr Leu Pro Ala Ser Val Phe Asn Asn 575 580 585

CAG GTG TCT CTA AAG TCA TTG AAC CTT CAG AAG AAT CTC ATA ACA TCC 1872

Gin Val Ser Leu Lys Ser Leu Asn Leu Gin Lys Asn Leu He Thr Ser 590 595 600

GTT GAG AAG AAG GTT TC GGG CCA GCT TTC AGG AAC CTG ACT GAG TTA 1920

Val Glu Lys Lys Val Phe Gly Pro Ala Phe Arg Asn Leu Thr Glu Leu 605 610 615 GAT ATG CGC TTT AAT CCC TTT GAT TGC ACG TGT GAA AGT ATT GCC TGG 1968 Asp Met Arg Phe Asn Pro Phe Asp Cys Thr Cys Glu Ser He Ala Trp 620 625 630 635 TTT GTT AAT TGG ATT AAC GAG ACC CAT ACC AAC ATC CCT GAG CTG TCA 2016 Phe Val Asn Trp He Asn Glu Thr -His Thr Asn^' He Pro Glu Leu Ser 640 645 ^• 650

AGC CAC TAC CTT TGC AAC ACT CCA CCT CAC TAT CAT GGG TTC CCA GTG 2064 Ser His Tyr Leu Cys Asn Thr Pro Pro His Tyr His Gly Phe Pro Val 655 660 665

AGA CTT TTT GAT ACA TCA TCT TGC AAA GAC AGT GCC CCC TTT GAA CTC 2112 Arg Leu Phe Asp Thr Ser Ser Cys Lys Asp Ser Ala Pro Phe Glu Leu 670 675 680

TTT TTC ATG ATC AAT ACC AGT ATC CTG TTG ATT TTT ATC TTT ATT GTA 2160

Phe Phe Met He Asn Thr Ser He Leu Leu He Phe He Phe He Val 685 690 695

CTT CTC ATC CAC 'TTT GAG GGC TGG AGG ATA TCT TTT TAT TGG AAT GTT 2208

Leu Leu He His Phe Glu Gly Trp Arg He Ser Phe Tyr Trp Asn Val 700 705 710 715 TCA GTA CAT CGA GTT CTT GGT TTC AAA GAA ATA GAC AGA CAG ACA GAA 2256 Ser Val His Arg Val Leu Gly Phe Lys Glu He Asp Arg Gin Thr Glu 720 725 730

CAG TTT GAA TAT GCA GCA TAT ATA ATT CAT GCC TAT AAA GAT AAG GAT 2304 Gin Phe Glu Tyr Ala Ala Tyr He He His Ala Tyr Lys Asp Lys Asp 735 740 745

TGG GTC TGG GAA CAT TTC TCT TCA ATG GAA AAG GAA GAC CAA TCT CTC 2352 Trp Val Trp Glu His Phe Ser Ser Met Glu Lys Glu Asp Gin Ser Leu 750 755 760

AAA TTT TGT CTG GAA GAA AGG GAC TTT GAG GCG GGT GTT TTT GAA CTA 2400

Lys Phe Cys Leu Glu Glu Arg Asp Phe Glu Ala Gly Val Phe Glu Leu 765 770 775

GAA GCA ATT GTT AAC AGC ATC AAA AGA AGC AGA AAA ATT ATT TTT GTT 2448

Glu Ala He Val Asn Ser He Lys Arg Ser Arg Lys He He Phe Val 780 785 790 795 ATA ACA CAC CAT CTA TTA AAA GAC CCA TTA TGC AAA AGA TTC AAG GTA 2496 He Thr His His Leu Leu Lys Asp Pro Leu Cys Lys Arg Phe Lys Val 800 805 810

CAT CAT GCA GTT CAA CAA GCT ATT GAA CAA AAT CTG GAT TCC ATT ATA 2544 His His Ala Val Gin Gin Ala He Glu Gin Asn Leu Asp Ser He He 815 820 825

TTG GTT TTC CTT GAG GAG ATT CCA GAT TAT AAA CTG AAC CAT GCA CTC 2592 Leu Val Phe Leu Glu Glu He Pro Asp Tyr Lys Leu Asn His Ala Leu 830 835 840 TGT TTG CGA AGA GGA ATG TTT AAA TCT CAC TGC ATC TTG AAC TGG CCA 2640

Cys Leu Arg Arg Gly Met Phe Lys Ser His Cys He Leu Asn Trp Pro 845 850 855

GTT CAG AAA GAA CGG ATA GGT GCC TTT CGT CAT AAA TTG CAA GTA GCA 2688

Val Gin Lys Glu Arg He Gly Ala Phe Arg Hi's Lys Leu Gin Val Ala 860 865 870 875 CTT GGA TCC AAA AAC TCT GTA CAT TAA 2715

Leu Gly Ser Lys Asn Ser Val His 880

MRQTLPCIYFWGGLLPFGMLCASSTTKCTVSHEVADCSHLKLTQVPDDLPTNITVLNLTHNQLRRLPAANFTRYS QLTSLDVGFNTΪSKLEPELCQKLPMLKVLNLQHNELSQLSDKTFAFCTNLTELHLMSNSIQKIKNNPFVKQKNLI

TLDLSHNGLSSTKLGTQVQLENLQELLLSNNKIQALKSEELDIFANSSLKKLELSSNQIKEFSPGCFHAIGRLFG

LFLNNVQLGPSLTEKLCLELANTSIRNLSLSNSQLSTTSNTTFLGLKWTNLTMLDLSYNNLNVVGNDSFAWLPQL

EYFFLEYNNIQHLFSHSLHGLFNVRYLNLKRSFTKQSISLASLPKIDDFSFQWLKCLEHLNMEDNDIPGIKSNMF

TGLINLKYLSLSNSFTSLRTLTNETFVSLAHSPLHILNLTKNKISKIESDAFS LGHLEVLDLGLNEIGQELTGQ E RGLENIFEIYLSYNKYLQLTRNSFALVPSLQRLMLRRVALKNVDSSPSPFQPLRNLTILDLSNNNIANINDDM

LEGLEKLEILDLQHNNLARLWKHANPGGPIYFLKGLSHLHILNLESNGFDEIPVEVFKDLFELKIIDLGLNNLNT

LPASVFNNQVSLKSLNLQKNLITSVEKKVFGPAFRNLTELDMRFNPFDCTCESIAWFVNWINETHTNIPELSSHY

LCNTPPHYHGFPVRLFDTSSCKDSAPFELFFMINTSILLIFIFIVLLIHFEGWRISFYWNVSVHRVLGFKEIDRQ

TEQFEYAAYHHAY DKD V EHFSSMEKEDQSLKFCLEERDFEAGVFELEAIVNSIKRSRKHFVITHHLLKDP LCKRFKVHHAVQQAIEQNLDSIILVFLEEIPDY LNHALCLRRGMFKSHCILNWPVQKERIGAFRHKLQVALGSK

NSVH

Table 4: Nucleotide and amino acid sequences (see SEQ ID NO: 7 and 8) of a mammalian, e.g., primate, human, DNAX Toll like Receptor 4 (DTLR4).

ATG GAG CTG AAT TTC TAC AAA ATC CCC GAC AAC CTC CCC TTC TCA ACC 48 Met Glu Leu Asn Phe Tyr Lys He Pro Asp Asn Leu Pro Phe Ser Thr

1 5 10 15

AAG AAC CTG GAC CTG AGC TTT AAT CCC CTG AGG CAT TTA GGC AGC TAT 96

Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr 20 25 30

AGC TTC TTC AGT TTC CCA GAA CTG CAG GTG CTG GAT TTA TCC AGG TGT 144

Ser Phe Phe Ser Phe Pro Glu Leu Gin Val Leu Asp Leu Ser Arg Cys 35 40 45

GAA ATC CAG ACA ATT GAA GAT GGG GCA TAT CAG AGC CTA AGC CAC CTC 192

Glu He Gin Thr He Glu Asp Gly Ala Tyr Gin Ser Leu Ser His Leu 50 55 60 TCT ACC TTA ATA TTG ACA GGA AAC CCC ATC CAG AGT TTA GCC CTG GGA 240

Ser Thr Leu He Leu Thr Gly Asn Pro He Gin Ser Leu Ala Leu Gly

65 70 75 80

GCC TTT TCT GGA CTA TCA AGT TTA CAG AAG CTG GTG GCT GTG GAG ACA 288 Ala Phe Ser Gly Leu Ser Ser Leu Gin Lys Leu Val Ala Val Glu Thr

85 90 95

AAT CTA GCA TCT CTA GAG AAC TTC CCC ATT GGA CAT CTC AAA ACT TTG 336

Asn Leu Ala Ser Leu Glu Asn Phe Pro He Gly His Leu Lys Thr Leu 100 105 110

AAA GAA CTT AAT GTG GCT CAC AAT CTT ATC CAA TCT TTC AAA TTA CCT 384

Lys Glu Leu Asn Val Ala His Asn Leu He Gin Ser Phe Lys Leu Pro 115 120 125

GAG TAT TTT TCT AAT CTG ACC AAT CTA GAG CAC TTG GAC CTT TCC AGC 432

Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser 130 135 140 AAC AAG ATT CAA AGT ATT TAT TGC ACA GAC TTG CGG GTT CTA CAT CAA 480

Asn Lys He Gin Ser He Tyr Cys Thr Asp Leu Arg Val Leu His Gin

145 150 155 160

ATG CCC CTA CTC AAT CTC TCT TTA GAC CTG TCC CTG AAC CCT ATG AAC 528 Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn

165 170 175

TTT ATC CAA CCA GGT GCA TTT AAA GAA ATT AGG CTT CAT AAG CTG ACT 576

Phe He Gin Pro Gly Ala Phe Lys Glu He Arg Leu His Lys Leu Thr 180 185 190

TTA AGA AAT AAT TTT GAT AGT TTA AAT GTA ATG AAA ACT TGT ATT CAA 624

Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys He Gin 195 200 205 GGT CTG GCT GGT TTA GAA GTC CAT CGT TTG GTT CTG GGA GAA TTT AGA 672

Gly Leu Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg 210 215 220

AAT GAA GGA AAC TTG GAA AAG TTT GAC AAA TCT ^•GCT CTA GAG GGC CTG 720

Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu

225 230 235 240

TGC AAT TTG ACC ATT GAA GAA TTC CGA TTA GCA TAC TTA GAC TAC TAC 768

Cys Asn Leu Thr He Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr 245 250 255

CTC GAT GAT ATT ATT GAC TTA TTT AAT TGT TTG ACA AAT GTT TCT TCA 816

Leu Asp Asp He He Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser 260 265 270

TTT TCC CTG GTG AGT GTG ACT ATT GAA AGG GTA AAA GAC TTT TCT TAT 864

Phe Ser Leu Val Ser Val Thr He Glu Arg Val Lys Asp Phe Ser Tyr 275 280 285

AAT TTC GGA TGG CAA CAT TTA GAA TTA GTT AAC TGT AAA TTT GGA CAG 912

Asn Phe Gly Trp Gin His Leu Glu Leu Val Asn Cys Lys Phe Gly Gin 290 295 300

TTT CCC ACA TTG AAA CTC AAA TCT CTC AAA AGG CTT ACT TTC ACT TCC 960

Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser

305 310 315 320

AAC AAA GGT GGG AAT GCT TTT TCA GAA GTT GAT CTA CCA AGC CTT GAG 1008

Asn Lys Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu 325 330 335 TT CTA GAT CTC AGT AGA AAT GGC TTG AGT TTC AAA GGT TGC TGT TCT 1056

Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser 340 345 350

CAA AGT GAT TTT GGG ACA ACC AGC CTA AAG TAT TTA GAT CTG AGC TTC 1104

Gin Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe 355 360 365

AAT GGT GTT ATT ACC ATG AGT TCA AAC TTC TTG GGC TTA GAA CAA CTA 1152

Asn Gly Val He Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gin Leu 370 375 380

GAA CAT CTG GAT TTC CAG CAT TCC AAT TTG AAA CAA ATG AGT GAG TTT 1200

Glu His Leu Asp Phe Gin His Ser Asn Leu Lys Gin Met Ser Glu Phe

385 390 395 400

TCA GTA TTC CTA TCA CTC AGA AAC CTC ATT TAC CTT GAC ATT CT CAT 1248

Ser Val Phe Leu Ser Leu Arg Asn Leu He Tyr Leu Asp He Ser His 405 410 415

ACT CAC ACC AGA GTT GCT TTC AAT GGC ATC TTC AAT GGC TTG TCC AGT 1296

Thr His Thr Arg Val Ala Phe Asn Gly He Phe Asn Gly Leu Ser Ser 420 425 430 CTC GAA GTC TTG AAA ATG GCT GGC AAT TCT TTC CAG GAA AAC TTC CTT 1344

Leu Glu Val Leu Lys Met Ala Gly Asn Ser Phe Gin Glu Asn Phe Leu 435 440 445

CCA GAT ATC TC ACA GAG CTG AGA AAC TTG ACC TTC CTG GAC CTC TCT 1392

Pro Asp He Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser 450 455 460

CAG TGT CAA CTG GAG CAG TTG TCT CCA ACA GCA TTT AAC TCA CTC TCC 1440

Gin Cys Gin Leu Glu Gin Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser

465 470 475 480

AGT CTT CAG GTA CTA AAT ATG AGC CAC AAC AAC TTC TTT TCA TTG GAT 1488

Ser Leu Gin Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp 485 490 495

ACG TTT CCT TAT AAG TGT CTG AAC TCC CTC CAG GTT CTT GAT TAC AGT 1536

Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gin Val Leu Asp Tyr Ser 500 505 510

CTC AAT CAC ATA ATG ACT TCC AAA AAA CAG GAA CTA CAG CAT TTT CCA 1584

Leu Asn His He Met Thr Ser Lys Lys Gin Glu Leu Gin His Phe Pro 515 520 525

AGT AGT CTA GCT TTC TTA AAT CTT ACT CAG AAT GAC TTT GCT TGT ACT 1632

Ser Ser Leu Ala Phe Leu Asn Leu Thr Gin Asn Asp Phe Ala Cys Thr 530 535 540

TGT GAA CAC CAG AGT TTC CTG CAA TGG ATC AAG GAC CAG AGG CAG CTC 1680

Cys Glu His Gin Ser Phe Leu Gin Trp He Lys Asp Gin Arg Gin Leu

545 550 555 560

TTG GTG GAA GTT GAA CGA ATG GAA TGT GCA ACA CCT TCA GAT AAG CAG 1728

Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gin 565 570 575

GGC ATG CCT GTG CTG AGT TTG AAT ATC ACC TGT CAG ATG AAT AAG ACC 1776

Gly Met Pro Val Leu Ser Leu Asn He Thr Cys Gin Met Asn Lys Thr 580 585 590

ATC ATT GGT GTG TCG GTC CTC AGT GTG CTT GTA GTA TCT GTT GTA GCA 1824

He He Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala 595 600 605

GTT CTG GTC TAT AAG TTC TAT TTT CAC CTG ATG CTT CTT GCT GGC TGC 1872

Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Ala Gly Cys 610 615 620

ATA AAG TAT GGT AGA GGT GAA AAC ATC TAT GAT GCC TTT GTT ATC TAC 1920

He Lys Tyr Gly Arg Gly Glu Asn He Tyr Asp Ala Phe Val He Tyr

625 630 635 640 TCA AGC CAG GAT GAG GAC TGG GTA AGG AAT GAG CTA GTA AAG AAT TTA 1968

Ser Ser Gin Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn Leu 645 650 655

GAA GAA GGG GTG CCT CCA TTT CAG CTC TGC CTT_ CAC TAC AGA GAC TTT 2016

Glu Glu Gly Val Pro Pro Phe Gin Leu Cys Leu His Tyr Arg Asp Phe 660 665 670

ATT CCC GGT GTG GCC^' ATT GCT GCC AAC ATC ATC CAT GAA GGT TTC CAT 2064

He Pro Gly Val Ala He Ala Ala Asn He He His Glu Gly Phe His 675 680 685

AAA AGC CGA AAG GTG ATT GTT GTG GTG TCC CAG CAC TTC ATC CAG AGC 2112

Lys Ser Arg Lys Val He Val Val Val Ser Gin His Phe He Gin Ser

690 695 700

CGC TGG TGT ATC TTT GAA TAT GAG ATT GCT CAG ACC TGG CAG TTT CTG 2160

Arg Trp Cys He Phe Glu Tyr Glu He Ala Gin Thr Trp Gin Phe Leu

705 710 715 720

AGC AGT CGT GCT ^'GGT ATC ATC TTC ATT GTC CTG CAG AAG GTG GAG AAG 2208

Ser Ser Arg Ala Gly He He Phe He Val Leu Gin Lys Val Glu Lys 725 730 735

ACC CTG CTC AGG CAG CAG GTG GAG CTG TAC CGC CTT CTC AGC AGG AAC 2256

Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn 740 745 750

ACT TAC CTG GAG TGG GAG GAC AGT GTC CTG GGG CGG CAC ATC TTC TGG 2304

Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His He Phe Trp

755 760 765

AGA CGA CTC AGA AAA GCC CTG CTG GAT GGT AAA TCA TGG AAT CCA GAA 2352

Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser rp Asn Pro Glu

770 775 780

GGA ACA GTG GGT ACA GGA TGC AAT TGG CAG GAA GCA ACA TCT ATC 2397

Gly Thr Val Gly Thr Gly Cys Asn Trp Gin Glu Ala Thr Ser He

785 790 795

TGA ' 2400

MELNFYKIPDNLPFSTKNLDLSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTIEDGAYQSLSHLSTLILTGNP IQSLALGAFSGLSSLQKLVAVETNLASLENFPIGHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHLDLSSNK IQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSLNVMKTCIQGLAGLEVHRLV LGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDHDLFNCLTNVSSFSLVSVTIERVKDFSYNFG QHLELVNCKFGQFPTLKLKSLKRLTFTSNKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLD LSFNGVITMSSNFLGLEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGIFNGLSSLEVLKM AGNSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPYKCLNSLQVLDY SLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQ IKDQRQLLVEVERMECATPSDKQGMPVLSLN ITCQMNKTHGVSVLSVLVVSVVAVLVYKFYFHLMLLAGCIKYGRGENIYDAFVIYSSQDED VRNELVKNLE EGVPPFQLCLHYRDFIPGVAIAANHHEGFHKSRKVIVWSQHFIQSRWCIFEYEIAQTWQFLSSRAGHFIV LQKVEKTLLRQQVELYRLLSRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCN QEATSI supplemented primate, e.g., human, DTLR4 sequence (SEQ ID NO: 25 and 26); note that nucleotides 81, 3144, 3205, and 3563 designated A, each may be A, C, G, or T; nucleotides 3132, 3532, 3538, and 3553 designated G, each may be G or T; nucleotide 3638 designated A, may be A or T; and nucleotides 3677, 3685, and 3736 designated C, each may be A or C :

AAAATACTCC CTTGCCTCAA AAACTGCTCG GTCAAACGGT GATAGCAAAC CACGCATTCA 60

CAGGGCCACT GCTGCTCACA AAACCAGTGA GGATGATGCC AGGATG ATG TCT GCC 115 Met Ser Ala

-22 -20

TCG CGC CTG GCT GGG ACT CTG ATC CCA GCC ATG GCC TTC CTC TCC TGC 163 Ser Arg Leu Ala Gly Thr Leu He Pro Ala Met Ala Phe Leu Ser Cys -15 -10 -5

GTG AGA CCA GAA AGC TGG GAG CCC TGC GTG GAG GTT CCT AAT ATT ACT 211

Val Arg Pro Glu Ser Trp Glu Pro Cys Val Glu Val Pro Asn He Thr

1 5 10

TAT CAA TGC ATG GAG CTG AAT TTC TAC AAA ATC CCC GAC AAC CTC CCC 259

Tyr Gin Cys Met Glu Leu Asn Phe Tyr Lys He Pro Asp Asn Leu Pro

15 20 25 TTC TCA ACC AAG AAC CTG GAC CTG AGC TTT AAT CCC CTG AGG CAT TTA 307 Phe Ser Thr Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu 30 35 40 45

GGC AGC TAT AGC TTC TTC AGT TTC CCA GAA CTG CAG GTG CTG GAT TTA 355 Gly Ser Tyr Ser Phe Phe Ser Phe Pro Glu Leu Gin Val Leu Asp Leu

50 55 60

TCC AGG TGT GAA ATC CAG ACA ATT GAA GAT GGG GCA TAT CAG AGC CTA 403 Ser Arg Cys Glu He Gin Thr He Glu Asp Gly Ala Tyr Gin Ser Leu 65 70 75

AGC CAC CTC TCT ACC TTA ATA TTG ACA GGA AAC CCC ATC CAG AGT TTA 451

Ser His Leu Ser Thr Leu He Leu Thr Gly Asn Pro He Gin Ser Leu 80 85 90

GCC CTG GGA GCC TTT TCT GGA CTA TCA AGT TTA CAG AAG CTG GTG GCT 499

Ala Leu Gly Ala Phe Ser Gly Leu Ser Ser Leu Gin Lys Leu Val Ala 95 100 105 GTG GAG ACA AAT CTA GCA TCT CTA GAG AAC TTC CCC ATT GGA CAT CTC 547 Val Glu Thr Asn Leu Ala Ser Leu Glu Asn Phe Pro He Gly His Leu 110 115 120 125

AAA ACT TTG AAA GAA CTT AAT GTG GCT CAC AAT CTT ATC CAA TCT TTC 595 Lys Thr Leu Lys Glu Leu Asn Val Ala His Asn Leu He Gin Ser Phe

130 135 140

AAA TTA CCT GAG TAT TTT TCT AAT CTG ACC AAT CTA GAG CAC TTG GAC 643 Lys Leu Pro Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp 145 150 155 CTT TCC AGC AAC AAG ATT CAA AGT ATT TAT TGC ACA GAC TTG CGG GTT 691

Leu Ser Ser Asn Lys He Gin Ser He Tyr Cys Thr Asp Leu Arg Val 160 165 170

CTA CAT CAA ATG CCC CTA CTC AAT CTC TCT TTA GAC CTG TCC CTG AAC 739

Leu His Gin Met Pro Leu Leu Asn Leu Ser Le'u Asp Leu Ser Leu Asn 175 180 185

CCT ATG AAC TTT ATC CAA CCA GGT GCA TTT AAA GAA ATT AGG CTT CAT 787

Pro Met Asn Phe He Gin Pro Gly Ala Phe Lys Glu He Arg Leu His

190 195 200 205

AAG CTG ACT TTA AGA AAT AAT TTT GAT AGT TTA AAT GTA ATG AAA ACT 835

Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr 210 215 220

TGT ATT CAA GGT CTG GCT GGT TTA GAA GTC CAT CGT TTG GTT CTG GGA 883

Cys He Gin Gly Leu Ala Gly Leu Glu Val His Arg Leu Val Leu Gly 225 230 235

GAA TTT AGA AAT GAA GGA AAC TTG GAA AAG TTT GAC AAA TCT GCT CTA 931

Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu 240 245 250

GAG GGC CTG TGC AAT TTG ACC ATT GAA GAA TTC CGA TTA GCA TAC TTA 979

Glu Gly Leu Cys Asn Leu Thr He Glu Glu Phe Arg Leu Ala Tyr Leu 255 260 265

GAC TAC TAC CTC GAT GAT ATT ATT GAC TTA TTT AAT TGT TTG ACA AAT 1027

Asp Tyr Tyr Leu Asp Asp He He Asp Leu Phe Asn Cys Leu Thr Asn

270 275 280 285

GTT TCT TCA TTT TCC CTG GTG AGT GTG ACT ATT GAA AGG GTA AAA GAC 1075

Val Ser Ser Phe Ser Leu Val Ser Val Thr He Glu Arg Val Lys Asp 290 295 300

TTT TCT TAT AAT TC GGA TGG CAA CAT TTA GAA TTA GTT AAC TGT AAA 1123

Phe Ser Tyr Asn Phe Gly Trp Gin His Leu Glu Leu Val Asn Cys Lys 305 310 315

TTT GGA CAG TTT CCC ACA TTG AAA CTC AAA TCT CTC AAA AGG CTT ACT 1171

Phe Gly Gin Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr 320 325 330 TC ACT TCC AAC AAA GGT GGG AAT GCT TTT TCA GAA GTT GAT CTA CCA 1219

Phe Thr Ser Asn Lys Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro 335 340 345

AGC CTT GAG TTT CTA GAT CTC AGT AGA AAT GGC TTG AGT TTC AAA GGT 1267

Ser Leu Glu Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly

350 355 360 365 TGC TGT TCT CAA AGT GAT TTT GGG ACA ACC AGC CTA AAG TAT TTA GAT 1315

Cys Cys Ser Gin Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp 370 375 380

CTG AGC TTC AAT GGT GTT ATT ACC ATG AGT TCA; 'AAC TTC TTG GGC TTA 1363

Leu Ser Phe Asn Gly Val He Thr Met Ser Ser Asn Phe Leu Gly Leu 385 390 395

GAA CAA CTA GAA CAT^' CTG GAT TTC CAG CAT TCC AAT TTG AAA CAA ATG 1411

Glu Gin Leu Glu His Leu Asp Phe Gin His Ser Asn Leu Lys Gin Met 400 405 410

AGT GAG TTT TCA GTA TTC CTA TCA CTC AGA AAC CTC ATT TAC CTT GAC 1459

Ser Glu Phe Ser Val Phe Leu Ser Leu Arg Asn Leu He Tyr Leu Asp 415 420 425

ATT TCT CAT ACT CAC ACC AGA GTT GCT TTC AAT GGC ATC TTC AAT GGC 1507

He Ser His Thr His Thr Arg Val Ala Phe Asn Gly He Phe Asn Gly

430 435 440 445

TTG TCC AGT CTC GAA GTC TTG AAA ATG GCT GGC AAT CT TTC CAG GAA 1555

Leu Ser Ser Leu Glu Val Leu Lys Met Ala Gly Asn Ser Phe Gin Glu 450 455 460

AAC TTC CTT CCA GAT ATC TTC ACA GAG CTG AGA AAC TTG ACC TTC CTG 1603

Asn Phe Leu Pro Asp He Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu 465 470 475

GAC CTC TCT CAG TGT CAA CTG GAG CAG TTG TCT CCA ACA GCA TTT AAC 1651

Asp Leu Ser Gin Cys Gin Leu Glu Gin Leu Ser Pro Thr Ala Phe Asn 480 485 490

TCA CTC TCC AGT CTT CAG GTA CTA AAT ATG AGC CAC AAC AAC TTC TTT 1699

Ser Leu Ser Ser Leu Gin Val Leu Asn Met Ser His Asn Asn Phe Phe 495 500 505

TCA TTG GAT ACG TTT CCT TAT AAG TGT CTG AAC TCC CTC CAG GTT CTT 1747

Ser Leu Asp Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gin Val Leu

510 515 520 525

GAT TAC AGT CTC AAT CAC ATA ATG ACT TCC AAA AAA CAG GAA CTA CAG 1795

Asp Tyr Ser Leu Asn His He Met Thr Ser Lys Lys Gin Glu Leu Gin 530 535 540

CAT TTT CCA AGT AGT CTA GCT TTC TTA AAT CTT ACT CAG AAT GAC TTT 1843

His Phe Pro Ser Ser Leu Ala Phe Leu Asn Leu Thr Gin Asn Asp Phe 545 550 555

GCT TGT ACT TGT GAA CAC CAG AGT TTC CTG CAA TGG ATC AAG GAC CAG 1891

Ala Cys Thr Cys Glu His Gin Ser Phe Leu Gin Trp He Lys Asp Gin 560 565 570

AGG CAG CTC TTG GTG GAA GTT GAA CGA ATG GAA TGT GCA ACA CCT TCA 1939

Arg Gin Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser 575 580 585 GAT AAG CAG GGC ATG CCT GTG CTG AGT TTG AAT ATC ACC TGT CAG ATG 1987

Asp Lys Gin Gly Met Pro Val Leu Ser Leu Asn He Thr Cys Gin Met

590 595 600 605

AAT AAG ACC ATC ATT GGT GTG TCG GTC CTC AGT GTG CTT GTA GTA TCT 2035

Asn Lys Thr He He Gly Val Ser Val Leu Se^'r Val Leu Val Val Ser 610 615 620

GTT GTA GCA GTT CTG GTC TAT AAG TTC TAT TTT CAC CTG ATG CTT CTT 2083

Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu 625 630 635

GCT GGC TGC ATA AAG TAT GGT AGA GGT GAA AAC ATC TAT GAT GCC TTT 2131

Ala Gly Cys He Lys Tyr Gly Arg Gly Glu Asn He Tyr Asp Ala Phe

640 645 650

GTT ATC TAC TCA AGC CAG GAT GAG GAC TGG GTA AGG AAT GAG CTA GTA 2179

Val He Tyr Ser Ser Gin Asp Glu Asp Tirp Val Arg Asn Glu Leu Val 655 660 665

AAG AAT TTA GAA GAA GGG GTG CCT CCA TTT CAG CTC TGC CTT CAC TAC 2227

Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gin Leu Cys Leu His Tyr

670 675 680 685

AGA GAC TTT ATT CCC GGT GTG GCC ATT GCT GCC AAC ATC ATC CAT GAA 2275

Arg Asp Phe He Pro Gly Val Ala He Ala Ala Asn He He His Glu 690 695 700

GGT TTC CAT AAA AGC CGA AAG GTG ATT GTT GTG GTG TCC CAG CAC TTC 2323

Gly Phe His Lys Ser Arg Lys Val He Val Val Val Ser Gin His Phe 705 710 715

ATC CAG AGC CGC TGG TGT ATC TTT GAA TAT GAG ATT GCT CAG ACC TGG 2371

He Gin Ser Arg Trp Cys He Phe Glu Tyr Glu He Ala Gin Thr Trp 720 725 730

CAG TTT CTG AGC AGT CGT GCT GGT ATC ATC TTC ATT GTC CTG CAG AAG 2419

Gin Phe Leu Ser Ser Arg Ala Gly He He Phe ^■He Val Leu Gin Lys 735 740 745

GTG GAG AAG ACC CTG CTC AGG CAG CAG GTG GAG CTG TAC CGC CTT CTC 2467

Val Glu Lys Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr Arg Leu Leu

750 755 760 765

AGC AGG AAC ACT TAC CTG GAG TGG GAG GAC AGT GTC CTG GGG CGG CAC 2515

Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His

770 775 780

ATC TTC TGG AGA CGA CTC AGA AAA GCC CTG CTG GAT GGT AAA TCA TGG 2563

He Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp 785 790 795 AAT CCA GAA GGA ACA GTG GGT ACA GGA TGC AAT TGG CAG GAA GCA ACA 2611 Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gin Glu Ala Thr 800 805 810

TCT ATC TGAAGAGGAA AAATAAAAAC CTCCTGAGGC ATTTCTTGCC CAGCTGGGTC 2667 Ser He 815

CAACACTTGT TCAGTTAATA AGTATTAAAT GCTGCCACAT GTCAGGCCTT ATGCTAAGGG 2727

TGAGTAATTC CATGGTGCAC TAGATATGCA GGGCTGCTAA TCTCAAGGAG CTTCCAGTGC 2787

AGAGGGAATA AATGCTAGAC TAAAATACAG AGTCTTCCAG GTGGGCATTT CAACCAACTC 2847 AGTCAAGGAA CCCATGACAA AGAAAGTCAT TTCAACTCTT ACCTCATCAA GTTGAATAAA 2907

GACAGAGAAA ACAGAAAGAG ACATTGTTCT TTTCCTGAGT CTTTTGAATG GAAATTGTAT 2967

TATGTTATAG CCATCATAAA ACCATTTTGG TAGTTTTGAC TGAACTGGGT GTTCACTTTT 3027

TCCTTTTTGA TTGAATACAA TTTAAATTCT ACTTGATGAC TGCAGTCGTC AAGGGGCTCC 3087

TGATGCAAGA TGCCCCTTCC ATTTTAAGTC TGTCTCCTTA CAGAGGTTAA AGTCTAATGG 3147 CTAATTCCTA AGGAAACCTG ATTAACACAT GCTCACAACC ATCCTGGTCA TTCTCGAACA 3207

TGTTCTATTT TTTAACTAAT CACCCCTGAT ATATTTTTAT TTTTATATAT CCAGTTTTCA 3267

TTTTTTTACG TCTTGCCTAT AAGCTAATAT CATAAATAAG GTTGTTTAAG ACGTGCTTCA 3327

AATATCCATA TTAACCACTA TTTTTCAAGG AAGTATGGAA AAGTACACTC TGTCACTTTG 3387

TCACTCGATG TCATTCCAAA GTTATTGCCT ACTAAGTAAT GACTGTCATG AAAGCAGCAT 3447 TGAAATAATT TGTTTAAAGG GGGCACTCTT TTAAACGGGA AGAAAATTTC CGCTTCCTGG 3507

TCTTATCATG GACAATTTGG GCTAGAGGCA GGAAGGAAGT GGGATGACCT CAGGAAGTCA 3567

CCTTTTCTTG ATTCCAGAAA CATATGGGCT GATAAACCCG GGGTGACCTC ATGAAATGAG 3627

TTGCAGCAGA AGTTTATTTT ^• TTTCAGAACA AGTGATGTTT GATGGACCTC TGAATCTCTT 3687

TAGGGAGACA CAGATGGCTG GGATCCCTCC CCTGTACCCT TCTCACTGCC AGGAGAACTA 3747 CGTGTGAAGG TATTCAAGGC AGGGAGTATA CATTGCTGTT TCCTGTTGGG CAATGCTCCT 3807

TGACCACATT TTGGGAAGAG TGGATGTTAT CATTGAGAAA ACAATGTGTC TGGAATTAAT 3867

GGGGTTCTTA TAAAGAAGGT TCCCAGAAAA GAATGTTCAT TCCAGCTTCT TCAGGAAACA 3927

GGAACATTCA AGGAAAAGGA CAATCAGGAT GTCATCAGGG AAATGAAAAT AAAAACCACA 3987

ATGAGATATC ACCTTAT CC AGGTAGATGG CTACTATAAA AAAATGAAGT GTCATCAAGG 4047 ATATAGAGAA ATTGGAACCC TTCTTCACTG CTGGAGGGAA TGGAAAATGG TGTAGCCGTT 4107 ATGAAAAACA GTACGGAGGT TTCTCAAAAA TTAAAAATAG AACTGCTATA TGATCCAGCA 4 167

ATCTCACTTC TGTATATATA CCCAAAATAA TTGAAATCAG AATTTCAAGA AAATATTTAC 4227

ACTCCCATGT TCATTGTGGC ACTCTTCACA ATCACTGTTT ^' CCAAAGTTAT GGAAACAACC 4287

CAAATTTCCA TTGGAAAATA AATGGACAAA GGAAATGTGC ATATAACGTA CAATGGGGAT 4347 ATTATTCAGC CTAAAAAAAG GGGGGATCCT GTTATTTATG ACAACATGAA TAAACCCGGA 44 07

GGCCATTATG CTATGTAAAA TGAGCAAGTA ACAGAAAGAC AAATACTGCC TGATTTCATT 44 67

TATATGAGGT TCTAAAATAG TCAAACTCAT AGAAGCAGAG AATAGAACAG TGGTTCCTAG 4527

GGAAAAGGAG GAAGGGAGAA ATGAGGAAAT AGGGAGTTGT CTAATTGGTA TAAAATTATA 4587

GTATGCAAGA TGAATTAGCT CTAAAGATCA GCTGTATAGC AGAGTTCGTA TAATGAACAA 4 647 TACTGTATTA TGCACTTAAC ATTTTGTTAA GAGGGTACCT CTCATGTTAA GTGTTCTTAC 4707

CATATACATA TACACAAGGA AGCTTTTGGA GGTGATGGAT ATATTTATTA CCTTGATTGT 4767

GGTGATGGTT TGACAGGTAT GTGACTATGT CTAAACTCAT CAAATTGTAT ACATTAAATA 4827

TATGCAGTTT TATAATATCA AAAAAAAAAA AAAAAAAA 4865

MSASRLAGTLIPAMAFLSCVRPESWEPCVEVPNITYQCMELNFYKIPDNLPFSTKNLDLSFNPLRHLGSYSFFSF PELQVLDLSRCEIQTIEDGAYQSLSHLSTLILTGNPIQSLALGAFSGLSSLQKLVAVETNLASLENFPIGHLKTL KELNVAHNLIQSFKLPEYFSNLTNLEHLDLSSNKIQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIR LHKLTLRNNFDSLNVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDIID LFNCLTNVSSFSLVSVTIERVKDFSYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTSNKGGNAFSEVDLPSLEF LDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLGLEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYL DISHTHTRVAFNGIFNGLSSLEVLKMAGNSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLΞSLQVLNM SHNNFFSLDTFPYKCLNSLQVLDYSLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQLLV EVERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLMLLAGCIKYGRGENIYDAF VIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIHEGFHKSRKVIWVSQHFIQSRWCIFE E IAQT QFLSSRAGIIFIVLQKVEKTLLRQQVELYRLLSRNTYLE EDSVLGRHIFWRRLRKALLDGKSWNPEGTV GTGCNWQEATSI

Table 5: Partial nucleotide and amino acid sequences (see SEQ ID NO: 9 and 10) of a mammalian, e.g., primate, human, DNAX Toll like Receptor 5 (DTLR5) . TGT TGG GAT GTT TTT GAG GGA CTT TCT CAT CTT. CAA GTT CTG TAT TTG 48 Cys Trp Asp Val Phe Glu Gly Leu Ser His Leu Gin Val Leu Tyr Leu 1 5 10 15

AAT CAT AAC TAT CTT^' AAT TCC CTT CCA CCA GGA GTA TTT AGC CAT CTG 96 Asn His Asn Tyr Leu Asn Ser Leu Pro Pro Gly Val Phe Ser His Leu 20 25 30

ACT GCA TTA AGG GGA CTA AGC CTC AAC TCC AAC AGG CTG ACA GTT CTT 144 Thr Ala Leu Arg Gly Leu Ser Leu Asn Ser Asn Arg Leu Thr Val Leu 35 40 45

TCT CAC AAT GAT TTA CCT GCT AAT TTA GAG ATC CTG GAC ATA TCC AGG 192

Ser His Asn Asp Leu Pro Ala Asn Leu Glu He Leu Asp He Ser Arg

50 55 ' 60

AAC CAG CTC CTA GCT CCT AAT CCT GAT GTA TTT GTA TCA CTT AGT GTC 240

Asn Gin Leu Leu Ala Pro Asn Pro Asp Val Phe Val Ser Leu Ser Val

65 70 75 _ 80 TTG GAT ATA ACT CAT AAC AAG TTC ATT TGT GAA TGT GAA CTT AGC ACT 288 Leu Asp He Thr His Asn Lys Phe He Cys Glu Cys Glu Leu Ser Thr 85 90 95

TTT ATC AAT TGG CTT AAT CAC ACC AAT^' GTC ACT ATA GCT GGG CCT CCT 336 Phe He Asn Trp Leu Asn His Thr Asn Val Thr He Ala Gly Pro Pro 100 105 110

GCA GAC ATA TAT TGT GTG TAC CCT GAC TCG TTC TCT GGG GTT TCC CTC ■- 384 Ala Asp He Tyr Cys Val Tyr Pro Asp Ser Phe Ser Gly Val Ser Leu 115 120 125

TTC TCT CTT TCC ACG GAA GGT TGT GAT GAA GAG GAA GTC TTA AAG TCC 432 Phe Ser Leu Ser Thr Glu Gly Cys Asp Glu Glu Glu Val Leu Lys Ser 130 135 140

CTA AAG TTC TCC CTT TTC ATT GTA TGC ACT GTC ACT CTG ACT CTG TTC 480 Leu Lys Phe Ser Leu Phe He Val Cys Thr Val Thr Leu Thr Leu Phe 145 150 155 160 CTC ATG ACC ATC CTC ACA GTC ACA AAG TTC CGG GGC TTC TGT TTT ATC 528 Leu Met Thr He Leu Thr Val Thr Lys Phe Arg Gly Phe Cys Phe He 165 170 175

TGT TAT AAG ACA GCC CAG AGA CTG GTG TTC AAG GAC CAT CCC CAG GGC 576 Cys Tyr Lys Thr Ala Gin Arg Leu Val Phe Lys Asp His Pro Gin Gly 180 185 190

ACA GAA CCT GAT ATG TAC AAA TAT GAT GCC TAT TTG TGC TTC AGC AGC 624 Thr Glu Pro Asp Met Tyr Lys Tyr Asp Ala Tyr Leu Cys Phe Ser Ser 195 200 205 AAA GAC TTC ACA TGG GTG CAG AAT GCT TTG CTC AAA CAC CTG GAC ACT 672

Lys Asp Phe Thr Trp Val Gin Asn Ala Leu Leu Lys His Leu Asp Thr

210 215 220

CAA TAC AGT GAC CAA AAC AGA TTC AAC CTG TGC TTT GAA GAA AGA GAC 720

Gin Tyr Ser Asp Gin Asn Arg Phe Asn Leu Cys Phe Glu Glu Arg Asp

225 _ 230 235 240 TTT GTC CCA GGA GAA AAC CGC ATT GCC AAT ATC CAG GAT GCC ATC TGG 768 Phe Val Pro Gly Glu Asn Arg He Ala Asn He Gin Asp Ala He Trp 245 250 255

AAC AGT AGA AAG ATC GTT TGT CTT GTG AGC AGA CAC TTC CTT AGA GAT 816 Asn Ser Arg Lys He Val Cys Leu Val Ser Arg His Phe Leu Arg Asp 260 265 270

GGC TGG TGC CTT GAA GCC TTC AGT TAT GCC CAG GGC AGG TGC TTA TCT 864 Gly Trp Cys Leu Glu Ala Phe Ser Tyr Ala Gin Gly Arg Cys Leu Ser 275 280 285

GAC CTT AAC AGT GCT CTC ATC ATG GTG GTG GTT GGG TCC TTG TCC CAG 912

Asp Leu Asn Ser Ala Leu He Met Val Val Val Gly Ser Leu Ser Gin 290 295 300

TAC CAG TTG ATG AAA CAT CAA TCC ATC AGA GGC TTT GTA CAG AAA CAG 960

Tyr Gin Leu Met Lys His Gin Ser He Arg Gly Phe Val Gin Lys Gin 305 310 315 320 CAG TAT TTG AGG TGG CCT GAG GAT CTC CAG GAT GTT GGC TGG TTT CTT 1008 Gin Tyr Leu Arg Trp Pro Glu Asp Leu Gin Asp Val Gly Trp Phe Leu 325 330 335

CAT AAA CTC TCT CAA CAG ATA CTA AAG AAA GAA AAG GAA AAG AAG AAA 1056 His Lys Leu Ser Gin Gin He Leu Lys Lys Glu Lys Glu Lys Lys Lys 340 345 350

GAC AAT AAC ATT CCG TTG CAA ACT GTA GCA ACC ATC TCC TAATCAAAGG 1105 Asp Asn Asn He Pro Leu Gin Thr Val Ala Thr He Ser 355 360 365

AGCAATTTCC AACTTATCTC AAGCCACAAA TAACTCTTCA CTTTGTATTT GCACCAAGTT 1165

ATCATTTTGG GGTCCTCTCT GGAGGTTTTT TTTTTCTTTT TGCTACTATG AAAACAACAT 1225

AAATCTCTCA ATTTTCGTAT CAAAAAAAAA AAAAAAAAAA TGGCGGCCGC 1275

C DVFEGLSHLQVLYLNHNYLNSLPPGVFSHLTALRGLSLNSNRLTVLSHNDLPANLEILDISRNQLLAPNPDVF VSLSVLDITHNKFICECELSTFINWLNHTNVTIAGPPADIYCVYPDSFSGVSLFSLSTEGCDEEEVLKSLKFSLF IVCTVTLTLFLMTILTVTKFRGFCFICYKTAQRLVFKDHPQGTEPDMYKYDAYLCFSSKDFTWVQNALLKHLDTQ YSDQNRFNLCFEERDFVPGENRIANIQDAI NSRKIVCLVSRHFLRDG CLEAFSYAQGRCLSDLNSALIMVWG SLSQYQLMKHQSIRGFVQKQQYLRWPEDLQDVGWFLHKLSQQILKKEKEKKKDNNIPLQTVATIS Table 5: Nucleotide and amino acid sequences of mammalian, e.g., primate or rodent DNAX Toll like Receptor 6 (DTLR6) . SEQ ID NO: 11 and 12 are from primate, e.g., human; SEQ ID NO: 13 and 14 are from rodent, e.g., mouse. primate:

ATG TGG ACA CTG AAG AGA CTA ATT CTT ATC CTT TTT AAC ATA ATC CTA 48 Met Trp Thr Leu Lys Arg Leu He Leu He Leu Phe Asn He He Leu -22 -20 ^" -15 -10

ATT TCC AAA CTC CTT GGG GCT AGA T G TTT CCT AAA ACT CTG CCC TGT. 96

He Ser Lys Leu Leu Gly Ala Arg Trp Phe Pro Lys Thr Leu Pro Cys

-5 1 5 10 GAT GTC ACT CTG GAT GTT CCA AAG AAC CAT GTG ATC GTG GAC TGC ACA 144

Asp Val Thr Leu Asp Val Pro Lys Asn His Val He Val Asp Cys Thr

15 20 25

GAC AAG CAT TTG ACA GAA ATT CCT GGA GGT ATT CCC ACG AAC ACC ACG 192 Asp Lys His Leu Thr Glu He Pro Gly Gly He Pro Thr Asn Thr Thr

30 35 40

AAC CTC ACC CTC ACC ATT AAC CAC ATA CCA GAC ATC TCC CCA GCG TCC 240

Asn Leu Thr Leu Thr He Asn His He Pro Asp He Ser Pro Ala Ser 45 50 55

TTT CAC AGA CTG GAC CAT CTG GTA GAG ATC GAT TTC AGA TGC AAC TGT 288

Phe His Arg Leu Asp His Leu Val Glu He Asp Phe Arg Cys Asn Cys

60 65 70

GTA CCT ATT CCA CTG GGG TCA AAA AAC AAC ATG TGC ATC AAG AGG CTG 336

Val Pro He Pro Leu Gly Ser Lys Asn Asn Met Cys He Lys Arg Leu

75 80 85 90 CAG ATT AAA CCC AGA AGC TTT AGT GGA CTC ACT TAT TTA AAA TCC CTT 384

Gin He Lys Pro Arg Ser Phe Ser Gly Leu Thr Tyr Leu Lys Ser Leu

95 100 105

TAC CTG GAT GGA AAC CAG CTA CTA GAG ATA CCG CAG GGC CTC CCG CCT 432 Tyr Leu Asp Gly Asn Gin Leu Leu Glu He Pro Gin Gly Leu Pro Pro

110 115 ^' 120

AGC TTA CAG CTT CTC AGC CTT GAG GCC AAC AAC ATC TTT TCC ATC AGA 480

Ser Leu Gin Leu Leu Ser Leu Glu Ala Asn Asn He Phe Ser He Arg 125 130 135

AAA GAG AAT CTA ACA GAA CTG GCC AAC ATA GAA ATA CTC TAC CTG GGC 528

Lys Glu Asn Leu Thr Glu Leu Ala Asn He Glu He Leu Tyr Leu Gly

140 145 150

CAA AAC TGT TAT TAT CGA AAT CCT TGT TAT GTT TCA TAT TCA ATA GAG 576 Gin Asn Cys Tyr Tyr Arg Asn Pro Cys Tyr Val Ser Tyr Ser He Glu 155 160 165 170 AAA GAT GCC TTC CTA AAC TTG ACA AAG TTA AAA GTG CTC TCC CTG AAA 624

Lys Asp Ala Phe Leu Asn Leu Thr Lys Leu Lys Val Leu Ser Leu Lys 175 180 185

GAT AAC AAT GTC ACA GCC GTC CCT ACT GTT TTG. CCA CT ACT TTA ACA 672

Asp Asn Asn Val Thr Ala Val Pro ^'Thr Val Leu Pro Ser Thr Leu Thr 190 195 200

GAA CTA TAT CTC TAC AAC AAC ATG ATT GCA AAA ATC CAA GAA GAT GAT 720

Glu Leu Tyr Leu Tyr Asn Asn Met He Ala Lys He Gin Glu Asp Asp 205 210 215

TTT AAT AAC CTC AAC CAA TTA CAA ATT CTT GAC CTA AGT GGA AAT TGC 768

Phe Asn Asn Leu Asn Gin Leu Gin He Leu Asp Leu Ser Gly Asn Cys 220 225 230

CCT CGT TGT TAT AAT GCC CCA TTT CCT TGT GCG CCG TGT AAA AAT AAT 816

Pro Arg Cys Tyr Asn Ala Pro Phe Pro Cys Ala Pro Cys Lys Asn Asn

235 240 245 250

TCT CCC CTA CAG ATC CCT GTA AAT GCT TTT GAT GCG CTG ACA GAA TTA 864

Ser Pro Leu Gin He Pro Val Asn Ala Phe Asp Ala Leu Thr Glu Leu 255 260 265

AAA GTT TTA CGT CTA CAC AGT AAC TCT r"pp CAG CAT GTG CCC CCA AGA 912

Lys Val Leu Arg Leu His Ser Asn Ser Leu Gin His Val Pro Pro Arg 270 275 280

TGG TTT AAG AAC ATC AAC AAA CTC CAG GAA CTG GAT CTG TCC CAA AAC 960

Trp Phe Lys Asn He Asn Lys Leu Gin Glu Leu Asp Leu Ser Gin Asn 285 290 295

TTC TTG GCC AAA GAA ATT GGG GAT GCT AAA TTT CTG CAT TTT CTC CCC 1008

Phe Leu Ala Lys Glu He Gly Asp Ala Lys Phe Leu His Phe Leu Pro 300 305 310

AGC CTC ATC CAA TTG GAT CTG TCT TTC AAT TTT GAA CTT CAG GTC TAT 1056

Ser Leu He Gin Leu Asp Leu Ser Phe Asn Phe Glu Leu Gin Val Tyr

315 320 325 330

CGT GCA TCT ATG AAT CTA TCA CAA GCA TTT TCT TCA CTG AAA AGC CTG 1104

Arg Ala Ser Met Asn Leu Ser Gin Ala Phe Ser Ser Leu Lys Ser Leu 335 340 345

AAA ATT CTG CGG ATC AGA GGA TAT GTC TTT AAA GAG TTG AAA AGC TTT 1152

Lys He Leu Arg He Arg Gly Tyr Val Phe Lys Glu Leu Lys Ser Phe 350 355 360

AAC CTC TCG CCA TTA CAT AAT CTT CAA AAT CTT GAA GTT CTT GAT CTT 1200

Asn Leu Ser Pro Leu His Asn Leu Gin Asn Leu Glu Val Leu Asp Leu 365 370 375

GGC ACT AAC TTT ATA AAA ATT GCT AAC CTC AGC ATG TTT AAA CAA TTT 1248

Gly Thr Asn Phe He Lys He Ala Asn Leu Ser Met Phe Lys Gin Phe 380 385 390 AAA AGA CTG AAA GTC ATA GAT CTT TCA GTG AAT AAA ATA TCA CCT TCA 1296

Lys Arg Leu Lys Val He Asp Leu Ser Val Asn Lys He Ser Pro Ser

395 400 405 410

GGA GAT TCA AGT GAA GTT GGC TTC TGC TCA AAT GCC AGA ACT TCT GTA 1344

Gly Asp Ser Ser Glu Val Gly Phe Cys Ser Ash Ala Arg Thr Ser Val

415 420 425

GAA AGT TAT GAA CCC CAG GTC CTG GAA CAA TTA CAT TAT TTC AGA TAT 1392

Glu Ser Tyr Glu Pro Gin Val Leu Glu Gin Leu His Tyr Phe Arg Tyr 430 435 440

GAT AAG TAT GCA AGG AGT TGC AGA TTC AAA AAC AAA GAG GCT TCT TTC 1440

Asp Lys Tyr Ala Arg Ser Cys Arg Phe Lys Asn Lys Glu Ala Ser Phe 445 450 455

ATG TCT GTT AAT GAA AGC TGC TAC AAG TAT GGG CAG ACC TTG GAT CTA 1488

Met Ser Val Asn Glu Ser Cys Tyr Lys Tyr Gly Gin Thr Leu Asp Leu 460 465 470

AGT AAA AAT AGT ATA TTT TTT GTC AAG TCC TCT GAT TTT ^'CAG CAT CTT 1536

Ser Lys Asn Ser He Phe Phe Val Lys Ser Ser Asp Phe Gin His Leu

475 480 485 490

TCT TTC CTC AAA TGC CTG AAT CTG TCA GGA AAT CTC ATT AGC CAA ACT 1584

Ser Phe Leu Lys Cys Leu Asn Leu Ser Gly Asn Leu He Ser Gin Thr 495 500 505

CTT AAT GGC AGT GAA TTC CAA CCT TTA GCA GAG CTG AGA TAT TTG GAC 1632

Leu Asn Gly Ser Glu Phe Gin Pro Leu Ala Glu Leu Arg Tyr Leu Asp

510 515 520

TTC TCC AAC AAC CGG CTT GAT TTA CTC CAT TCA ACA GCA TTT GAA GAG 1680

Phe Ser Asn Asn Arg Leu Asp Leu Leu His Ser Thr Ala Phe Glu Glu 525 530 535

CTT CAC AAA CTG GAA GTT CTG GAT ATA AGC AGT AAT AGC CAT TAT TTT 1728

Leu His Lys Leu Glu Val Leu Asp He Ser Ser Asn Ser His Tyr Phe 540 545 550

CAA TCA GAA GGA ATT ACT CAT ATG CTA AAC TTT ACC AAG AAC CTA AAG 1776

Gin Ser Glu Gly He Thr His Met Leu Asn Phe Thr Lys Asn Leu Lys

555 560 565 570

GTT CTG CAG AAA CTG ATG ATG AAC GAC AAT GAC ATC TCT TCC TCC ACC 1824

Val Leu Gin Lys Leu Met Met Asn Asp Asn Asp He Ser Ser Ser Thr 575 580 585

AGC AGG ACC ATG GAG AGT GAG TCT CTT AGA ACT CTG GAA TTC AGA GGA 1872

Ser Arg Thr Met Glu Ser Glu Ser Leu Arg Thr Leu Glu Phe Arg Gly 590 595 600 AAT CAC TTA GAT GTT TTA TGG AGA GAA GGT GAT AAC AGA TAC TTA CAA 1920 Asn His Leu Asp Val Leu Trp Arg Glu Gly Asp Asn Arg Tyr Leu Gin 605 610 615 TTA TTC AAG AAT CTG CTA AAA TTA GAG GAA TTA GAC ATC TCT AAA AAT 1968 Leu Phe Lys Asn Leu Leu Lys Leu Glu Glu Leu Asp He Ser Lys Asn 620 625 ' 630

TCC CTA AGT TTC TTG^'CCT TCT GGA GTT TTT GAT GGT ATG CCT CCA AAT 2016 Ser Leu Ser Phe Leu Pro Ser Gly Val Phe Asp Gly Met Pro Pro Asn 635 640 645 650

CTA AAG AAT CTC TCT TTG GCC AAA AAT GGG CTC AAA TCT TTC AGT TGG 2064 Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys Ser Phe Ser Trp 655 660 665

AAG AAA CTC CAG TGT CTA AAG AAC CTG GAA ACT TTG GAC CTC AGC CAC 2112

Lys Lys Leu Gin Cys Leu Lys Asn Leu Glu Thr Leu Asp Leu Ser His

670 675 ^' 680

AAC CAA CTG ACC ACT GTC CCT GAG AGA TTA TCC AAC TGT TCC AGA AGC 2160

Asn Gin Leu Thr Thr Val Pro Glu Arg Leu Ser Asn Cys Ser Arg Ser

685 690 695 CTC AAG AAT CTG ATT CTT AAG AAT AAT CAA ATC AGG AGT CTG ACG AAG 2208 Leu Lys Asn Leu He Leu Lys Asn Asn Gin He Arg Ser Leu Thr Lys 700 705 710

TAT TTT CTA CAA GAT GCC TTC CAG TTG CGA TAT CTG GAT CTC AGC TCA 2256 Tyr Phe Leu Gin Asp Ala Phe Gin Leu Arg Tyr Leu Asp Leu Ser Ser 715 720 725 730

AAT AAA ATC CAG ATG ATC CAA AAG ACC AGC TTC CCA GAA AAT GTC CTC - 2304 Asn Lys He Gin Met He Gin Lys Thr Ser Phe Pro Glu Asn Val Leu 735 740 745

AAC AAT CTG AAG ATG TTG CTT TTG CAT CAT AAT CGG TTT CTG TGC ACC 2352

Asn Asn Leu Lys Met Leu Leu Leu His His Asn Arg Phe Leu Cys Thr

750 755 • 760

TGT GAT GCT GTG TGG TTT GTC TGG TGG GTT AAC CAT ACG GAG GTG ACT 2400

Cys Asp Ala Val Trp Phe Val Trp Trp Val Asn His Thr Glu Val Thr

765 770 775 ATT CCT TAC CTG GCC ACA GAT GTG ACT TGT GTG GGG CCA GGA GCA CAC 2448 He Pro Tyr Leu Ala Thr Asp Val Thr Cys Val Gly Pro Gly Ala His 780 785 790

AAG GGC CAA AGT GTG ATC TCC CTG GAT CTG TAC ACC TGT GAG TTA GAT 2496 Lys Gly Gin Ser Val He Ser Leu Asp Leu Tyr Thr Cys Glu Leu Asp 795 800 805 810

CTG ACT AAC CTG ATT CTG TTC TCA CTT TCC ATA TCT GTA TCT CTC TTT 2544 Leu Thr Asn Leu He Leu Phe ≤er Leu Ser He Ser Val Ser Leu Phe 815 820 825 CTC ATG GTG ATG ATG ACA GCA AGT CAC CTC TAT TTC TGG GAT GTG TGG 2592

Leu Met Val Met Met Thr Ala Ser His Leu Tyr Phe Trp Asp Val Trp 830 835 840

TAT ATT TAC CAT TTC TGT AAG GCC AAG ATA AAG GGG TAT CAG CGT CTA 2640 Tyr He Tyr His Phe Cys Lys Ala Lys He Lys Gly Tyr Gin Arg Leu 845 850 855 ATA TCA CCA GAC TGT TGC TAT GAT GCT TTT ATT GTG TAT GAC ACT AAA 2688 He Ser Pro Asp Cys Cys Tyr Asp Ala Phe He Val Tyr Asp Thr Lys 860 865 870

GAC CCA GCT GTG ACC GAG TGG GTT TTG GCT GAG CTG GTG GCC AAA CTG 2736 Asp Pro Ala Val Thr Glu Trp Val Leu Ala Glu Leu Val Ala Lys Leu 875 880 885 890

GAA GAC CCA AGA GAG AAA CAT TTT AAT TTA TGT CTC GAG GAA AGG GAC 2754 Glu Asp Pro Arg Glu Lys His Phe Asn Leu Cys Leu Glu Glu Arg Asp 895 900 905

TGG TTA CCA GGG CAG CCA GTT CTG GAA AAC CTT TCC CAG AGC ATA CAG 2832

Trp Leu Pro Gly Gin Pro Val Leu Glu Asn Leu Ser Gin Ser He Gin

910 915 920

CTT AGC AAA AAG ACA GTG TTT GTG ATG ACA GAC AAG TAT GCA AAG ACT 2880

Leu Ser Lys Lys Thr Val Phe Val Met Thr Asp Lys Tyr Ala Lys Thr

925 930 935 GAA AAT TTT AAG ATA GCA TTT TAC TTG TCC CAT CAG AGG CTC ATG GAT 2928 Glu Asn Phe Lys He Ala Phe Tyr Leu Ser His Gin Arg Leu Met Asp 940 945 950

GAA AAA GTT GAT GTG ATT ATC TTG ATA TTT CTT GAG AAG CCC TTT CAG 2976 Glu Lys Val Asp Val He He Leu He Phe Leu Glu Lys Pro Phe Gin 955 960 965 970

AAG TCC AAG TTC CTC CAG CTC CGG AAA AGG CTC TGT GGG AGT TCT GTC 3024 Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg Leu Cys Gly Ser Ser Val 975 980 985

CTT GAG TGG CCA ACA AAC CCG CAA GCT CAC CCA TAC TTC TGG CAG TGT 3072

Leu Glu Trp Pro Thr Asn Pro Gin Ala His Pro Tyr Phe Trp Gin Cys

990 995 1000

CTA AAG AAC GCC CTG GCC ACA GAC AAT CAT GTG GCC TAT AGT CAG GTG 3120

Leu Lys Asn Ala Leu Ala Thr Asp Asn His Val Ala Tyr Ser Gin Val

1005 1010 1015 TTC AAG GAA ACG GTC TAG 3138

Phe Lys Glu Thr Val 1020

M TLKRLILILFNIILISKLLGARWFPKTLPCDVTLDVPKNH_VIVDCTDKHLTEIPGGIPTNTTNLTLTINHIP DISPASFHRLDHLVEIDFRCNCVPIPLGSKNNMCIKRLQIKPRSFSGLTYLKSLYLDGNQLLEIPQGLPPSLQL LSLEANNIFSIRKENLTΞLANIEILYLGQNCYYRNPCYVSYSIEKDAFLNLTKLKVLSLKDNNVTAVPTV PST LTELYLYNNMIAKIQEDDFNNLNQLQILDLSGNCPRCYNAPFPCAPCKNNSPLQIPVNAFDALTELKVLRLHSN SLQHVPPR FKNINKLQELDLSQNFLAKEIGDAKFLHFLPSLIQLDLSFNFELQVYRASMNLSQAFSSLKSLKI LRIRGYVFKELKSFNLSPLHNLQNLEVLDLGTNFIKIANLSMFKQFKRLKVIDLSVNKISPSGDSSEVGFCSNA RTSVESYEPQVLEQLHYFRYDKYARSCRFKNKEASFMSVNESCY YGQTLDLSKNSIFFVKSSDFQHLSFLKCL NLSGNLISQTLNGSEFQPLAELRYLDFSNNRLDLLHSTAFEELHKLEVLDΪSSNSHYFQSEGITHMLNFTKNLK VLQKLMMNDNDISSSTSRTMESESLRTLEFRGNHLDVL REGDNRYLQLFKNLLKLEELDISKNSLSFLPSGVF DGMPPNLKNLSLA NGLKSFSWKKLQCLKNLETLDLSHNQLTTVPERLSNCSRSLKNLILKNNQIRSLTKYFLQ DAFQLRYLDLSSNKIQMIQKTSFPENVLNNLKMLLLHHNRFLCTCDAV FVWWVNHTEVTIPYLATDVTCVGPG AHKGQSVISLDLYTCELDLTNLILFSLSISVSLFLMVMMTASHLYF DVWYIYHFCKAKIKGYQRLISPDCCYD AFIVYDTKDPAVTEWVLAELVAKLEDPREKHFNLCLEERDWLPGQPVLENLSQSIQLSKKTVFVMTDKYAKTEN FKIAFYLSHQRLMDEKVDVIILIFLEKPFQ SKFLQLRKRLCGSSVLE PTNPQAHPYF QCLKNALATDNHVA YSQVFKETV

rodent (SEQ ID NO : 13 and 14 ) :

CTT GGA AAA CCT CTT CAG AAG TCT AAG TTT CTT CAG CTC AGG AAG AGA 48

Leu Gly Lys Pro Leu Gin Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg

1 5 10 /^• 15

CTC TGC AGG AGC TCT GTC CTT GAG TGG CCT GCA AAT CCA CAG GCT CAC 96

Leu Cys Arg Ser Ser Val Leu Glu Trp Pro Ala Asn Pro Gin Ala His

20 ^' 25 30

CCA TAC TTC TGG CAG TGC CTG AAA AAT GCC CTG ACC ACA GAC AAT CAT 144 Pro Tyr Phe Trp Gin Cys Leu Lys Asn Ala Leu Thr Thr Asp Asn His 35 40 45 GTG GCT TAT AGT CAA ATG TTC AAG GAA ACA GTC TAG 180 Val Ala Tyr Ser Gin Met Phe Lys Glu Thr Val 50 55

LGKPLQKSKFLQLRKRLCRSSVLEWPANPQAHPYFWQCLKALTTDNHV_AYSQMFKETV

additional rodent, e.g., mouse sequences: upstream (SEQ ID NO: 27 and 28); nucleotides 186, 196, 217, 276, and 300 designated C, each may be A, C, G, or T:

TCC TAT TCT ATG GAA AAA GAT GCT TTC CTA TTT ATG AGA AAT TTG AAG 48 Ser Tyr Ser Met Glu Lys Asp Ala Phe Leu Phe Met Arg Asn Leu Lys 1 5 10 15

GTT CTC TCA CTA AAA GAT AAC AAT GTC ACA GCT GTC CCC ACC ACT TTG 96 Val Leu Ser Leu Lys Asp Asn Asn Val Thr Ala Val Pro Thr Thr Leu 20 25 30 CCA CCT AAT TTA CTA GAG CTC TAT CTT TAT AAC AAT ATC ATT AAG AAA 144 Pro Pro Asn Leu Leu Glu Leu Tyr Leu Tyr Asn Asn He He Lys Lys 35 40 45

ATC CAA GAA AAT GAT TTC AAT AAC CTC AAT GAG TTG CAA GTC CTT GAC 192 He Gin Glu Asn Asp Phe Asn Asn Leu Asn Glu Leu Gin Val Leu Asp 50 ^• 55 60

CTA CGT GGA AAT TGC CCT CGA TGT CAT AAT GTC CCA TAT CCG TGT ACA 240 Leu Arg Gly Asn Cys Pro Arg Cys His Asn Val Pro Tyr Pro Cys Thr 65 70 75 80

CCG TGT GAA AAT AAT TCC CCC TTA CAG ATC CAT GAC AAT GCT TTC AAT 288 Pro Cys Glu Asn Asn Ser Pro Leu Gin He His Asp Asn Ala Phe Asn 85 90 95

TCA TCG ACA GAC 300

Ser Ser Thr Asp 100 SYSMEKDAFLFMRNL VLSLKDNNVTAVPTTLPPNLLELYLYNNIIK IQENDFNNLNELQXLDLXGNCPRCXNV PYPCTPCENNSPLQIHXNAFNΞSTX

downstream (SEQ ID NO: 29 and 30); nucleotide 1643 designated A, may be A or G; nucleotide 1664 designated C, may be A, C, G, or T; nucleotides 1680 and 1735 designated G, may be G or T; nucle'otide 1719 designated C, may be C or T; and nucleotide 1727 designated A, may be A, G, or T: TCT CCA GAA ATT CCC TGG AAT TCC TTG CCT CCT GAG GTT TTT GAG GGT 48 Ser Pro Glu He Pro Trp Asn Ser Leu Pro Pro Glu Val Phe Glu Gly 1 5 10 15

ATG CCG CCA AAT CTA AAG AAT CTC TCC TTG GCC AAA AAT GGG CTC AAA 96 Met Pro Pro Asn Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys 20 25 30

TCT TTC TTT TGG GAC AGA CTC CAG TTA CTG AAG CAT TTG GAA ATT TTG 144 Ser Phe Phe Trp Asp Arg Leu Gin Leu Leu Lys His Leu Glu He Leu 35 40 45

GAC CTC AGC CAT AAC CAG CTG ACA AAA GTA CCT GAG AGA TTG GCC AAC 192

Asp Leu Ser His Asn Gin Leu Thr Lys Val Pro Glu Arg Leu Ala Asn

50 55 60

TGT TCC AAA AGT CTC ACA ACA CTG ATT CTT AAG CAT AAT CAA ATC AGG 240

Cys Ser Lys Ser Leu Thr Thr Leu He Leu Lys His Asn Gin He Arg

65 70 75 80 CAA TTG ACA AAA TAT TTT CTA GAA GAT GCT TTG CAA TTG CGC TAT CTA 288 Gin Leu Thr Lys Tyr Phe Leu Glu Asp Ala Leu Gin Leu Arg Tyr Leu 85 90 95

GAC ATC AGT TCA AAT AAA ATC CAG GTC ATT CAG AAG ACT AGC TTC CCA 336 Asp He Ser Ser Asn Lys He Gin Val He Gin Lys Thr Ser Phe Pro 100 105 HO

GAA AAT GTC CTC AAC AAT CTG GAG ATG TTG GTT TTA CAT CAC AAT CGC 384 Glu Asn Val Leu Asn Asn Leu Glu Met Leu Val Leu His His Asn Arg 115 120 125

TTT CTT TGC AAC TGT GAT GCT GTG TGG TTT GTC TGG TGG GTT AAC CAT 432

Phe Leu Cys Asn Cys Asp Ala Val Trp Phe Val Trp Trp Val Asn His

130 135 140

ACA GAT GTT ACT ATT CCA TAC CTG GCC ACT GAT GTG ACT TGT GTA GGT 480

Thr Asp Val Thr He Pro Tyr Leu Ala Thr Asp Val Thr Cys Val Gly

145 150 155 160 CCA GGA GCA CAC AAA GGT CAA AGT GTC ATA TCC CTT GAT CTG TAT ACG 528 Pro Gly Ala His Lys Gly Gin Ser Val He Ser Leu Asp Leu Tyr Thr 165 170 175 TGT GAG TTA GAT CTC ACA AAC CTG ATT CTG TTC TCA GTT TCC ATA TCA 576 Cys Glu Leu Asp Leu Thr Asn Leu He Leu Phe Ser Val Ser He Ser 180 185 190 TCA GTC CTC TTT CTT ATG GTA GTT ATG ACA ACA. AGT CAC CTC TTT TTC 624 Ser Val Leu Phe Leu Met Val Val Met Thr Thr^' Ser His Leu Phe Phe 195 200 ' 205

TGG GAT ATG TGG TAC ATT TAT TAT TTT TGG AAA GCA AAG ATA AAG GGG 672 Trp Asp Met Trp Tyr He Tyr Tyr Phe Trp Lys Ala Lys He Lys Gly 210 215 220

TAT CCA GCA TCT GCA ATC CCA TGG AGT CCT TGT TAT GAT GCT TTT ATT 720 Tyr Pro Ala Ser Ala He Pro Trp Ser Pro Cys Tyr Asp Ala Phe He 225 230 235 240

GTG TAT GAC ACT AAA AAC TCA GCT GTG ACA GAA TGG GTT TTG CAG GAG 768

Val Tyr Asp Thr Lys Asn Ser Ala Val Thr Glu Trp Val Leu Gin Glu

245 250 255

CTG GTG GCA AAA TTG GAA GAT CCA AGA GAA AAA CAC TTC AAT TTG TGT 816

Leu Val Ala Lys Leu Glu Asp Pro Arg Glu Lys His Phe Asn Leu Cys

260 265 270 CTA GAA GAA AGA GAC TGG CTA CCA GGA CAG CCA GTT CTA GAA AAC CTT 864 Leu Glu Glu Arg Asp Trp Leu Pro Gly Gin Pro Val Leu Glu Asn Leu 275 280 285

TCC CAG AGC ATA CAG CTC AGC AAA AAG ACA GTG TTT GTG ATG ACA CAG 912 Ser Gin Ser He Gin Leu Ser Lys Lys Thr Val Phe Val Met Thr Gin 290 295 300

AAA TAT GCT AAG ACT GAG AGT TTT AAG ATG GCA TTT TAT TTG TCT CAT ■_ 960 Lys Tyr Ala Lys Thr Glu Ser Phe Lys Met Ala Phe Tyr Leu Ser His 305 310 315 320

CAG AGG CTC CTG GAT GAA AAA GTG GAT GTG ATT ATC TTG ATA TTC TTG 1008 Gin Arg Leu Leu Asp Glu Lys Val Asp Val He He Leu He Phe Leu 325 330 335

GAA AGA CCT CTT CAG AAG TCT AAG TTT CTT CAG CTC AGG AAG AGA CTC 1056 Glu Arg Pro Leu Gin Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg Leu 340 345 350 TGC AGG AGC TCT GTC CTT GAG TGG CCT GCA AAT CCA CAG GCT CAC CCA 1104 Cys Arg Ser Ser Val Leu Glu Trp Pro Ala Asn Pro Gin Ala His Pro 355 360 365

TAC TTC TGG CAG TGC CTG AAA AAT GCC CTG ACC ACA GAC AAT CAT GTG 1152 Tyr Phe Trp Gin Cys Leu Lys Asn Ala Leu Thr Thr Asp Asn His Val 370 375 380

GCT TAT AGT CAA ATG TTC AAG GAA ACA GTC TAGCTCTCTG AAGAATGTCA 1202 Ala Tyr Ser Gin Met Phe Lys 'Glu Thr Val 385 390 CCACCTAGGA CATGCCTTGG TACCTGAAGT TTTCATAAAG GTTTCCATAA ATGAAGGTCT 1262

GAATTTTTCC TAACAGTTGT CATGGCTCAG ATTGGTGGGA AATCATCAAT ATATGGCTAA 1322

GAAATTAAGA AGGGGAGACT GATAGAAGAT AATTTCTTTC TTCATGTGCC ATGCTCAGTT 1382

AAATATTTCC CCTAGCTCAA ATCTGAAAAA CTGTGCCTAG GAGACAACAC AAGGCTTTGA 1442 TTTATCTGCA TACAATTGAT AAGAGCCACA CATCTGCCCT GAAGAAGTAC TAGTAGTTTT 1502

AGTAGTAGGG TAAAAATTAC ACAAGCTTTC TCTCTCTCTG ATACTGAACT GTACCAGAGT 1562

TCAATGAAAT AAAAGCCCAG AGAACTTCTC AGTAAATGGT TTCATTATCA TGTAGTATCC 1622

ACCATGCAAT ATGCCACAAA ACCGCTACTG GTACAGGACA GCTGGTAGCT GCTTCAAGGC 1682

CTCTTATCAT TTTCTTGGGG CCCATGGAGG GGTTCTCTGG GAAAAAGGGA AGGTTTTTTT 1742 TGGCCATCCA TGAA 1756

SPEIPWNSLPPEVFEGMPPNLKNLSLAKNGLKSFFWDRLQLLKHLEILDLSHNQLTKVPERLANCSKSLTTLILK HNQIRQLTKYFLEDALQLRYLDISSNKIQVIQKTSFPENVLNNLEMLVLHHNRFLCNCDAV FVWWVNHTDVTIP YLATDVTCVGPGAHKGQSVISLDLYTCE DLTNLILFSVSISSVLFLMWMTTSHLFFWDMWYIYYF KAKIKGY PASAIPWSPCYDAFIVYDTKNSAVTE VLQELVAK EDPREKHFNLCLEERD LPGQPVLENLSQSIQLSKKTVF VMTQKYAKTESFKMAFYLSHQRLLDEKVDVIILIFLERPLQKSKFLQLRKRLCRSSVLE PANPQAHPYFWQCLK NALTTDNHVAYΞQMFKETV

Table 7: Nucleotide and amino acid sequences of a mammalian, e.g., primate, human, DNAX Toll like Receptor 7 (DTLR7) . upstream (SEQ ID NO: 15 and 16):

G AAT TCC AGA CTT ATA AAC TTG AAA AAT CTC TAT TTG GCC TGG AAC 46

Asn Ser Arg Leu He Asn Leu Lys Asn Leu Tyr Leu Ala Trp Asn 1 5 10 15 TGC TAT TTT AAC AAA GTT TGC GAG AAA ACT AAC ATA GAA GAT GGA GTA 94 Cys Tyr Phe Asn Lys Val Cys Glu Lys Thr Asn He Glu Asp Gly Val 20 25 30

TTT GAA ACG CTG ACA AAT TTG GAG TTG CTA TCA CTA TCT TTC AAT TCT 142 Phe Glu Thr Leu Thr Asn Leu Glu Leu Leu Ser Leu Ser Phe Asn Ser 35 40 45

CTT TCA CAT GTG CCA CCC AAA CTG CCA AGC TCC CTA CGC AAA CTT TTT 190 Leu Ser His Val Pro Pro Lys Leu Pro Ser Ser Leu Arg Lys Leu Phe 50 55 60

CTG AGC AAC ACC CAG ATC AAA TAC ATT AGT GAA GAA GAT TTC AAG GGA 238 Leu Ser Asn Thr Gin He Lys Tyr He Ser Glu Glu Asp Phe Lys Gly 65 70 75

TTG ATA AAT TTA ACA TTA CTA GAT TTA AGC GGG AAC TGT CCG AGG TGC 286 Leu He Asn Leu Thr Leu Leu Asp Leu Ser Gly Asn Cys Pro Arg Cys 80 85 90 95 TTC AAT GCC CCA TTT CCA TGC GTG CCT TGT GAT GGT GGT GCT TCA ATT 334 Phe Asn Ala Pro Phe Pro Cys Val Pro Cys Asp Gly Gly Ala Ser He 100 105 110

AAT ATA GAT CGT TTT GCT TTT CAA AAC TTG ACC CAA CTT CGA TAC CTA ' 382 Asn He Asp Arg Phe Ala Phe Gin Asn Leu Thr Gin Leu Arg Tyr Leu 115 120 125

AAC CTC TCT AGC ACT TCC CTC AGG AAG ATT AAT GCT GCC TGG TTT AAA 430 Asn Leu Ser Ser Thr Ser Leu Arg Lys He Asn Ala Ala Trp Phe Lys 130 135 140

AAT ATG CCT CAT CTG AAG GTG CTG GAT CTT GAA TTC AAC TAT TTA GTG 478

Asn Met Pro His Leu Lys Val Leu Asp Leu Glu Phe Asn Tyr Leu Val

145 150 155

GGA GAA ATA GCC TCT GGG GCA TTT TTA ACG ATG CTG CCC CGC TTA GAA 526

Gly Glu He Ala Ser Gly Ala Phe Leu Thr Met Leu Pro Arg Leu Glu

160 165 170 175 ATA CTT GAC TTG TCT TTT AAC TAT ATA AAG GGG AGT TAT CCA CAG CAT 574 He Leu Asp Leu Ser Phe Asn Tyr He Lys Gly Ser Tyr Pro Gin His 180 185 190 ATT AAT ATT TCC AGA AAC TTC TCT AAA CTT TTG TCT CTA CGG GCA TTG 622 He Asn He Ser Arg Asn Phe Ser Lys Leu Leu Ser Leu Arg Ala Leu 195 200 205 CAT TTA AGA GGT TAT GTG TTC CAG GAA CTC AGA GAA GAT GAT TTC CAG 670 His Leu Arg Gly Tyr Val Phe Gin Glu Leu Arg Glu Asp Asp Phe Gin 210 215 ' 220

CCC CTG ATG CAG CTT ^'CCA AAC TTA TCG ACT ATC AAC TTG GGT ATT AAT 718 Pro Leu Met Gin Leu Pro Asn Leu Ser Thr He Asn Leu Gly He Asn 225 230 235

TTT ATT AAG CAA ATC GAT TTC AAA CTT TTC CAA AAT TTC TCC AAT CTG 766 Phe He Lys Gin He Asp Phe Lys Leu Phe Gin Asn Phe Ser Asn Leu 240 245 250 255

GAA ATT ATT TAC TTG TCA GAA AAC AGA ATA TCA CCG TTG GTA AAA GAT 814

Glu He He Tyr Leu Ser Glu Asn Arg He Ser Pro Leu Val Lys Asp

260 265 270

ACC CGG CAG AGT TAT GCA AAT AGT TCC TCT TTT CAA CGT CAT ATC CGG 862

Thr Arg Gin Ser Tyr Ala Asn Ser Ser Ser Phe Gin Arg His He Arg

275 280 285 AAA CGA CGC TCA ACA GAT TTT GAG TTT GAC CCA CAT TCG AAC TTT TAT 910 Lys Arg Arg Ser Thr Asp Phe Glu Phe Asp Pro His Ser Asn Phe Tyr 290 295 300

CAT TTC ACC CGT CCT TTA ATA AAG CCA CAA TGT GCT GCT TAT GGA AAA 958 His Phe Thr Arg Pro Leu He Lys Pro Gin Cys Ala Ala Tyr Gly Lys 305 310 315

GCC TTA GAT TTA AGC CTC AAC AGT ATT TTC TT 990

Ala Leu Asp Leu Ser Leu Asn Ser He Phe 320 325

NSRLINLKNLYLAWNCYFNKVCEKTNIEDGVFETLTNLELLSLSFNSLSHVPPKLPSSLRKLFLSNTQIKYISE EDFKGLINLTLLDLSGNCPRCFNAPFPCVPCDGGASINIDRFAFQNLTQLRYLNLSSTSLRKINAAWFKNMPHL KVLDLEFNYLVGEIASGAFLTMLPRLEILDLSFNYIKGSYPQHINISRNFSKLLSLRALHLRGYVFQELREDDF QPLMQLPNLSTINLGINFIKQIDFKLFQNFSNLEIIYLSENRISPLVKDTRQSYANSSSFQRHIRKRRSTDFEF DPHSNFYHFTRPLIKPQCAAYG ALDLSLNSIF

downstream (SEQ ID NO: 17 and 18) :

CAG TCT CTT TCC ACA TCC CAA ACT TTC TAT GAT GCT TAC ATT TCT TAT 48

Gin Ser Leu Ser Thr Ser Gin Thr Phe Tyr Asp Ala Tyr He Ser Tyr

1 5 10 -15 GAC ACC AAA GAT GCC TCT GTT ACT GAC TGG GTG ATA AAT GAG CTG CGC 96

Asp Thr Lys Asp Ala Ser Val Thr Asp Trp Val He Asn Glu Leu Arg

20 25 30 TAC CAC CTT GAA GAG AGC CGA GAC AAA AAC GTT CTC CTT TGT CTA GAG 144 Tyr His Leu Glu Glu Ser Arg Asp Lys Asn Val Leu Leu Cys Leu Glu 35 40 45 GAG AGG GAT TGG GAC CCG GGA TTG GCC ATC ATC. GAC AAC CTC ATG CAG 192 Glu Arg Asp Trp Asp Pro Gly Leu ^'Ala He He Asp Asn Leu Met Gin 50 55 60

AGC ATC AAC CAA AGC AAG AAA ACA GTA TTT GTT TTA ACC AAA AAA TAT 240 Ser He Asn Gin Ser Lys Lys Thr Val Phe Val Leu Thr Lys Lys Tyr 65 70 75 80

GCA AAA AGC TGG AAC TTT AAA ACA GCT TTT TAC TTG GGC TTG CAG AGG 288 Ala Lys Ser Trp Asn Phe Lys Thr Ala Phe Tyr Leu Gly Leu Gin Arg 85 90 95

CTA ATG GGT GAG AAC ATG GAT GTG ATT ATA TTT ATC CTG CTG GAG CCA 336

Leu Met Gly Glu Asn Met Asp Val He He Phe He Leu Leu Glu Pro

100 105 110

GTG TTA CAG CAT TCT CCG TAT TTG AGG CTA CGG CAG CGG ATC TGT AAG 384

Val Leu Gin His Ser Pro Tyr Leu Arg Leu Arg Gin Arg He Cys Lys 115 120 125 AGC TCC ATC CTC CAG TGG CCT GAC AAC CCG AAG GCA GAA AGG TTG TTT 432 Ser Ser He Leu Gin Trp Pro Asp Asn Pro Lys Ala Glu Arg Leu Phe 130 135 140

TGG CAA ACT CTG AGA AAT GTG GTC TTG ACT GAA AAT GAT TCA CGG TAT 480 Trp Gin Thr Leu Arg Asn Val Val Leu Thr Glu Asn Asp Ser Arg Tyr 145 150 155 160

AAC AAT ATG TAT GTC GAT TCC ATT AAG CAA TAC TAACTGACGT TAAGTCATGA 533 Asn Asn Met Tyr Val Asp Ser He Lys Gin Tyr 165 170

TTTCGCGCCA TAATAAAGAT GCAAAGGAAT GACATTTCCG TATTAGTTAT CTATTGCTAC 593

GGTAACCAAA TTACTCCCAA AAACCTTACG TCGGTTTCAA AACAACCACA TTCTGCTGGC 653

CCCACAGTTT TTGAGGGTCA GGAGTCCAGG CCCAGCATAA CTGGGTCTTC TGCTTCAGGG 713

TGTCTCCAGA GGCTGCAATG TAGGTGTTCA CCAGAGACAT AGGCATCACT GGGGTCACAC 773 TCCATGTGGT TGTTTTCTGG ATTCAATTCC TCCTGGGCTA TTGGCCAAAG GCTATACTCA 833

TGTAAGCCAT GCGAGCCTAT CCCACAACGG CAGCTTGCTT CATCAGAGCT AGCAAAAAAG 893

AGAGGTTGCT AGCAAGATGA AGTCACAATC TTTTGTAATC GAATCAAAAA AGTGATATCT 953

CATCACTTTG GCCATATTCT ATTTGTTAGA AGTAAACCAC AGGTCCCACC AGCTCCATGG 1013

GAGTGACCAC CTCAGTCCAG GGAAAACAGC TGAAGACCAA GATGGTGAGC TCTGATTGCT 1073 TCAGTTGGTC ATCAACTATT TTCCCTTGAC TGCTGTCCTG GGATGGCCGG CTATCTTGAT 1133 GGATAGATTG TGAATATCAG GAGGCCAGGG ATCACTGTGG ACCATCTTAG CAGTTGACCT 1193

AACACATCTT CTTTTCAATA TCTAAGAACT TTTGCCACTG TGACTAATGG TCCTAATATT 1253

AAGCTGTTGT TTATATTTAT CATATATCTA TGGCTACATG GTTATATTAT GCTGTGGTTG 1313

CGTTCGGTTT TATTTACAGT TGCTTTTACA AATATTTGCT GTAACATTTG ACTTCTAAGG 1373 TTTAGATGCC ATTTAAGAAC TGAGATGGAT AGCTTTTAAA GCATCTTTTA CTTCTTACCA 1433

TTTTTTAAAA GTATGCAGCT AAATTCGAAG CTTTTGGTCT ATATTGTTAA TTGCCATTGC 1493

TGTAAATCTT AAAATGAATG AATAAAAATG TTTCATTTTA AAAAAAAAAA AAAAAAAAAA 1553

AAAA 1557

QSLSTSQTFYDAYISYDT DASVTDWVINELRYHLEESRDKNVLLCLEERD DPGLAIIDNLMQSINQSKKTVFV LTKKYAKS NFKTAFYLGLQRLMGENMDVHFILLEPVLQHSPYLRLRQRICKSSILQWPDNPKAERLFWQTLRN WLTENDSRYNNMYVDSIKQY

Further primate, e.g, human, DTLR7 sequence (SEQ ID NO: 36 and 37). atg ctg ace tgc att ttc ctg eta ata tct ggt tec tgt gag tta tgc 48

Met Leu Thr Cys He Phe Leu Leu He Ser Gly Ser Cys Glu Leu Cys

-15 -10 -5 gcc gaa gaa aat ttt tct aga age tat cct tgt gat gag aaa aag caa 96 Ala Glu Glu Asn Phe Ser Arg Ser Tyr Pro Cys Asp Glu Lys Lys Gin

-1 1 5 10 15 aat gac tea gtt att gca gag tgc age aat cgt cga eta cag gaa gtt 144

Asn Asp Ser Val He Ala Glu Cys Ser Asn Arg Arg Leu Gin Glu Val ^■— 20 25 30 ccc caa acg gtg ggc aaa tat gtg aca gaa eta gac ctg tct gat aat 192

Pro Gin Thr Val Gly Lys Tyr Val Thr Glu Leu Asp Leu Ser Asp Asn

35 40 45 ttc ate aca cac ata acg aat gaa tea ttt caa ggg ctg caa aat etc 240

Phe He Thr His He Thr Asn Glu Ser Phe Gin Gly Leu Gin Asn Leu

50 55 60 act aaa ata aat eta aac cac aac ccc aat gta cag cac cag aac gga 288

Thr Lys He Asn Leu Asn His Asn Pro Asn Val Gin His Gin Asn Gly

65 70 75 aat ccc ggt ata caa tea aat ggc ttg aat ate aca gac ggg gca ttc 336 Asn Pro Gly He Gin Ser Asn Gly Leu Asn He Thr Asp Gly Ala Phe

80 85 90 95 etc aac eta aaa aac eta agg gag tta ctg ctt gaa gac aac cag tta 384

Leu Asn Leu Lys Asn Leu Arg Glu Leu Leu Leu Glu Asp Asn Gin Leu 100 105 110 ccc caa ata ccc tct ggt ttg cca gag tct ttg aca gaa ctt agt eta 432

Pro Gin He Pro Ser Gly Leu Pro Glu Ser Leu Thr Glu Leu Ser Leu

115 120 125 att caa aac aat ata tac aac ata act aaa gag ,ggc att tea aga ctt 480

He Gin Asn Asn He Tyr Asn He Thr Lys Glu' Gly He Ser Arg Leu

130 135 . 140 ata aac ttg aaa aat- etc tat ttg gcc tgg aac tgc tat ttt aac aaa 528 He Asn Leu Lys Asn Leu Tyr Leu Ala Trp Asn Cys Tyr Phe Asn Lys

145 150 155 gtt tgc gag aaa act aac ata gaa gat gga gta ttt gaa acg ctg aca 576

Val Cys Glu Lys Thr Asn He Glu Asp Gly Val Phe Glu Thr Leu Thr 160 165 170 175 aat ttg gag ttg eta tea eta tct ttc aat tct ctt tea cat gtg cca 624

Asn Leu Glu Leu Leu Ser Leu Ser Phe Asn Ser Leu Ser His Val Pro

180 185 190 ccc aaa ctg cca age tec eta cgc aaa ctt ttt ctg age aac ace cag 672

Pro Lys Leu Pro Ser Ser Leu Arg Lys Leu Phe Leu Ser Asn Thr Gin

195 200 205 ate aaa tac att agt gaa gaa gat ttc aag gga ttg ata aat tta aca 720

He Lys Tyr He Ser Glu Glu Asp Phe Lys Gly Leu He Asn Leu Thr

210 215 220 tta eta gat tta age ggg aac tgt ccg agg tgc ttc aat gcc cca ttt 768 Leu Leu Asp Leu Ser Gly Asn Cys Pro Arg Cys Phe Asn Ala Pro Phe

225 230 235 cca tgc gtg cct tgt gat ggt ggt get tea att aat ata gat cgt ttt 816

Pro Cys Val Pro Cys Asp Gly Gly Ala Ser He Asn He Asp Arg Phe 240 245 250 255 get ttt caa aac ttg ace caa ctt cga tac eta aac etc tct age act 864

Ala Phe Gin Asn Leu Thr Gin Leu Arg Tyr Leu Asn Leu Ser Ser Thr

260 265 270 tec etc agg aag att aat get gcc tgg ttt aaa aat atg cct cat ctg 912

Ser Leu Arg Lys He Asn Ala Ala Trp Phe Lys Asn Met Pro His Leu

275 280 285 aag gtg ctg gat ctt gaa ttc aac tat tta gtg gga gaa ata gcc tct 960

Lys Val Leu Asp Leu Glu Phe Asn Tyr Leu Val Gly Glu He Ala Ser

290 295 300 ggg gca ttt tta acg atg ctg ccc cgc tta gaa ata ctt gac ttg tct 1008 Gly Ala Phe Leu Thr Met Leu Pro Arg Leu Glu He Leu Asp Leu Ser

305 310 315 ttt aac tat ata aag ggg agt tat cca cag cat att aat att tec aga 1056

Phe Asn Tyr He Lys Gly Ser Tyr Pro Gin His He Asn He Ser Arg 320 325 330 335 aac ttc tct aaa ctt ttg tct eta egg gca ttg cat tta aga ggt tat 1104

Asn Phe Ser Lys Leu Leu Ser Leu Arg Ala Leu His Leu Arg Gly Tyr

340 345 350 gtg ttc cag gaa etc aga gaa gat gat ttc cag ccc ctg atg cag ctt 1152

Val Phe Gin Glu Leu Arg Glu Asp Asp Phe Gin'^' Pro Leu Met Gin Leu

355 360 . 365 cca aac tta teg act. ate aac ttg ggt att aat ttt att aag caa ate 1200 Pro Asn Leu Ser Thr He Asn Leu Gly He Asn Phe He Lys Gin He

370 375 380 gat ttc aaa ctt ttc caa aat ttc tec aat ctg gaa att att tac ttg 1248

Asp Phe Lys Leu Phe Gin Asn Phe Ser Asn Leu Glu He He Tyr Leu 385 390 395 tea gaa aac aga ata tea ccg ttg gta aaa gat ace egg cag agt tat 1296

Ser Glu Asn Arg He Ser Pro Leu Val Lys Asp Thr Arg Gin Ser Tyr

400 405 410 415 gca aat agt tec tct ttt caa cgt cat ate egg aaa cga cgc tea aca 1344

Ala Asn Ser Ser Ser Phe Gin Arg His He Arg Lys Arg Arg Ser Thr

420 425 430 gat ttt gag ttt gac cca cat teg aac ttt tat cat ttc ace cgt cct 1392

Asp Phe Glu Phe Asp Pro His Ser Asn Phe Tyr His Phe Thr Arg Pro

435 440 445 tta ata aag cca caa tgt get get tat gga aaa gcc tta gat tta age 1440 Leu He Lys Pro Gin Cys Ala Ala Tyr Gly Lys Ala Leu Asp Leu Ser

450 455 460 etc aac agt att ttc ttc att ggg cca aac caa ttt gaa aat ctt cct 1488

Leu Asn Ser He Phe Phe He Gly Pro Asn Gin Phe Glu Asn Leu Pro 465 470 475 gac att gcc tgt tta aat ctg tct gca aat age aat get caa gtg tta 1536

Asp He Ala Cys Leu Asn Leu Ser Ala Asn Ser Asn Ala Gin Val Leu

480 485 490 495 agt gga act gaa ttt tea gcc att cct cat gtc aaa tat ttg gat ttg 1584

Ser Gly Thr Glu Phe Ser Ala He Pro His Val Lys Tyr Leu Asp Leu

500 505 510 aca aac aat aga eta gac ttt gat aat get agt get ctt act gaa ttg 1632

Thr Asn Asn Arg Leu Asp Phe Asp Asn Ala Ser Ala Leu Thr Glu Leu

515 520 525 tec gac ttg gaa gtt eta gat etc age tat aat tea cac tat ttc aga 1680 Ser Asp Leu Glu Val Leu Asp Leu Ser Tyr Asn Ser His Tyr Phe Arg

530 535 . 540 ata gca ggc gta aca cat cat eta gaa ttt att caa aat ttc aca aat 1728

He Ala Gly Val Thr His His Leu Glu Phe He Gin Asn Phe Thr Asn 545 550 555 eta aaa gtt tta aac ttg age cac aac aac att tat act tta aca gat 1776

Leu Lys Val Leu Asn Leu Ser His Asn Asn He Tyr Thr Leu Thr Asp 560 565 570 575 aag tat aac ctg gaa age aag tec ctg gta gaa tta gtt ttc agt ggc 1824

Lys Tyr Asn Leu Glu Ser Lys Ser Leu Val Glu Leu Val Phe Ser Gly 580 585 590 aat cgc ctt gac att ttg tgg aat gat gat gac aac agg tat ate tec 1872

Asn Arg Leu Asp He Leu Trp Asn Asp Asp Asp Asn Arg Tyr He Ser 595 • 600 605

att ttc aaa ggt etc aag aat ctg aca cgt ctg gat tta tec ctt aat 1920

He Phe Lys Gly Leu Lys Asn Leu Thr Arg Leu Asp Leu Ser Leu Asn

610 615 620 agg etc aag cac ate cca aat gaa gca ttc ctt aat ttg cca gcg agt 1968

Arg Leu Lys His He Pro Asn Glu Ala Phe Leu'Αsn Leu Pro Ala Ser 625 630 . 635 etc act gaa eta cat- ata aat gat aat atg tta aag ttt ttt aac tgg 2016 Leu Thr Glu Leu His He Asn Asp Asn Met Leu Lys Phe Phe Asn Trp 640 645 650 655 aca tta etc cag cag ttt cct cgt etc gag ttg ctt gac tta cgt gga 2064

Thr Leu Leu Gin Gin Phe Pro Arg Leu Glu Leu Leu Asp Leu Arg Gly 660 665 670 aac aaa eta etc ttt tta act gat age eta tct gac ttt aca tct tec 2112

Asn Lys Leu Leu Phe Leu Thr Asp Ser Leu Ser Asp Phe Thr Ser Ser

675 680 685 ctt egg aca ctg ctg ctg agt cat aac agg att tec cac eta ccc tct 2160

Leu Arg Thr Leu Leu Leu Ser His Asn Arg He Ser His Leu Pro Ser

690 695 700 ggc ttt ctt tct gaa gtc agt agt ctg aag cac etc gat tta agt tec 2208

Gly Phe Leu Ser Glu Val Ser Ser Leu Lys His Leu Asp Leu Ser Ser 705 710 715 aat ctg eta aaa aca atm aac aaa tec gca ctt gaa act aag ace ace 2256 Asn Leu Leu Lys Thr Xaa Asn Lys Ser Ala Leu Glu Thr Lys Thr Thr 720 725 730 735 ace aaa tta tct atg ttg gaa eta cac gga aac ccc ttt gaa tgc ace 2304

Thr Lys Leu Ser Met Leu Glu Leu His Gly Asn Pro Phe Glu Cys Thr 740 745 750 tgt gac att gga gat ttc cga aga tgg atg gat gaa cat ctg aat gtc 2352

Cys Asp He Gly Asp Phe Arg Arg Trp Met Asp Glu His Leu Asn Val

755 760 765 aaa att ccc aga ctg gta gat gtc att tgt gcc agt cct ggg gat caa 2400

Lys He Pro Arg Leu Val Asp Val He Cys Ala Ser Pro Gly Asp Gin

770 . 775 780 aga ggg aag agt att gtg agt ctg gag eta aca act tgt gtt tea gat 2448

Arg Gly Lys Ser He Val Ser Leu Glu Leu Thr Thr Cys Val Ser Asp 785 790 795 gtc act gca gtg ata tta ttt ttc ttc acg ttc ttt ate ace ace atg 2496 Val Thr Ala Val He Leu Phe Phe Phe Thr Phe Phe He Thr Thr Met 800 805 ^' 810 815 gtt atg ttg get gcc ctg get cac cat ttg ttt tac tgg gat gtt tgg 2544

Val Met Leu Rla Ala Leu Ala His His Leu Phe Tyr Trp Asp Val Trp 820 825 830 ttt ata tat aat gtg tgt tta get aag tta aaa ggc tac agg tct ctt 2592 Phe He Tyr Asn Val Cys Leu Ala Lys Leu Lys Gly Tyr Arg Ser Leu 835 840 845 tec aca tec caa act ttc tat gat get tac att /tct tat gac ace aaa 2640 Ser Thr Ser Gin Thr Phe Tyr Asp Ala Tyr He-" Ser Tyr Asp Thr Lys 850 855 . 860 gat gcc tct gtt act- gac tgg gtg ata aat gag ctg cgc tac cac ctt 2688 Asp Ala Ser Val Thr Asp Trp Val He Asn Glu Leu Arg Tyr His Leu 865 870 875 gaa gag age cga gac aaa aac gtt etc ctt tgt eta gag gag agg gat 2736 Glu Glu Ser Arg Asp Lys Asn Val Leu Leu Cys Leu Glu Glu Arg Asp 880 885 890 895 tgg gac ccg gga ttg gcc ate ate gac aac etc atg cag age ate aac 2784

Trp Asp Pro Gly Leu Ala He He Asp Asn Leu Met Gin Ser He Asn 900 905 910 caa age aag aaa aca gta ttt gtt tta ace aaa aaa tat gca aaa age 2832

Gin Ser Lys Lys Thr Val Phe Val Leu Thr Lys Lys Tyr Ala Lys Ser 915 920 925 tgg aac ttt aaa aca get ttt tac ttg gcc ttg cag agg eta atg ^"ggt 2880 Trp Asn Phe Lys Thr Ala Phe Tyr Leu Ala Leu Gin Arg Leu Met Gly 930 935 940 gag aac atg gat gtg att ata ttt ate ctg ctg gag cca gtg tta cag 2928 Glu Asn Met Asp Val He He Phe He Leu Leu Glu Pro Val Leu Gin 945 ^' 950 955 cat tct ccg tat ttg agg eta egg cag egg ate tgt aag age tec ate 2976 His Ser Pro Tyr Leu Arg Leu Arg Gin Arg He Cys Lys Ser Ser He 960 965 970 975 - etc cag tgg cct gac aac ccg aag gca gaa ggc ttg ttt tgg caa act 3024

Leu Gin Trp Pro Asp Asn Pro Lys Ala Glu Gly Leu Phe Trp Gin Thr 980 985 990 ctg aga aat gtg gtc ttg act gaa aat gat tea egg tat aac aat atg 3072

Leu Arg Asn Val Val Leu Thr Glu Asn Asp Ser Arg Tyr Asn Asn Met 995 1000 1005 tat gtc gat tec att aag caa tac taa 3099

Tyr Val Asp Ser He Lys Gin Tyr 1010 1015 MLTCIFLLISGSCELCAEENFSRSYPCDEKKQNDSVIAECSNRRLQEVPQTVGKYVTELDLSDNFITHI TNESFQGLQNLTKINLNHNPNVQHQNGNPGIQSNGLNITDGAFLNLKNLRELLLEDNQLPQIPSGLPES LTELSLIQNNIYNITKEGISRLINLKNLYLA NCYFNKVCEKTNIEDGVFETLTNLELLSLSFNSLSHV PPKLPSSLRKLFLSNTQIKYISEEDFKGLINLTLLDLSGNCPRCFNAPFPCVPCDGGASINIDRFAFQN LTQLRYLNLSSTSLRKINAAWFKNMPHLKVLDLEFNYLVGEIASGAFLTMLPRLEILDLSFNYIKGSYP QHINISRNFSKLLSLRALHLRGYVFQELREDDFQPLMQLPNLSTINLGINFIKQIDFKLFQNFSNLEII YLSENRISPLVKDTRQSYANSSSFQRHIRKRRΞTDFEFDPHSNFYHFTRPLIKPQCAAYGKALDLSLNS IFFIGPNQFENLPDIACLNLSANSNAQVLSGTEFSAIPHVKYLDLTNJRLDFDNASALTELSDLEVLDL SYNSHYFRIAGVTHHLEFIQNFTNLKVLNLSHN IYTLTDKYNLESKSLVELVFSGNRLDILWNDDDNR YISIFKGLKNLTRLDLSLNRLKHIPNEAFLNLPASLTELHINDNMLKFFNWTLLQQFPRLELLDLRGNK LLFLTDSLSDFTSSLRTLLLSHNRISHLPSGFLSEVSSLKHLDLSSNLLKTINKSALETKTTTKLSMLE LHGNPFECTCDIGDFRR MDEHLNVKIPRLVDVICASPGDQRGKSIVSLELTTCVSDVTAVILFFFTFF ITTMV LAALAHHLFY DV FIYNVCLAKLKGYRSLSTSQTFYDAYISYDTKDASVTD VINELRYHLE ESRDKNVLLCLEERDWDPGLAIIDNLMQSINQSKKTVFVLTKKYAKSWNFKTAFYLALQRLMGENMDVI IFILLEPVLQHΞPYLRLRQRICKSSILQWPDNPKAEGLFWQTLRNVVLTENDSRYNNMYVDSIKQY

Table 8: Partial nucleotide and amino acid sequences (see SEQ ID NO: 19 and 20) of a mammalian, e.g., primate, human, DNAX Toll like Receptor 8 (DTLR8) . AAT GAA TTG ATC CCC AAT CTA GAG AAG GAA GAT.-'GGT TCT ATC TTG ATT 48

Asn Glu Leu He Pro Asn Leu Glu Lys Glu Asp Gly Ser He Leu He

1 5 10 15

TGC CTT TAT GAA AGC TAC TTT GAC CCT GGC AAA AGC ATT AGT GAA AAT 96 Cys Leu Tyr Glu Ser Tyr Phe Asp Pro Gly Lys Ser He Ser Glu Asn

20 25 30

ATT GTA AGC TTC ATT GAG AAA AGC TAT AAG TCC ATC TTT GTT TTG TCC 144

He Val Ser Phe He Glu Lys Ser Tyr Lys Ser He Phe Val Leu Ser 35 40 45

CCC AAC TTT GTC CAG AAT GAG TGG TGC CAT TAT GAA TTC TAC TTT GCC 192

Pro Asn Phe Val Gin Asn Glu Trp Cys His Tyr Glu Phe Tyr Phe Ala 50 55 60

CAC CAC AAT CTC TTC CAT GAA AAT TCT GAT CAC ATA ATT CTT ATC TTA 240

His His Asn Leu Phe His Glu Asn Ser Asp His He He Leu He Leu

65 70 75 80 CTG GAA CCC ATT CCA TTC TAT TGC ATT CCC ACC AGG TAT CAT AAA CTG 288

Leu Glu Pro He Pro Phe Tyr Cys He Pro Thr Arg Tyr His Lys Leu

85 90 95

GAA GCT CTC CTG GAA AAA AAA GCA TAC TTG GAA TGG CCC AAG GAT AGG 336 Glu Ala Leu Leu Glu Lys Lys Ala Tyr Leu Glu Trp Pro Lys Asp Arg

100 105 110

CGT AAA TGT GGG CTT TTC TGG GCA AAC CTT CGA GCT GCT GTT AAT GTT 384

Arg Lys Cys Gly Leu Phe Trp Ala Asn Leu Arg Ala Ala Val Asn Val 115 120 125

AAT GTA TTA GCC ACC AGA GAA ATG TAT GAA CTG CAG ACA TTC ACA GAG 432

Asn Val Leu Ala Thr Arg Glu Met Tyr Glu Leu Gin Thr Phe Thr Glu 130 135 140

TTA AAT GAA GAG TCT CGA GGT TCT ACA ATC TCT CTG ATG AGA ACA GAC 480

Leu Asn Glu Glu Ser Arg Gly Ser Thr He Ser Leu Met Arg Thr Asp

145 150 155 160 TGT CTA TAAAATCCCA CAGTCCTTGG GAAGTTGGGG ACCACATACA CTGTTGGGAT 536 Cys Leu

GTACATTGAT ACAACCTTTA TGATGGCAAT TTGACAATAT TTATTAAAAT AAAAAATGGT 59 €

TATTCCCTTC AAAAAAAAAA AAAAAAAAAA AAA 62 £

NELI PNLEKEDGS ILICLYESYFDPGKSISENIVSFIEKSYKSI FVLS PNFVQNEWCHYEFYFAHHNLFHEN. HHLILLEPIPFYCIPTRYHKLEALLEKKAYLE PKDRRKCGLFWANLRAAVNVNVLATREMYELQTFTELNI SRGSTISLMRTDCL additional primate, e.g., human sequence (SEQ ID NO: 31 and 32); nucleotides 4 and 23 designated C, may be A, C, G, or T; nucleotide 845 designated C, may be C or T: C TCC GAT GCC AAG ATT CGG CAC CAG GCA TAT TCA GAG GTC ATG ATG 46

Ser Asp Ala Lys He Arg His Gin Ala Tyr Ser Glu Val Met Met 1 5 10 ^' 15

GTT GGA TGG TCA GAT^' TCA TAC ACC TGT GAA TAC CCT TTA AAC CTA AGG 94 Val Gly Trp Ser Asp Ser Tyr Thr Cys Glu Tyr Pro Leu Asn Leu Arg

20 25 30

GGA ACT AGG TTA AAA GAC GTT CAT CTC CAC GAA TTA TCT TGC AAC ACA 142 Gly Thr Arg Leu Lys Asp Val His Leu His Glu Leu Ser Cys Asn Thr 35 40 45

GCT CTG TTG ATT GTC ACC ATT GTG GTT ATT ATG CTA GTT CTG GGG TTG 190

Ala Leu Leu He Val Thr He Val Val He Met Leu Val Leu Gly Leu 50 55 60

GCT GTG GCC TTC TGC TGT CTC CAC TTT GAT CTG CCC TGG TAT CTC AGG 238

Ala Val Ala Phe Cys Cys Leu His Phe Asp Leu Pro Trp Tyr Leu Arg 65 70 75 ATG CTA GGT CAA TGC ACA CAA ACA TGG CAC AGG GTT AGG AAA ACA ACC 286 Met Leu Gly Gin Cys Thr Gin Thr Trp His Arg Val Arg Lys Thr Thr 80 85 90 95

CAA GAA CAA CTC AAG AGA AAT GTC CGA TTC CAC GCA TTT ATT TCA TAC 334 Gin Glu Gin Leu Lys Arg Asn Val Arg Phe His Ala Phe He Ser Tyr

100 105 110

AGT GAA CAT GAT TCT CTG TGG GTG AAG AAT GAA TTG ATC CCC AAT CTA 382 Ser Glu His Asp Ser Leu Trp Val Lys Asn Glu Leu He Pro Asn Leu 115 120 125

GAG AAG GAA GAT GGT TCT ATC TTG ATT TGC CTT TAT GAA AGC TAC TTT 430

Glu Lys Glu Asp Gly Ser He Leu He Cys Leu Tyr Glu Ser Tyr Phe 130 135 140

GAC CCT GGC AAA AGC ATT AGT GAA AAT ATT GTA AGC TTC ATT GAG AAA 478 Asp Pro Gly Lys Ser He Ser Glu Asn He Val Ser Phe He Glu Lys 145 150 155 AGC TAT AAG TCC ATC TTT GTT TTG TCT CCC AAC TTT GTC CAG AAT GAG 526 Ser Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Asn Glu 160 165 170 175

TGG TGC CAT TAT GAA TTC TAC TTT GCC CAC CAC AAT CTC TTC CAT GAA 57' Trp Cys His Tyr Glu Phe Tyr Phe Ala His His Asn Leu Phe His Glu

180 185 190

AAT TCT GAT CAC ATA ATT CTT ATC TTA CTG GAA CCC ATT CCA TTC TAT 62; Asn Ser Asp His He He Leu He Leu Leu Glu Pro He Pro Phe Tyr 195 200 205 TGC ATT CCC ACC AGG TAT CAT AAA CTG GAA GCT CTC CTG GAA AAA AAA 670

Cys He Pro Thr Arg Tyr His Lys Leu Glu Ala Leu Leu Glu Lys Lys

210 215 220

GCA TAC TTG GAA TGG CCC AAG GAT AGG CGT AAA TGT GGG CTT TTC TGG 718

Ala Tyr Leu Glu Trp Pro Lys Asp Arg Arg Lys Cys Gly Leu Phe Trp 225 _ 230 235 GCA AAC CTT CGA GCT GCT GTT AAT GTT AAT GTA TTA GCC ACC AGA GAA 766 Ala Asn Leu Arg Ala Ala Val Asn Val Asn Val Leu Ala Thr Arg Glu 240 245 250 255

ATG TAT GAA CTG CAG ACA TTC ACA GAG TTA AAT GAA GAG TCT CGA GGT 814 Met Tyr Glu Leu Gin Thr Phe Thr Glu Leu Asn Glu Glu Ser Arg Gly

260 265 270

TCT ACA ATC TCT CTG ATG AGA ACA GAC TGT CTA TAAAATCCCA CAGTCCTTGG 867 Ser Thr He Ser Leu Met Arg Thr Asp Cys Leu 275 280

GAAGTTGGGG ACCACATACA CTGTTGGGAT GTACATTGAT ACAACCTTTA TGATGGCAAT 927

TTGACAATAT TTATTAAAAT AAAAAATGGT TATTCCCTTC AAAAAAAAAA AAAAAAAAAA 987

AAAAAAAAAA AA 999

SDAKIRHQAYSEVMMVGWSDSYTCEYPLNLRGTRLKDVHLHELSCNTALLIVTIVVIMLVLGLAVAFCCLHFD] YLRMLGQCTQT HRVRKTTQEQLKRNVRFHAFISYSEHDSLWVKNELIPNLEKEDGSILICLYESYFDPGKS: ENIVSFIEKSYKSIFVLSPNFVQNEWCHYEFYFAHHNLFHENSDHIILILLEPIPFYCIPTRYHKLEALLEKK2 LEWPKDRRKCGLFWANLRAAVNVNVLATREMYELQTFTELNEESRGSTISLMRTDCL

Further primate, e.g., human, DTLR8 (SEQ ID NO: 38 and 39): gaatcatcca cgcacctgca gctctgctga gagagtgcaa gccgtggggg ttttgagctc 60 atcttcatca ttcatatgag gaaataagtg gtaaaatcct tggaaataca atg aga 116

Met Arg etc ate aga aac att tac ata ttt tgt agt att gtt atg aca gca gag 164 Leu He Arg Asn He Tyr He Phe Cys Ser He Val Met Thr Ala Glu -15 -10 -5 ggt gat get cca gag ctg cca gaa gaa agg gaa ctg atg ace aac tgc 212 Gly Asp Ala Pro Glu Leu Pro Glu Glu Arg Glu Leu Met Thr Asn Cys -1 1 5 10 15 tec aac atg tct eta aga aag gtt ccc gca gac ttg ace cca gcc aca 260 Ser Asn Met Ser Leu Arg Lys Val Pro Ala Asp Leu Thr Pro Ala Thr

20 25 30 acg aca ctg gat tta tec tat aac etc ctt ttt caa etc cag agt tea 308 Thr Thr Leu Asp Leu Ser Tyr Asn Leu Leu Phe Gin Leu Gin Ser Ser 35 40 45 gat ttt cat tct gtc tec aaa ctg aga gtt ttg att eta tgc cat aac 356

Asp Phe His Ser Val Ser Lys Leu Arg Val Leu He Leu Cys His Asn

50 55 60 aga att caa cag ctg gat etc aaa ace ttt gaa-ttc aac aag gag tta 404

Arg He Gin Gin Leu Asp Leu Lys Thr Phe Glu^' Phe Asn Lys Glu Leu

65 70 • 75 aga tat tta gat ttg- tct aat aac aga ctg aag agt gta act tgg tat 452 Arg Tyr Leu Asp Leu Ser Asn Asn Arg Leu Lys Ser Val Thr Trp Tyr

80 85 90 95 tta ctg gca ggt etc agg tat tta gat ctt tct ttt aat gac ttt gac 500

Leu Leu Ala Gly Leu Arg Tyr Leu Asp Leu Ser Phe Asn Asp Phe Asp 100 105 110 ace atg cct ate tgt gag gaa get ggc aac atg tea cac ctg gaa ate 548

Thr Met Pro He Cys Glu Glu Ala Gly Asn Met Ser His Leu Glu He

115 120 125 eta ggt ttg agt ggg gca aaa ata caa aaa tea gat ttc cag aaa att 596

Leu Gly Leu Ser Gly Ala Lys He Gin Lys Ser Asp Phe Gin Lys He

130 135 140 get cat ctg cat eta aat act gtc ttc tta gga ttc aga act ctt cct 644

Ala His Leu His Leu Asn Thr Val Phe Leu Gly Phe Arg Thr Leu Pro

145 150 155 cat tat gaa gaa ggt age ctg ccc ate tta aac aca aca aaa ctg cac 692 His Tyr Glu Glu Gly Ser Leu Pro He Leu Asn Thr Thr Lys Leu His

160 165 170 175 att gtt tta cca atg gac aca aat ttc tgg gtt ctt ttg cgt gat gga 740

He Val Leu Pro Met Asp Thr Asn Phe Trp Val Leu Leu Arg Asp Gly 180 185 190 ate aag act tea aaa ata tta gaa atg aca aat ata gat ggc aaa age 788

He Lys Thr Ser Lys He Leu Glu Met Thr Asn He Asp Gly Lys Ser

195 200 205 caa ttt gta agt tat gaa atg caa cga aat ctt -agt tta gaa aat get 836

Gin Phe Val Ser Tyr Glu Met Gin Arg Asn Leu Ser Leu Glu Asn Ala

210 215 . 220 aag aca teg gtt eta ttg ctt aat aaa gtt gat tta etc tgg gac gac 884

Lys Thr Ser Val Leu Leu Leu Asn Lys Val Asp Leu Leu Trp Asp Asp

225 230 235 ctt ttc ctt ate tta caa ttt gtt tgg cat aca tea gtg gaa cac ttt - 932 Leu Phe Leu He Leu Gin Phe Val Trp His Thr Ser Val Glu His Phe

240 245 250 255 cag ate cga aat gtg act ttt ggt ggt aag get tat ctt gac cac aat 980 Gin He Arg Asn Val Thr Phe Gly Gly Lys Ala Tyr Leu Asp His Asn 260 265 270 tea ttt gac tac tea aat act gta atg aga act ata aaa ttg gag cat 1028 Ser Phe Asp Tyr Ser Asn Thr Val Met Arg Thr He Lys Leu Glu His 275 280 285 gta cat ttc aga gtg ttt tac att caa cag gat ,.aaa ate tat ttg ctt 1076 Val His Phe Arg Val Phe Tyr He Gin Gin Asp' Lys He Tyr Leu Leu 290 295 . 300 ttg ace aaa atg gac ata gaa aac ctg aca ata tea aat gca caa atg 1124 Leu Thr Lys Met Asp He Glu Asn Leu Thr He Ser Asn Ala Gin Met 305 310 315 cca cac atg ctt ttc ccg aat tat cct acg aaa ttc caa tat tta aat 1172 Pro His Met Leu Phe Pro Asn Tyr Pro Thr Lys Phe Gin Tyr Leu Asn 320 325 330 335 ttt gcc aat aat ate tta aca gac gag ttg ttt aaa aga act ate caa 1220 Phe Ala Asn Asn He Leu Thr Asp Glu Leu Phe Lys Arg Thr He Gin 340 345 350 ctg cct cac ttg aaa act etc att ttg aat ggc aat aaa ctg gag aca 1268 Leu Pro His Leu Lys Thr Leu He Leu Asn Gly Asn Lys Leu Glu Thr 355 360 365 ctt tct tta gta agt tgc ttt get aac aac aca ccc ttg gaa cac ttg 1316 Leu Ser Leu Val Ser Cys Phe Ala Asn Asn Thr Pro Leu Glu His Leu 370 375 380 gat ctg agt caa aat eta tta caa cat aaa aat gat gaa aat tgc tea 1364 Asp Leu Ser Gin Asn Leu Leu Gin His Lys Asn Asp Glu Asn Cys Ser 385 390 395 tgg cca gaa act gtg gtc aat atg aat ctg tea tac aat aaa ttg tct 1412 Trp Pro Glu Thr Val Val Asn Met Asn Leu Ser Tyr Asn Lys Leu Ser 400 405 410 415 gat tct gtc ttc agg tgc ttg ccc aaa agt att caa ata ctt gac eta 1460

Asp Ser Val Phe Arg Cys Leu Pro Lys Ser He Gin He Leu Asp Leu

420 425 430 aat aat aac caa ate caa act gta cct aaa gag act att cat ctg atg 1508

Asn Asn Asn Gin He Gin Thr Val Pro Lys Glu Thr He His Leu Met

435 440 445 gcc tta cga gaa eta aat att gca ttt aat ttt eta act gat etc cct 1556 Ala Leu Arg Glu Leu Asn He Ala Phe Asn Phe Leu Thr Asp Leu Pro 450 455 460 gga tgc agt cat ttc agt aga ctt tea gtt ctg aac att gaa atg aac 1604 Gly Cys Ser His Phe Ser Arg Leu Ser Val Leu Asn He Glu Met Asn 465 470. 475 ttc att etc age cca tct ctg gat ttt gtt cag age tgc cag gaa gtt 1652 Phe He Leu Ser Pro Ser Leu Asp Phe Val Gin Ser Cys Gin Glu Val 480 485 490 495 aaa act eta aat gcg gga aga aat cca ttc egg tgt ace tgt gaa tta 1700 Lys Thr Leu Asn Ala Gly Arg Asn Pro Phe Arg Cys Thr Cys Glu Leu 500 505 510 aaa aat ttc att cag ctt gaa aca tat tea gag,-gtc atg atg gtt gga 1748 Lys Asn Phe He Gin Leu Glu Thr Tyr Ser Glu^' Val Met Met Val Gly 515 520 525 tgg tea gat tea tac ace tgt gaa tac cct tta aac eta agg gga act 1796 Trp Ser Asp Ser Tyr Thr Cys Glu Tyr Pro Leu Asn Leu Arg Gly Thr 530 535 540 agg tta aaa gac gtt cat etc cac gaa tta tct tgc aac aca get ctg 1844 Arg Leu Lys Asp Val His Leu His Glu Leu Ser Cys Asn Thr Ala Leu 545 550 555 ttg att gtc ace att gtg gtt att atg eta gtt ctg ggg ttg get gtg 1892 Leu He Val Thr He Val Val He Met Leu Val Leu Gly Leu Ala Val 560 565 570 575 gcc ttc tgc tgt etc cac ttt gat ctg ccc tgg tat etc agg atg eta 1940 Ala Phe Cys Cys Leu His Phe Asp Leu Pro Trp Tyr Leu Arg Met Leu 580 585 590 ggt caa tgc aca caa aca tgg cac agg gtt agg aaa aca ace caa gaa 1988 Gly Gin Cys Thr Gin Thr Trp His Arg Val Arg Lys Thr Thr Gin Glu 595 600 605 caa etc aag aga aat gtc cga ttc cac gca ttt att tea tac agt gaa 2036 Gin Leu Lys Arg Asn Val Arg Phe His Ala Phe He Ser Tyr Ser Glu 610 615 620 cat gat tct ctg tgg gtg aag aat gaa ttg ate ccc aat eta gag aag 2084 His Asp Ser Leu Trp Val Lys Asn Glu Leu He Pro Asn Leu Glu Lys 625 630 635 gaa gat ggt tct ate ttg att tgc ctt tat gaa age tac ttt gac cct 2132 Glu Asp Gly Ser He Leu He Cys Leu Tyr Glu Ser Tyr Phe Asp Pro 640 645 650 655 ggc aaa age att agt gaa aat att gta age ttc att gag aaa age tat 2180 Gly Lys Ser He Ser Glu Asn He Val Ser Phe He Glu Lys Ser Tyr 660 665 670 aag tec ate ttt gtt ttg tct ccc aac ttt gtc cag aat gag tgg tgc 2228 Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Asn Glu Trp Cys 675 680 685 cat tat gaa ttc tac ttt gcc cac cac aat etc ttc cat gaa aat tct 2276 His Tyr Glu Phe Tyr Phe Ala His His Asn Leu Phe His Glu Asn Ser 690 695 - 700 gat cat ata att ctt ate tta ctg gaa ccc att cca ttc tat tgc att 2324 Asp His He He Leu He Leu Leu Glu Pro He Pro Phe Tyr Cys He 705 710 715 ccc ace agg tat cat aaa ctg aaa get etc ctg gaa aaa aaa gca' tac 2372 Pro Thr Arg Tyr His Lys Leu Lys Ala Leu Leu Glu Lys Lys Ala Tyr 720 725 730 735 ttg gaa tgg ccc aag gat agg cgt aaa tgt ggg ctt ttc tgg gca aac 2420 Leu Glu Trp Pro Lys Asp Arg Arg Lys Cys Gly ^'Leu Phe Trp Ala Asn 740 745 . 750 ctt cga get get att- aat gtt aat gta tta gcc ace aga gaa atg tat 2468 Leu Arg Ala Ala He Asn Val Asn Val Leu Ala Thr Arg Glu Met Tyr 755 760 765 gaa ctg cag aca ttc aca gag tta aat gaa gag tct cga ggt tct aca 2516 Glu Leu Gin Thr Phe Thr Glu Leu Asn Glu Glu Ser Arg Gly Ser Thr 770 775 780 ate tct ctg atg aga aca gat tgt eta taaaatccca cagtccttgg 2563 He Ser Leu Met Arg Thr Asp Cys Leu 785 790 gaagttgggg accaeataca ctgttgggat gtacattgat aeaaccttta tgatggeaat 2623 ttgaeaatat ttattaaaat aaaaaatggt tattccettc atatcagttt etagaaggat 2683 ttctaagaat gtatcctata gaaacacctt cacaagttta taagggctta tggaaaaagg 2743 tgttcatccc aggattgttt ataatcatga aaaatgtggc caggtgcagt ggctcactct 2803 tgtaatecca geaetatggg aggecaaggt gggtgaccea cgaggtcaag agatggagac 2863 catcctggcc aacatggtga aaccctgtct ctactaaaaa tacaaaaatt agctgggcgt 2923 gatggtgcac gcctgtagtc ccagctactt gggaggctga ggcaggagaa tcgcttgaac 2983 ccgggaggtg gcagttgcag tgagctgaga tcgagccact gcactccagc ctggtgacag 3043 age 3046

MRLIRNIYIFCSIVMTAEGDAPELPEERELMTNCSNMSLRKVPADLTPATTTLDLSYNLLFQLQSSDFH SVSKLRVLILCHNRIQQLDLKTFEFNKELRYLDLSNNRLKSVT YLLAGLRYLDLSFNDFDTMPICEEA

GNMSHLEILGLSGAKIQKSDFQKIAHLHLNTVFLGFRTLPHYΞEGSLPILNTTKLHIVLPMDTNFWVLL

RDGIKTSKILEMTNIDGKSQFVSYEMQRNLSLENAKTSVLLLNKVDLLWDDLFLILQFVHTSVEHFQI

RNVTFGGKAYLDHNSFDYSNTVMRTIKLEHVHFRVFYIQQDKIYLLLTKMDIENLTISNAQMPHMLFPN

_YP_TKFQYLNFANNILTDELFKRTIQLPHLKTLILNGNKLETLSLVSCFANNTPLEHLDLSQNLLQHKND _EN_{CS P}E_TVVNMNLSYNKLSDSVFRCLPKSIQ_ILDLNNNQ_IQTVPKETIHLMALRELNIAFNFLTDLPG

_CSHFS_RLSVLNIEMNFILSPSLDFVQSCQEV_KT_LN_AGRN_PFRCTCELKNFIQLETYSEVMMVGWSDSYT

_CEYPLN_LRGTRLKDVHLHELSCNTALLIV_TIW_IM_LV_LGLAVAFCCLHFDLPWYLRMLGQCTQTHRVR

_KTT_QEQ_LK_RNV_RFHAFISYSEHDS_LWV_K E_LIPNL_EK_EDGSILICLYESYFDPGKSISENIVSFIEKSY

_KSIFVLSPNFVQNE CHYEFYFA_HHNLF_HENSDH_IIL_ILLEPIPFYCIPTRYHKLKALLEKKAYLEWPK DRRKCGLF ANLRAAINVNVLATREMYELQTFTELNEESRGSTISLMRTDCL Table 9: Partial nucleotide and amino acid sequences (see SEQ ID NO: 21 and 22) of a mammalian, e.g., primate, human, DNAX Toll like Receptor 9 (DTLR9) . AAG AAC TCC AAA GAA AAC CTC CAG TTT CAT GCH-TTT ATT TCA TAT AGT 48 Lys Asn Ser Lys Glu Asn Leu Gin ^"Phe His Ala Phe He Ser Tyr Ser 1 5 10 15

GAA CAT GAT TCT GCC TGG GTG AAA AGT GAA TTG GTA CCT TAC CTA GAA 96 Glu His Asp Ser Ala Trp Val Lys Ser Glu Leu Val Pro Tyr Leu Glu

20 25 30

AAA GAA GAT ATA CAG ATT TGT CTT CAT GAG AGA AAC TTT GTC CCT GGC 144 Lys Glu Asp He Gin He Cys Leu His Glu Arg Asn Phe Val Pro Gly 35 40 45

AAG AGC ATT GTG GAA AAT ATC ATC AAC TGC ATT GAG AAG AGT TAC AAG 192

Lys Ser He Val Glu Asn He He Asn Cys He Glu Lys Ser Tyr Lys 50 55 60

TCC ATC TTT GTT TTG TCT CCC AAC TTT GTC CAG AGT GAG TGG TGC CAT 240 Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Ser Glu Trp Cys His 65 70 75 80 TAC GAA CTC TAT TTT GCC CAT CAC AAT CTC TTT CAT GAA GGA TCT AAT 288 Tyr Glu Leu Tyr Phe Ala His His Asn Leu Phe His Glu Gly Ser Asn 85 90 95

AAC TTA ATC CTC ATC TTA CTG GAA CCC ATT CCA CAG AAC AGC ATT CCC 336 Asn Leu He Leu He Leu Leu Glu Pro He Pro Gin Asn Ser He Pro 100 105 110

AAC AAG TAC CAC AAG CTG AAG GCT CTC ATG ACG CAG CGG ACT TAT TTG 384 Asn Lys Tyr His Lys Leu Lys Ala Leu Met Thr Gin Arg Thr Tyr Leu 115 120 125

CAG TGG CCC AAG GAG AAA AGC AAA CGT GGG CTC TTT TGG GCT 426

Gin Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe Trp Ala 130 135 140

A ' 427

KNSKENLQFHAFISYSEHDSAWVKSELVPYLEKEDIQICLHERNFVPGKSIVENHNCIEKSYKSIFVLSPNΪ SE CHYELYFAHHNLFHEGSNNLILILLEPIPQNSIPNKYHKLKALMTQRTYLQ PKEKSKRGLF A

Further primate, e.g., human DTLR9 (SEQ ID NO: 40 and 41): aagaatttgg actcatatca agatgetctg aagaagaaca acectttagg atagecactg 60 caacatc atg ace aaa gac aaa gaa cct att gtt ,aaa age ttc cat ttt 109 Met Thr Lys Asp Lys Glu Pro He Val'Lys Ser Phe His Phe -30 -25 . -20 gtt tgc ctt atg ate- ata ata gtt gga ace aga ate cag ttc tec gac 157 Val Cys Leu Met He He He Val Gly Thr Arg He Gin Phe Ser Asp -15 -10 -5 gga aat gaa ttt gca gta gac aag tea aaa aga ggt ctt att cat gtt 205 Gly Asn Glu Phe Ala Val Asp Lys Ser Lys Arg Gly Leu He His Val -1 1 5 10 15 cca aaa gac eta ccg ctg aaa ace aaa gtc tta gat atg tct cag aac 253

Pro Lys Asp Leu Pro Leu Lys Thr Lys Val Leu Asp Met Ser Gin Asn

20 25 30 tac ate get gag ctt cag gtc tct gac atg age ttt eta tea gag ttg 301

Tyr He Ala Glu Leu Gin Val Ser Asp Met Ser Phe Leu Ser Glu Leu

35 40 45 aca gtt ttg aga ctt tec cat aac aga ate cag eta ctt gat tta agt 349 Thr Val Leu Arg Leu Ser His Asn Arg He Gin Leu Leu Asp Leu Ser 50 55 60 gtt ttc aag ttc aac cag gat tta gaa tat ttg gat tta tct cat aat 397 Val Phe Lys Phe Asn Gin Asp Leu Glu Tyr Leu Asp Leu Ser His Asn 65 70 75 cag ttg caa aag ata tec tgc cat cct att gtg agt ttc agg cat tta 445 Gin Leu Gin Lys He Ser Cys His Pro He Val Ser Phe Arg His Leu 80 85 90 95- gat etc tea ttc aat gat ttc aag gcc ctg ccc ate tgt aag gaa ttt 493 Asp Leu Ser Phe Asn Asp Phe Lys Ala Leu Pro He Cys Lys Glu Phe 100 105 110 ggc aac tta tea caa ctg aat ttc ttg gga ttg. agt get atg aag ctg 541 Gly Asn Leu Ser Gin Leu Asn Phe Leu Gly Leu Ser Ala Met Lys Leu 115 120 125 caa aaa tta gat ttg ctg cca att get cac ttg cat eta agt tat ate 589 Gin Lys Leu Asp Leu Leu Pro He Ala His Leu His Leu Ser Tyr He 130 135 140 ctt ctg gat tta aga aat tat tat ata aaa gaa aat gag aca gaa agt. 637 Leu Leu Asp Leu Arg Asn Tyr Tyr He Lys Glu Asn Glu Thr Glu Ser 145 150 155 eta caa att ctg aat gca aaa ace ctt cac ctt gtt ttt cac cca act 685 Leu Gin He Leu Asn Ala Lys Thr Leu His Leu Val Phe His Pro Thr 160 165 170 175 agt tta ttc get ate caa gtg aac ata tea gtt aat act tta ggg tgc 733 Ser Leu Phe Ala He Gin Val Asn He Ser Val Asn Thr Leu Gly Cys 180 185 190 tta caa ctg act aat att aaa ttg aat gat gac .aac tgt caa gtt ttc 781 Leu Gin Leu Thr Asn He Lys Leu Asn Asp Asp Asn Cys Gin Val Phe 195 200 . 205 att aaa ttt tta tea. gaa etc ace aga ggt cca ace tta ctg aat ttt 829 He Lys Phe Leu Ser Glu Leu Thr Arg Gly Pro Thr Leu Leu Asn Phe 210 215 220 ace etc aac cac ata gaa acg act tgg aaa tgc ctg gtc aga gtc ttt 877 Thr Leu Asn His He Glu Thr Thr Trp Lys Cys Leu Val Arg Val Phe 225 230 235 caa ttt ctt tgg ccc aaa cct gtg gaa tat etc aat att tac aat tta 925

Gin Phe Leu Trp Pro Lys Pro Val Glu Tyr Leu Asn He Tyr Asn Leu

240 245 250 255 aca ata att gaa age att cgt gaa gaa gat ttt act tat tct aaa acg 973

Thr He He Glu Ser He Arg Glu Glu Asp Phe Thr Tyr Ser Lys Thr

260 265 270 aca ttg aaa gca ttg aca ata gaa cat ate acg aac caa gtt ttt ctg 1021 Thr Leu Lys Ala Leu Thr He Glu His He Thr Asn Gin Val Phe Leu 275 280 285 ttt tea cag aca get ttg tac ace gtg ttt tct gag atg aac att atg 1069 Phe Ser Gin Thr Ala Leu Tyr Thr Val Phe Ser Glu Met Asn He Met 290 295 300 atg tta ace att tea gat aca cct ttt ata cac atg ctg tgt cct cat 1117 Met Leu Thr He Ser Asp Thr Pro Phe He His Met Leu Cys Pro His 305 310 315 gca cca age aca ttc aag ttt ttg aac ttt ace cag aac gtt ttc aca 1165

Ala Pro Ser Thr Phe Lys Phe Leu Asn Phe Thr Gin Asn Val Phe Thr 320 325 330 335 gat agt att ttt gaa aaa tgt tec acg tta gtt aaa ttg gag aca ctt 1213

Asp Ser He Phe Glu Lys Cys Ser Thr Leu Val Lys Leu Glu Thr Leu 340 345 350 ate tta caa aag aat gga tta aaa gac ctt ttc aaa gta ggt etc atg 1261 He Leu Gin Lys Asn Gly Leu Lys Asp Leu Phe Lys Val Gly Leu Met 355 360 365 acg aag gat atg cct tct ttg gaa ata ctg gat gtt age tgg aat tct 1309 Thr Lys Asp Met Pro Ser Leu Glu He Leu Asp Val Ser Trp Asn Ser 370 .375 380 ttg gaa tct ggt aga cat aaa gaa aac tgc act tgg gtt gag agt ata 1357 Leu Glu Ser Gly Arg His Lys Glu Asn Cys Thr Trp Val Glu Ser He 385 390 395 gtg gtg tta aat ttg tct tea aat atg ctt act gac tct gtt ttc aga 1405

Val Val Leu Asn Leu Ser Ser Asn Met Leu Thr Asp Ser Val Phe Arg

400 405 410 415 tgt tta cct ccc agg ate aag gta ctt gat ctt cac age aat aaa ata 1453

Cys Leu Pro Pro Arg He Lys Val Leu Asp Leu ^'His Ser Asn Lys He

420 425 • 430 aag age gtt cct aaa' caa gtc gta aaa ctg gaa get ttg caa gaa etc 1501 Lys Ser Val Pro Lys Gin Val Val Lys Leu Glu Ala Leu Gin Glu Leu

435 440 445 aat gtt get ttc aat tct tta act gac ctt cct gga tgt ggc age ttt 1549

Asn Val Ala Phe Asn Ser Leu Thr Asp Leu Pro Gly Cys Gly Ser Phe 450 455 460 age age ctt tct gta ttg ate att gat cac aat tea gtt tec cac cca 1597

Ser Ser Leu Ser Val Leu He He Asp His Asn Ser Val Ser His Pro

465 470 475 teg get gat ttc ttc cag age tgc cag aag atg agg tea ata aaa gca 1645

Ser Ala Asp Phe Phe Gin Ser Cys Gin Lys Met Arg Ser He Lys Ala

480 485 490 495 ggg gac aat cca ttc caa tgt ace tgt gag eta aga gaa ttt gtc aaa 1693

Gly Asp Asn Pro Phe Gin Cys Thr Cys Glu Leu Arg Glu Phe Val Lys

500 505 510 aat ata gac caa gta tea agt gaa gtg tta gag ggc tgg cct gat tct 1741 Asn He Asp Gin Val Ser Ser Glu Val Leu Glu Gly Trp Pro Asp Ser

515 520 525 tat aag tgt gac tac cca gaa agt tat aga gga age cca eta aag gac 1789

Tyr Lys Cys Asp Tyr Pro Glu Ser Tyr Arg Gly Ser Pro Leu Lys Asp 530 535 540 ttt cac atg tct gaa tta tec tgc aac ata act ctg ctg ate gtc ace 1837

Phe His Met Ser Glu Leu Ser Cys Asn He Thr Leu Leu He Val Thr

545 550 555 ate ggt gcc ace atg ctg gtg ttg get gtg act gtg ace tec etc tgc 1885

He Gly Ala Thr Met Leu Val Leu Ala Val Thr Val Thr Ser Leu Cys

560 565 570 575 ate tac ttg gat ctg ccc tgg tat etc agg atg gtg tgc cag tgg ace 1933

He Tyr Leu Asp Leu Pro Trp Tyr Leu Arg Met Val Cys Gin Trp Thr

580 585 590 cag act egg cgc agg gcc agg aac ata ccc tta gaa gaa etc caa aga 1981 Gin Thr Arg Arg Arg Ala Arg Asn He Pro Leu Glu Glu Leu Gin Arg

595 600 605 aac etc cag ttt cat get ttt att tea tat agt gaa cat gat tct gcc 2029

Asn Leu Gin Phe His Ala Phe He Ser Tyr Ser Glu His Asp Ser Ala 610 615 620 tgg gtg aaa agt gaa ttg gta cct tac eta gaa aaa gaa gat ata cag 2077 Trp Val Lys Ser Glu Leu Val Pro Tyr Leu Glu Lys Glu Asp He Gin 625 630 635 att tgt ctt cat gag agg aac ttt gtc cct ggc .aag age att gtg gaa 2125 He Cys Leu His Glu Arg Asn Phe Val Pro Gly ^'Lys Ser He Val Glu 640 645 650 655 aat ate ate aac tgc^' att gag aag agt tac aag tec ate ttt gtt ttg 2173 Asn He He Asn Cys He Glu Lys Ser Tyr Lys Ser He Phe Val Leu

660 665 670 tct ccc aac ttt gtc cag agt gag tgg tgc cat tac gaa etc tat ttt 2221 Ser Pro Asn Phe Val Gin Ser Glu Trp Cys His Tyr Glu Leu Tyr Phe 675 680 685 gcc cat cac aat etc ttt cat gaa gga tct aat aac tta ate etc ate 2269

Ala His His Asn Leu Phe His Glu Gly Ser Asn Asn Leu He Leu He

690 695 700 tta ctg gaa ccc att cca cag aac age att ccc aac aag tac cac aag 2317

Leu Leu Glu Pro He Pro Gin Asn Ser He Pro Asn Lys Tyr His Lys

705 710 715 ctg aag get etc atg acg cag egg act tat ttg cag tgg ccc aag gag 2365 Leu Lys Ala Leu Met Thr Gin Arg Thr Tyr Leu Gin Trp Pro Lys Glu 720 725 730 735 aaa age aaa cgt ggg etc ttt tgg get aac att aga gcc get ttt aat 2413 Lys Ser Lys Arg Gly Leu Phe Trp Ala Asn He Arg Ala Ala Phe Asn

740 745 750 atg aaa tta aca eta gtc act gaa aac aat gat gtg aaa tct 2455

Met Lys Leu Thr Leu Val Thr Glu Asn Asn Asp Val Lys Ser 755 760 765 taaaaaaatt taggaaattc aacttaagaa accattattt acttggatga tggtgaatag 2515 taeagtcgta agtnactgte tggaggtgce tccattatce teatgcettc aggaaagact 2575 taacaaaaac aatgtttcat ctggggaact gagctaggcg gtgaggttag cctgccagtt 2635 agagacagec cagtetcttc tggtttaate attatgtttc aaattgaaac agtctctttt 2695 gagtaaatgc tcagtttttc agetcctctc cactctgctt teccaaatgg attctgttgg 2755 tgaag 2760 MTKDKEPIVKSFHFVCLMIIIVGTRIQFSDGNEFAVDKSKRGLIHVPKDLPLKTKVLDMSQNYIAELQV SDMSFLSELTVLRLSHNRIQLLDLSVFKFNQDLEYLDLSHNQLQKISCHPIVSFRHLDLSFNDFKALPI CKEFGNLSQLNFLGLSAMKLQKLDLLPIAHLHLSYILLDLRNYYIKENETESLQILNAKTLHLVFHPTS LFAIQVNISVNTLGCLQLTNIKLNDDNCQVFIKFLSELTRGPTLLNFTLNHIETTW CLVRVFQFLWPK PVEYLNIYNLTIIESIREEDFTYSKTTLKALTJEHITNQVFLFSQTALYTVFSEMNIMMLTISDTPFIH MLCPHAPSTFKFLNFTQNVFTDSIFEKCSTLVKLETLILQKNGLKDLFKVGLMTKDMPSLEILDVSW S LESGRHKENCTWVESIWLNLSSNMLTDSVFRCLPPRIKVLDLHSNKIKSVPKQWKLEALQELNVAFN SLTDLPGCGSFSSLSVLIIDHNSVSHPSADFFQSCQKMRSIKAGDNPFQCTCELREFVKNIDQVSSEVL EG PDSYKCDYPESYRGSPLKDFHMSELSCNITLLIVTIGATMLVLAVTVTSLCIYLDLP YLRMVCQW TQTRRRARNIPLEELQRNLQFHAFISYSΞHDSA VKSELVPYLEKEDIQICLHERNFVPGKSIVENIIN CIEKSYKΞIFVLSPNFVQSEWCHYELYFAHHNLFHEGSNNLILILLEPIPQNSIPNKYHKLKALMTQRT YLQWPKEKSKRGLF A IRAAFNMKLTLVTENNDV S

Table 10: Nucleotide and amino acid sequences (see SEQ ID NO: 23 and 24) of a mammalian, e.g., primate, human, DNAX Toll like Receptor 10 (DTLRIO). Nucleotides 54, 103, and 345 are designated A; each may be A or G; nucleotide 313 designated G, may be G or T; and nucleotides 316, 380, 407, and 408 designated C; each may be A, C, G, or T.

GCT TCC ACC TGT GCC TGG CCT GGC TTC CCT GGC GGG GGC GGC AAA GTG 48 Ala Ser Thr Cys Ala. Trp Pro Gly Phe Pro Gly Gly Gly Gly Lys Val 1 5 10 15

GGC GAA ATG AGG ATG CCC TGC CCT ACG ATG CCT TCG TGG TCT TCG ACA 96 Gly Glu Met Arg Met Pro Cys Pro Thr Met Pro Ser Trp Ser Ser Thr 20 25 30 AAA CGC AGA GCG CAG TGG CAG ACT GGG TGT ACA ACG AGC TTC GGG GGC 144 Lys Arg Arg Ala Gin Trp Gin Thr Gly Cys Thr Thr Ser Phe Gly Gly 35 40 45

AGC TGG AGG AGT GCC GTG GGC GCT GGG CAC TCC GCC TGT GCC TGG AGG 192 Ser Trp Arg Ser Ala Val Gly Ala Gly His Ser Ala Cys Ala Trp Arg 50 55 60

AAC GCG ACT GGC TGC CTG GCA AAA CCC TCT TTG AGA ACC TGT GGG CCT 240 Asn Ala Thr Gly Cys Leu Ala Lys Pro Ser Leu Arg Thr Cys Gly Pro 65 70 75 80

CGG TCT ATG GCA GCC GCA AGA CGC TGT TTG TGC TGG CCC ACA CGG ACC 288 Arg Ser Met Ala Ala Ala Arg Arg Cys Leu Cys Trp Pro Thr Arg Thr 85 90 95

GGG TCA GTG GTC TCT TGC GCG CCA GTT CTC CTG CTG GCC CAG CAG CGC 336 Gly Ser Val Val Ser Cys Ala Pro Val Leu Leu Leu Ala Gin Gin Arg

100 105 110 _v CTG CTG GAA GAC CGC AAG GAC GTC GTG GTG CTG GTG ATC CTA ACG CCT 384 Leu Leu Glu Asp Arg Lys Asp Val Val Val Leu Val He Leu Thr Pro 115 120 125

GAC GGC CAA GCC TCC CGA CTA CCC GAT GCG CTG- ACC AGC GCC TCT GCC 432 Asp Gly Gin Ala Ser Arg Leu Pro Asp Ala Leu Thr Ser Ala Ser Ala 130 135 140

GCC AGA GTG TCC TCC TCT GGC CCC ACC AGC CCA GTG GTC GCG CAG CTT 480 Ala Arg Val Ser Ser Ser Gly Pro Thr Ser Pro Val Val Ala Gin Leu 145 150 155 160

CTG AGG CCA GCA TGC ATG GCC CTG ACC AGG GAC AAC CAC CAC TTC TAT~ 528 Leu Arg Pro Ala Cys Met Ala Leu Thr Arg Asp Asn His His Phe Tyr 165 170 175

AAC CGG AAC TTC TGC CAG GGA ACC CAC GGC CGA ATA GCC GTG AGC CGG 576 Asn Arg Asn Phe Cys Gin Gly Thr His Gly Arg He Ala Val Ser Arg 180 185 190 AAT CCT GCA CGG TGC CAC CTC CAC ACA CAC CTA ACA TAT GCC TGC CTG 624 Asn Pro Ala Arg Cys His Leu His Thr His Leu Thr Tyr Ala Cys Leu 195 200 205 ATC TGACCAACAC ATGCTCGCCA CCCTCACCAC ACACC .' 662

He

ASTCAWPGFPGGGGKVGEMRMPCPTMPSWSSTKRRAQWQTGCTTSFGGSWRSAVGAGHSACAWRNATGCLAKPSL RTCGPRSMAAARRCLC PTRTGSWSCAPVLLLAQQRLLEDRKDWVLVILTPDGQASRLPDALTSASAARVSSS GPTSPWAQLLRPACMALTRDNHHFYNRNFCQGTHGRIAVSRNPARCHLHTHLTYACLI

additional primate, e.g., human DTLRIO sequence (SEQ ID NO: 33 and 34); nucleotide 854 designated A, may be A or T; and nucleotides 1171 and 1172 designated C, each may be A, C, G, or T:

CTG CCT GCT GGC ACC CGG CTC CGG AGG CTG GAT GTC AGC TGC AAC AGC 48

Leu Pro Ala Gly Thr Arg Leu Arg Arg Leu Asp Val Ser Cys Asn Ser

1 5 10 15

ATC AGC TTC GTG GCC CCC GGC TTC TTT TCC AAG GCC AAG GAG CTG CGA 96

He Ser Phe Val Ala Pro Gly Phe Phe Ser Lys Ala Lys Glu Leu Arg

20 25 30 GAG CTC AAC CTT AGC GCC AAC GCC CTC AAG ACA GTG GAC CAC TCC TGG 144

Glu Leu Asn Leu Ser Ala Asn Ala Leu Lys Thr Val Asp His Ser Trp

35 40 45

TTT GGG CCC CTG GCG AGT GCC CTG CAA ATA CTA GAT GTA AGC GCC AAC 192 Phe Gly Pro Leu Ala Ser Ala Leu Gin He Leu Asp Val Ser Ala Asn

50 55 60

CCT CTG CAC TGC GCC TGT GGG GCG GCC TTT ATG GAC TTC CTG CTG GAG 240

Pro Leu His Cys Ala Cys Gly Ala Ala Phe Met Asp Phe Leu Leu Glu 65 70 75 80

GTG CAG GCT GCC GTG CCC GGT CTG CCC AGC CGG GTG AAG TGT GGC AGT 288

Val Gin Ala Ala Val Pro Gly Leu Pro Ser Arg Val Lys Cys Gly Ser

85 90 95

CCG GGC CAG CTC CAG GGC CTC AGC ATC TTT GCA CAG GAC CTG CGC CTC 336

Pro Gly Gin Leu Gin Gly Leu Ser He Phe Ala Gin Asp Leu Arg Leu

100 105 110 TGC CTG GAT GAG GCC CTC TCC TGG GAC TGT TTC GCC CTC TCG CTG CTG 384

Cys Leu Asp Glu Ala Leu Ser Trp Asp Cys Phe Ala Leu Ser Leu Leu

115 120 125

GCT GTG GCT CTG GGC CTG GGT GTG CCC ATG CTG CAT CAC CTC TGT GGC 432 Ala Val Ala Leu Gly Leu Gly Val Pro Met Leu His His Leu Cys Gly

130 135 140

TGG GAC CTC TGG TAC TGC TTC CAC CTG TGC CTG GCC TGG CTT CCC TGG 480

Trp Asp Leu Trp Tyr Cys Phe His Leu Cys Leu Ala Trp Leu Pro Trp 145 150 155 160 CGG GGG CGG CAA AGT GGG CGA GAT GAG GAT GCC CTG CCC TAC GAT GCC 528 Arg Gly Arg Gin Ser Gly Arg Asp Glu Asp Ala Leu Pro Tyr Asp Ala 165 170 175

TTC GTG GTC TTC GAC AAA ACG CAG AGC GCA GTG GCA GAC TGG GTG TAC 576 Phe Val Val Phe Asp Lys Thr Gin Ser Ala Val Ala Asp Trp Val Tyr 180 . 185 190 AAC GAG CTT CGG GGG CAG CTG GAG GAG TGC CGT GGG CGC TGG GCA CTC 624 Asn Glu Leu Arg Gly Gin Leu Glu Glu Cys Arg Gly Arg Trp Ala Leu 195 200 205

CGC CTG TGC CTG GAG GAA CGC GAC TGG CTG CCT GGC AAA ACC CTC TTT 672 Arg Leu Cys Leu Glu Glu Arg Asp Trp Leu Pro Gly Lys Thr Leu Phe 210 215 220

GAG AAC CTG TGG GCC TCG GTC TAT GGC AGC CGC AAG ACG CTG TTT GTG 720 Glu Asn Leu Trp Ala Ser Val Tyr Gly Ser Arg Lys Thr Leu Phe Val 225 230 235 240

CTG GCC CAC ACG GAC CGG GTC AGT GGT CTC TTG CGC GCC AGC TTC CTG 768

Leu Ala His Thr Asp Arg Val Ser Gly Leu Leu Arg Ala Ser Phe Leu 245 250 255

CTG GCC CAG CAG CGC CTG CTG GAG GAC CGC AAG GAC GTC GTG GTG CTG 816

Leu Ala Gin Gin Arg Leu Leu Glu Asp Arg Lys Asp Val Val Val Leu 260 265 270 GTG ATC CTG AGC CCT GAC GGC CGC CGC TCC CGC TAC GAG CGG CTG CGC 864 Val He Leu Ser Pro Asp Gly Arg Arg Ser Arg Tyr Glu Arg Leu Arg 275 280 285

CAG CGC CTC TGC CGC CAG AGT GTC CTC CTC TGG CCC CAC CAG CCC AGT 912 Gin Arg Leu Cys Arg Gin Ser Val Leu Leu Trp Pro His Gin Pro Ser 290 295 300

GGT CAG CGC AGC TTC TGG GCC CAG CTG GGC ATG GCC CTG ACC AGG GAC 960 Gly Gin Arg Ser Phe Trp Ala Gin Leu Gly Met Ala Leu Thr Arg Asp 305 310 315 320

AAC CAC CAC TTC TAT AAC CGG AAC TTC TGC CAG GGA CCC ACG GCC GAA 1008 Asn His His Phe Tyr Asn Arg Asn Phe Cys Gin Gly Pro Thr Ala Glu 325 330 335

TAGCCGTGAG CCGGAATCCT GCACGGTGCC ACCTCCACAC TCACCTCACC TCTGCCTGCC 1068

TGGTCTGACC CTCCCCTGCT CGCCTCCCTC ACCCCACACC TGACACAGAG CAGGCACTCA 1128 ATAAATGCTA CCGAAGGCTA AAAAAAAAAA AAAAAAAAAA AACCA 1173 LPAGTRLRRLDVSCISISISFVAPGFFSKAKELRELNLSANALKTVDHS FGPLASALQILDVSA PLHCACGAAFM DFLLEVQAAVPGLPSRVKCGSPGQLQGLSIFAQDLRLCLDEALS DCFALSLLAVALGLGVPM HH CG DL YC FHLCLA LPWRGRQSGRDEDALPYDAFWFDKTQSAVAD VYNELRGQLEECRGRWALRLCLEERD LPGKTLFΞ NLWASVYGSRKTLFVLAHTDRVSGLLRASFLLAQQRLLEDRKDVWLVILSPDGRRSRY.RLRQRLCRQSV LWP HQPSGQRSFWAQLGMA TRDNHHFYNRNFCQGPTAE

Further primate, e.g., human, DTLRIO (SEQ ID NO: 42 and 43): atg ccc atg aag tgg agt ggg tgg agg tgg age tgg ggg ccg gcc act 48

Met Pro Met Lys Trp Ser Gly Trp Arg Trp Ser Trp Gly Pro Ala Thr

-45 -40 -35 cac aca gcc etc cca ccc cca cag ggt ttc tgc cgc age gcc ctg cac 96 His Thr Ala Leu Pro Pro Pro Gin Gly Phe Cys Arg Ser Ala Leu His

-30 -25 -20 ccg ctg tct etc ctg gtg cag gcc ate atg ctg gcc atg ace ctg gcc 144

Pro Leu Ser Leu Leu Val Gin Ala He Met Leu Ala Met Thr Leu Ala -15 -10 -5 -1 ctg ggt ace ttg cct gcc ttc eta ccc tgt gag etc cag ccc cac ggc 192

Leu Gly Thr Leu Pro Ala Phe Leu Pro Cys Glu Leu Gin Pro His Gly

1 5 10 15 ctg gtg aac tgc aac tgg ctg ttc ctg aag tct gtg ccc cac ttc tec 240

Leu Val Asn Cys Asn Trp Leu Phe Leu Lys Ser Val Pro His Phe Ser

20 25 30 atg gca gca ccc cgt ggc aat gtc ace age ctt tec ttg tec tec aac 288

Met Ala Ala Pro Arg Gly Asn Val Thr Ser Leu Ser Leu Ser Ser Asn

35 40 45 cgc ate cac cac etc cat gat tct gac ttt gcc cac ctg ccc age ctg 336 Arg He His His Leu His Asp Ser Asp Phe Ala His Leu Pro Ser Leu

50 55 60 egg cat etc aac etc aag tgg aac tgc ccg ccg gtt ggc etc age ccc 384

Arg His Leu Asn Leu Lys Trp Asn Cys Pro Pro Val Gly Leu Ser Pro 65 70 75 80 atg cac ttc ccc tgc cac atg ace ate gag ccc age ace ttc ttg get 432

Met His Phe Pro Cys His Met Thr He Glu Pro Ser Thr Phe Leu Ala

85 90 95 gtg ccc ace ctg gaa gag eta aac ctg age tac aac aac ate atg act 480

Val Pro Thr Leu Glu Glu Leu Asn Leu Ser Tyr Asn Asn He Met Thr

100 105 110 gtg cct gcg ctg ccc aaa tec etc ata tec ctg tec etc age cat ace 528

Val Pro Ala Leu Pro Lys Ser Leu He Ser Leu Ser Leu Ser -His Thr

115 120 125 aac ate ctg atg eta gac tct gcc age etc gcc ggc ctg cat gcc ctg 576 Asn He Leu Met Leu Asp Ser Ala Ser Leu Ala Gly Leu His Ala Leu

130 135 140 cgc ttc eta ttc atg gac ggc aac tgt tat tac aag aac ccc tgc agg 624 Arg Phe Leu Phe Met Asp Gly Asn Cys Tyr Tyr Lys Asn Pro Cys Arg 145 150 155 160 cag gca ctg gag gtg gcc ccg ggt gcc etc ctt ggc ctg ggc aac etc 672 Gin Ala Leu Glu Val Ala Pro Gly Ala Leu Leu 'Gly Leu Gly Asn Leu 165 ' 170 ^'' 175 ace cac ctg tea etc aag tac aac aac etc act gtg gtg ccc cgc aac 720 Thr His Leu Ser Leu' Lys Tyr Asn Asn Leu Thr Val Val Pro Arg Asn 180 185 190 ctg cct tec age ctg gag tat ctg ctg ttg tec tac aac cgc ate gtc 768 Leu Pro Ser Ser Leu Glu Tyr Leu Leu Leu Ser Tyr Asn Arg He Val 195 200 205 aaa ctg gcg cct gag gac ctg gcc aat ctg ace gcc ctg cgt gtg etc 816

Lys Leu Ala Pro Glu Asp Leu Ala Asn Leu Thr Ala Leu Arg Val Leu

210 215 220 gat gtg ggc gga aat tgc cgc cgc tgc gac cac get ccc aac ccc tgc 864

Asp Val Gly Gly Asn Cys Arg Arg Cys Asp His Ala Pro Asn Pro Cys

225 ^' 230 235 240 atg gag tgc cct cgt cac ttc ccc cag eta cat ccc gat ace ttc age 912 Met Glu Cys Pro Arg His Phe Pro Gin Leu His Pro Asp Thr Phe Ser 245 250 255 cac ctg age cgt ctt gaa ggc ctg gtg ttg aag gac agt tct etc tec 960 His Leu Ser Arg Leu Glu Gly Leu Val Leu Lys Asp Ser Ser Leu Ser 260 265 270 tgg ctg aat gcc agt tgg ttc cgt ggg ctg gga aac etc cga gtg ctg 1008 Trp Leu Asn Ala Ser Trp Phe Arg Gly Leu Gly Asn Leu Arg Val Leu 275 280 285 gac ctg agt gag aac ttc etc tac aaa tgc ate act aaa ace aag gcc 1056

Asp Leu Ser Glu Asn Phe Leu Tyr Lys Cys He Thr Lys Thr Lys Ala

290 295 300 ttc cag ggc eta aca cag ctg cgc aag ctt aac ctg tec ttc aat tac 1104

Phe Gin Gly Leu Thr Gin Leu Arg Lys Leu Asn Leu Ser Phe Asn Tyr

305 310 315 320 caa aag agg gtg tec ttt gcc cac ctg tct ctg gcc cct tec ttc ggg 1152 Gin Lys Arg Val Ser Phe Ala His Leu Ser Leu Ala Pro Ser Phe Gly 325 330 335 age ctg gtc gcc ctg aag gag ctg gac atg cac ggc ate ttc ttc cgc 1200 Ser Leu Val Ala Leu Lys Glu Leu Asp Met His Gly He Phe Phe Arg 340 345 350 tea etc gat gag ace acg etc egg cca ctg gcc cgc ctg ccc atg etc 1248 Ser Leu Asp Glu Thr Thr Leu Arg Pro Leu Ala Arg Leu Pro Met Leu 355 360 365 cag act ctg cgt ctg cag atg aac ttc ate aac cag gcc cag etc ggc 1296 Gin Thr Leu Arg Leu Gin Met Asn Phe He Asn Gin Ala Gin Leu Giy 370 375 380 ate ttc agg gcc ttc cct ggc ctg cgc tac gtg gac ctg teg gac aac 1344 He Phe Arg Ala Phe Pro Gly Leu Arg Tyr Val' Asp Leu Ser Asp Asn 385 390 395 400 cgc ate age gga get teg gag ctg aca gcc ace atg ggg gag gca gat 1392 Arg He Ser Gly Ala Ser Glu Leu Thr Ala Thr Met Gly Glu Ala Asp

405 410 415 gga ggg gag aag gtc tgg ctg cag cct ggg gac ctt get ccg gcc cca 1440 Gly Gly Glu Lys Val Trp Leu Gin Pro Gly Asp Leu Ala Pro Ala Pro 420 425 430 gtg gac act ccc age tct gaa gac ttc agg ccc aac tgc age ace etc 1488

Val Asp Thr Pro Ser Ser Glu Asp Phe Arg Pro Asn Cys Ser Thr Leu 435 440 445 aac ttc ace ttg gat ctg tea egg aac aac ctg gtg ace gtg cag ccg 1536

Asn Phe Thr Leu Asp Leu Ser Arg Asn Asn Leu Val Thr Val Gin Pro 450 455 460 gag atg ttt gcc cag etc teg cac ctg cag tgc ctg cgc ctg age cac 1584 Glu Met Phe Ala Gin Leu Ser His Leu Gin Cys Leu Arg Leu Ser His 465 470 475 480 aac tgc ate teg cag gca gtc aat ggc tec cag ttc ctg ccg ctg ace 1632 Asn Cys He Ser Gin Ala Val Asn Gly Ser Gin Phe Leu Pro Leu Thr

485 490 495 ggt ctg cag gtg eta gac ctg tec cac aat aag ctg gac etc tac cac 1680 Gly Leu Gin Val Leu Asp Leu Ser His Asn Lys Leu Asp Leu Tyr His 500 505 510 gag cac tea ttc acg gag eta cca cga ctg gag gcc ctg gac etc age 1728

Glu His Ser Phe Thr Glu Leu Pro Arg Leu Glu Ala Leu Asp Leu Ser 515 520 525 tac aac age cag ccc ttt ggc atg cag ggc gtg ggc cac aac ttc age 1776

Tyr Asn Ser Gin Pro Phe Gly Met Gin Gly Val -Gly His Asn Phe Ser 530 535 540 ttc gtg get cac ctg cgc ace ctg cgc cac etc age ctg gcc cac aac 1824 Phe Val Ala His Leu Arg Thr Leu Arg His Leu Ser Leu Ala His Asn 545 550 555 560 aac ate cac age caa gtg tec cag cag etc tgc agt acg teg ctg egg 1872 Asn He His Ser Gin Val Ser Gin Gin Leu Cys Ser Thr Ser Leu Arg-

565 570 575 gcc ctg gac ttc age ggc aat gca ctg ggc cat atg tgg gcc gag gga 1920 Ala Leu Asp Phe Ser Gly Asn Ala Leu Gly His Met Trp Ala GGlluu GGllyy

580 585 590 gac etc tat ctg cac ttc ttc caa ggc ctg age ggt ttg ate tgg ctg 1968

Asp Leu Tyr Leu His Phe Phe Gin Gly Leu Ser Gly Leu He Trp Leu 595 600 605 gac ttg tec cag aac cgc ctg cac ace etc ctg ccc caa ace ctg cgc 2016

Asp Leu Ser Gin Asn Arg Leu His Thr Leu Leu Pro Gin Thr Leu Arg 610 615 ^''620 aac etc ccc aag age eta cag gtg ctg cgt etc cgt gac aat tac ctg 2064 Asn Leu Pro Lys Ser "Leu Gin Val Leu Arg Leu Arg Asp Asn Tyr Leu 625 630 635 640 gcc ttc ttt aag tgg tgg age etc cac ttc ctg ccc aaa ctg gaa gtc 2112

Ala Phe Phe Lys Trp Trp Ser Leu His Phe Leu Pro Lys Leu Glu Val 645 650 655 etc gac ctg gca gga aac cag ctg aag gcc ctg ace aat ggc age ctg 2160

Leu Asp Leu Ala Gly Asn Gin Leu Lys Ala Leu Thr Asn Gly Ser Leu 660 665 670 cct get ggc ace egg etc egg agg ctg gat gtc age tgc aac age ate 2208

Pro Ala Gly Thr Arg Leu Arg Arg Leu Asp Val Ser Cys Asn Ser He 675 680 685 age ttc gtg gcc ccc ggc ttc ttt tec aag gcc aag gag ctg cga gag 2256

Ser Phe Val Ala Pro Gly Phe Phe Ser Lys Ala Lys Glu Leu Arg Glu 690 695 700 etc aac ctt age gcc aac gcc etc aag aca gtg gac cac tec tgg ttt 2304 Leu Asn Leu Ser Ala Asn Ala Leu Lys Thr Val Asp His Ser Trp Phe 705 710 715 720 ggg ccc ctg gcg agt gcc ctg caa ata eta gat gta age gcc aac cct 2352

Gly Pro Leu Ala Ser Ala Leu Gin He Leu Asp Val Ser Ala Asn Pro 725 730 735 ctg cac tgc gcc tgt ggg gcg gcc ttt atg gac ttc ctg ctg gag gtg 2400

Leu His Cys Ala Cys Gly Ala Ala Phe Met Asp Phe Leu Leu Glu Val 740 745 750 cag get gcc gtg ccc ggt ctg ccc age egg gtg aag tgt ggc agt ccg 2448

Gin Ala Ala Val Pro Gly Leu Pro Ser Arg Val Lys Cys Gly Ser Pro 755 760 765 ggc cag etc cag ggc etc age ate ttt gca cag gac ctg cgc etc tgc 2496

Gly Gin Leu Gin Gly Leu Ser He Phe Ala Gin Asp Leu Arg Leu Cys 770 775 780 ctg gat gag gcc etc tec tgg gac tgt ttc gcc etc teg ctg ctg get 2544 Leu Asp Glu Ala Leu Ser Trp Asp Cys Phe Ala Leu Ser Leu Leu Ala 785 790 795 800 gtg get ctg ggc ctg ggt gtg ccc atg ctg cat cac etc tgt ggc tgg 2592

Val Ala Leu Gly Leu Gly Val Pro Met Leu His His Leu Cys Gly Trp 805 810 815 gac etc tgg tac tgc ttc cac ctg tgc ctg gcc tgg ctt ccc tgg egg 2640 Asp Leu Trp Tyr Cys Phe His Leu Cys Leu Ala Trp Leu Pro Trp Arg 820 825 830 ggg egg caa agt ggg cga gat gag gat gcc ctg ccc tac gat gcc ttc 2688 Gly Arg Gin Ser Gly Arg Asp Glu Asp Ala Leu 'Pro Tyr Asp Ala Phe 835 840 ' 845 gtg gtc ttc gac aaa acg cag age gca gtg gca gac tgg gtg tac aac 2736 Val Val Phe Asp Lys^' Thr Gin Ser Ala Val Ala Asp Trp Val Tyr Asn 850 855 860 gag ctt egg ggg cag ctg gag gag tgc cgt ggg cgc tgg gca etc cgc 2784 Glu Leu Arg Gly Gin Leu Glu Glu Cys Arg Gly Arg Trp Ala Leu Arg 865 870 875 880 ctg tgc ctg gag gaa cgc gac tgg ctg cct ggc aaa ace etc ttt gag 2832

Leu Cys Leu Glu Glu Arg Asp Trp Leu Pro Gly Lys Thr Leu Phe Glu

885 890 895 aac ctg tgg gcc teg gtc tat ggc age cgc aag acg ctg ttt gtg ctg 2880

Asn Leu Trp Ala Ser Val Tyr Gly Ser Arg Lys Thr Leu Phe Val Leu

900 905 910 gcc cac acg gac egg gtc agt ggt etc ttg cgc gcc age ttc ctg ctg 2928 Ala His Thr Asp Arg Val Ser Gly Leu Leu Arg Ala Ser Phe Leu Leu 915 920 925 gcc cag cag cgc ctg ctg gag gac cgc aag gac gtc gtg gtg ctg gtg 2976 Ala Gin Gin Arg Leu Leu Glu Asp Arg Lys Asp Val Val Val Leu Val 930 935 940 ate ctg age cct gac ggc cgc cgc tec cgc tat gtg egg ctg cgc cag 3024 He Leu Ser Pro Asp Gly Arg Arg Ser Arg Tyr Val Arg Leu Arg Gin 945 950 955 960 cgc etc tgc cgc cag agt gtc etc etc tgg ccc cac cag ccc agt ggt 3072

Arg Leu Cys Arg Gin Ser Val Leu Leu Trp Pro His Gin Pro Ser Gly 965 970 975 cag cgc age ttc tgg gcc cag ctg ggc atg gcc ctg ace agg gac aac 3120

Gin Arg Ser Phe Trp Ala Gin Leu Gly Met Ala Leu Thr Arg Asp Asn 980 985 990 cac cac ttc tat aac egg aac ttc tgc cag gga ccc acg gcc gaa tag 3168 His His Phe Tyr Asn Arg Asn Phe Cys Gin Gly Pro Thr Ala Glu 995 1000 1005

MPMK SG R SWGPATHTALPPPQGFCRSALHPLSLLVQAIMLAMTLALGTLPAFLPCELQPHGLVNCN WLFLKSVPHFΞMAAPRGNVTSLSLSSNRIHHLHDSDFAHLPSLRHLNLK NCPPVGLSPMHFPCHMTIE PSTFLAVPTLEELNLSYNNIMTVPALPKSLISLSLSHTNILMLDSASLAGLHALRFLFMDGNCYYKNPC RQALEVAPGALLGLGNLTHLSLKYWNLTWPRNLPSSLEYLLLSYWRIVKLAPEDLANLTALRVLDVGG NCRRCDHAPNPCMECPRHFPQLHPDTFSHLSRLEGLVLKDSSLSWLNASWFRGLGNLRVLDLSENFLYR CITKTKAFQGLTQLRKLNLSFNYQKRVSFAHLSLAPSFGSLVALKELDMHGIFFRSLDETTLRPLARLP MLQTLRLQMNFINQAQLGIFRAFPGLRYVDLSDNRISGASELTATMGEADGGEKV LQPGDLAPAPVDT PSSEDFRPNCSTLNFTLDLSR NLVTVQPEMFAQLSHLQCLRLSHNCISQAV GSQFLPLTGLQVLDLS HNKLDLYHEHSFTE PRLEALDIjΞYNSQPFGMQGVGHNFSFVAHIiRTLRHLSLAHNWIHSQVSQQLCST SLRALDFSGNALGHMWAEGDLYLHFFQGLSGLI LDLSQNRLHTLLPQTLRNLPKSLQVLRLRDNYLAF FKWWSLHFLPKLEVLDLAGNQL ALTNGSLPAGTRLRRLDVSCNSISFVAPGFFSKAKELRELNLSANA LKTVDHS FGPLASALQILDVSANPLHCACGAAFMDFLLEVQAAVPGLPSRVKCGSPGQLQGLSIFAQD LRLCLDEALSWDCFALSLLAVALGLGVPMLHHLCGWDLWYCFHLCLAWLPWRGRQSGRDEDALPYDAFV VFDKTQSAVADWVYNELRGQLEECRGRWALRLCLEERD LPGKTLFENL ASVYGSRKTLFVLAHTDRV SGLLRASFLLAQQRLLEDRKDWVLVILSPDGRRSRYVRLRQRLCRQSVLLWPHQPSGQRSFWAQLGMA LTRDNHHFYNRNFCQGPTAE

partial rodent , e . g . , mouse DTLRIO nucleotide sequence ( SEQ ID NO : 35 ) :

TGGCCCACAC GGACCGCGTC AGTGGCCTCC TGCGCACCAG CTTCCTGCTG GCTCAGCAGC 60

GCCTGTTGGA AGACCGCAAG GACGTGGTGG TGTTGGTGAT CCTGCGTCCG GATGCCCCAC 120 CGTCCCGCTA TGTGCGACTG CGCCAGCGTC TCTGCCGCCA GAGTGTGCTC TTCTGGCCCC 180

AGCGACCCAA CGGGCAGGGG GGCTTCTGGG CCCAGCTGAG TACAGCCCTG ACTAGGGACA 240

ACCGCCACTT CTATAACCAG AACTTCTGCC GGGGACCTAC AGCAGAATAG CTCAGAGCAA 300

CAGCTGGAAA CAGCTGCATC TTCATGTCTG GTTCCCGAGT TGCTCTGCCT GCCTTGCTCT 360

GTCTTACTAC ACCGCTATTT GGCAAGTGCG CAATATATGC TACCAAGCCA CCAGGCCCAC 420 GGAGCAAAGG TTGGCTGTAA AGGGTAGTTT TCTTCCCATG CATCTTTCAG GAGAGTGAAG 480

ATAGACACCA AACCCAC 497

Further rodent , e . g . , mouse , DTLRIO (SEQ ID NO : 44 and 45) : aac ctg tec ttc aat tac cgc aag aag gta tec ttt gcc cgc etc cac 48

Asn Leu Ser Phe Asn Tyr^' Arg Lys Lys Val Ser Phe Ala Arg Leu His

1 5 10 15 ctg gca agt tec ttt aag aac ctg gtg tea ctg cag gag ctg aac atg 96

Leu Ala Ser Ser Phe Lys Asn Leu Val Ser Leu Gin Glu Leu Asn Met

20 25 30 aac ggc ate ttc ttc cgc ttg etc aac aag tac acg etc aga tgg ctg 144 Asn Gly He Phe Phe Arg Leu Leu Asn Lys Tyr Thr Leu Arg Trp Leu 35 40 45 gcc gat ctg ccc aaa etc cac act ctg cat ctt caa atg aac ttc ate 192 Ala Asp Leu Pro Lys Leu His Thr Leu His Leu Gin Met Asn Phe He 50 55 60 aac cag gca cag etc age ate ttt ggt ace ttc cga gcc ctt cgc ttt 240

Asn Gin Ala Gin Leu Ser He Phe Gly Thr Phe Arg Ala Leu Arg Phe

65 70 75 80 gtg gac ttg tea gac aat cgc ate agt ggg cct tea acg ctg tea gaa 288

Val Asp Leu Ser Asp Asn Arg He Ser Gly Pro .-Ser Thr Leu Ser Glu

85 90 ^'' 95 gcc ace cct gaa gag gca gat gat gca gag cag gag gag ctg ttg tct 336 Ala Thr Pro Glu Glu Ala Asp Asp Ala Glu Gin Glu Glu Leu Leu Ser

100 105 110 gcg gat cct cac cca get ccg ctg age ace cct get tct aag aac ttc 384

Ala Asp Pro His Pro Ala Pro Leu Ser Thr Pro Ala Ser Lys Asn Phe 115 120 125 atg gac agg tgt aag aac ttc aag ttc aac atg gac ctg tct egg aac 432

Met Asp Arg Cys Lys Asn Phe Lys Phe Asn Met Asp Leu Ser Arg Asn

130 135 140 aac ctg gtg act ate aca gca gag atg ttt gta aat etc tea cgc etc 480

Asn Leu Val Thr He Thr Ala Glu Met Phe Val Asn Leu Ser Arg Leu

145 150 155 160 cag tgt ctt age ctg age cac aac tea att gca cag get gtc aat ggc 528

Gin Cys Leu Ser Leu Ser His Asn Ser He Ala Gin Ala Val Asn Gly

165 170 175 tct cag ttc ctg ccg ctg ace ggt ctg cag gtg eta gac ctg tec cac 576 Ser Gin Phe Leu Pro Leu Thr Gly Leu Gin Val Leu Asp Leu Ser His

180 185 190 aat aag ctg gac etc tac cac gag cac tea ttc acg gag eta cca cga 624

Asn Lys Leu Asp Leu Tyr His Glu His Ser Phe Thr Glu Leu Pro Arg 195 200 205 ctg gag gcc ctg gac etc age tac aac age cag ccc ttt age atg aag 672

Leu Glu Ala Leu Asp Leu Ser Tyr Asn Ser Gin Pro Phe Ser Met Lys

210 215 220 ggt ata ggc cac aat ttc agt ttt gtg ace cat ctg tec atg eta cag 720

Gly He Gly His Asn Phe Ser Phe Val Thr His Leu Ser Met Leu Gin

225 230 235 240 age ctt age ctg gca cac aat gac att cat ace cgt gtg tec tea cat 768

Ser Leu Ser Leu Ala His Asn Asp He His Thr Arg Val Ser Ser His

245 250 255 etc aac age aac tea gtg agg ttt ctt gac ttc age ggc aac ggt atg 816 Leu Asn Ser Asn Ser Val Arg Phe Leu Asp Phe Ser Gly Asn Gly Met 260 265 270 ggc cgc atg tgg gat gag ggg ggc ctt tat etc cat ttc ttc caa ggc 864 Gly Arg Met Trp Asp Glu Gly Gly Leu Tyr Leu His Phe Phe Gin Gly 275 280 285 ctg agt ggc gtg ctg aag ctg gac ctg tct caa aat aac ctg cat ate 912

Leu Ser Gly Val Leu Lys Leu Asp Leu Ser Gin Asn Asn Leu His He 290 295 300 etc egg ccc cag aac ctt gac aac etc ccc aag age ctg aag ctg ctg 960

Leu Arg Pro Gin Asn Leu Asp Asn Leu Pro Lys Ser Leu Lys Leu Leu 305 310 315 ^'' 320 age etc cga gac aac tac eta tct ttc ttt aac tgg ace agt ctg tec 1008 Ser Leu Arg Asp Asn ^'Tyr Leu Ser Phe Phe Asn Trp Thr Ser Leu Ser

325 330 335 ttc eta ccc aac ctg gaa gtc eta gac ctg gca ggc aac cag eta aag 1056

Phe Leu Pro Asn Leu Glu Val Leu Asp Leu Ala Gly Asn Gin Leu Lys 340 345 350 gcc ctg ace aat ggc ace ctg cct aat ggc ace etc etc cag aaa etc 1104

Ala Leu Thr Asn Gly Thr Leu Pro Asn Gly Thr Leu Leu Gin Lys Leu

355 360 365 gat gtc agt age aac agt ate gtc tct gtg^' gcc ccc ggc ttc ttt tec 1152

Asp Val Ser Ser Asn Ser He Val Ser Val Ala Pro Gly Phe Phe Ser 370 375 380 aag gcc aag gag ctg cga gag etc aac ctt age gcc aac gcc etc aag 1200

Lys Ala Lys Glu Leu Arg Glu Leu Asn Leu Ser Ala Asn Ala Leu Lys 385 390 395 400 aca gtg gac cac tec tgg ttt ggg ccc att gtg atg aac ctg aca gtt 1248 Thr Val Asp His Ser Trp Phe Gly Pro He Val Met Asn Leu Thr Val

405 410 415 eta gac gtg aga age aac cct ctg cac tgt gcc tgt ggg gca gcc ttc 1296

Leu Asp Val Arg Ser Asn Pro Leu His Cys Ala Cys Gly Ala Ala Phe 420 425 430 gta gac tta ctg ttg gag gtg cag ace aag gtg cct ggc ctg get aat 1344

Val Asp Leu Leu Leu Glu Val Gin Thr Lys Val Pro Gly Leu Ala Asn

435 440 445 ggt gtg aag tgt ggc age ccc ggc cag ctg cag ggc cgt age ate ttc 1392

Gly Val Lys Cys Gly Ser Pro Gly Gin Leu Gin Gly Arg Ser He Phe 450 455 460 gcg cag gac ctg egg ctg tgc ctg gat gag gtc etc tct tgg gac tgc 1440

Ala Gin Asp Leu Arg Leu Cys Leu Asp Glu Val Leu Ser Trp Asp Cys 465 470 475 480 ttt ggc ctt tea etc ttg get gtg gcc gtg ggc atg gtg gtg cct ata 1488 Phe Gly Leu Ser Leu Leu Ala Val Ala Val Gly Met Val Val Pro He

485 490 495 ctg cac cat etc tgc ggc tgg gac gtc tgg tac tgt ttt cat ctg tgc 1536 Leu His His Leu Cys Gly Trp Asp Val Trp Tyr Cys Phe His Leu Cys 500 505 510 ctg gca tgg eta cct ttg eta gcc cgc age cga cgc age gcc caa act 1584 Leu Ala Trp Leu Pro Leu Leu Ala Arg Ser Arg Arg Ser Ala Gin Thr 515 520 525 etc cct tat gat gcc ttc gtg gtg ttc gat aag gca cag age gca gtt 1632 Leu Pro Tyr Asp Ala Phe Val Val Phe Asp Lys .-Ala Gin Ser Ala Val 530 535 ^'' 540 gcc gac tgg gtg tat aac gag ctg egg gtg egg ctg gag gag egg cgc 1680 Ala Asp Trp Val Tyr Asn Glu Leu Arg Val Arg Leu Glu Glu Arg Arg 545 550 555 560 ggc cgc tgg gca etc cgc ctg tgc ctg gag gac cga gat tgg ctg cct 1728 Gly Arg Trp Ala Leu Arg Leu Cys Leu Glu Asp Arg Asp Trp Leu Pro 565 570 575 ggc cag acg etc ttc gag aac etc tgg get tec ate tat ggg age cgc 1776

Gly Gin Thr Leu Phe Glu Asn Leu Trp Ala Ser He Tyr Gly Ser Arg 580 585 590 aag act eta ttt gtg ctg gcc cac acg gac cgc gtc agt ggc etc ctg 1824

Lys Thr Leu Phe Val Leu Ala His Thr Asp Arg Val Ser Gly Leu Leu 595 600 605 cgc ace age ttc ctg ctg get cag cag cgc ctg ttg gaa gac cgc aag 1872 Arg Thr Ser Phe Leu Leu Ala Gin Gin Arg Leu Leu Glu Asp Arg Lys 610 615 620 gac gtg gtg gtg ttg gtg ate ctg cgt ccg gat gcc cac cgc tec cgc 1920 Asp Val Val Val Leu Val He Leu Arg Pro Asp Ala His Arg Ser Arg 625 630 635 640 tat gtg cga ctg cgc cag cgt etc tgc cgc cag agt gtg etc ttc tgg 1968 Tyr Val Arg Leu Arg Gin Arg Leu Cys Arg Gin Ser Val Leu Phe Trp 645 650 655 ccc cag cag ccc aac ggg cag ggg ggc ttc tgg gcc cag ctg agt aca 2016 Pro Gin Gin Pro Asn Gly Gin Gly Gly Phe Trp Ala Gin Leu Ser Thr 660 665 670 gcc ctg act agg gac aac cgc ^'cac ttc tat aac cag aac ttc tgc egg 2064 Ala Leu Thr Arg Asp Asn Arg His Phe Tyr Asn Gin Asn Phe Cys Arg 675 680 685 gga cct aca gca gaa tagctcagag caacagctgg aaacagctgc atcttcatgt 2119 Gly Pro Thr Ala Glu 690 ctggttcceg agttgctctg cctgecttgc tctgtettac tacaccgcta tttggcaagt 2179 gegcaatata tgctaceaag ccaecaggce eaeggagcaa aggttggctg taaagggtag 2239 ttttcttccc atgcatcttt caggagagtg aagatagaca ccaaacccac 2289 NLSFNYRKKVSFARLHLASSFKNLVSLQELNMNGIFFRLLNKYTLRWLADLPKLHTLHLQMNFINQAQL SIFGTFRALRFVDLSDNRISGPSTLSEATPEEADDAEQEELLSADPHPAPLSTPASKNFMDRCKNFKFN MDLSRNNLVTITAEMFVNLSRLQCLSLSHNSIAQAV GSQFLPLTGLQVLDLSHNKLDLYHEHSFTELP RLEALDLSYNSQPFSMKGIGHNFSFVTHLSMLQSLSLAHNDIHTRVSSHLNSNSVRFLDFSGNGMGRM DEGGLYLHFFQGLSGVLKLDLSQNNLHILRPQNLDNLPKSLKLLSLRDNYLSFFNWTSLSFLPNLEVLD LAGNQL ALTNGTLPNGTLLQKLDVSSNSIVSVAPGFFSKAKELRELNLSANALKTVDHSWFGPIVMNL TVLDVRSNPLHCACGAAFVDLLLEVQTKVPGLANGVKCGSPGQLQGRSIFAQDLRLCLDEVLS DCFGL SLLAVAVGMVVPILHHLCGΫTOVVfYCFHLCLAW PLLARSRRSAQTLPYDAFVVFDKlVQSAVADWVYNEL RVRLEERRGRWALRLCLEDRD LPGQTLFENLWASIYGSRKTLFVLAHTDRVSGLLRTSFLLAQQRLLE DRKDVWLVIIiRPDAHRSRYVRLRQRLCRQSVLF PQQPNGQGGF AQLSTALTRDNRHFYNQNFCRGP TAE

Table 11: Comparison of intracellular domains of human DTLRs. DTLR1 is SEQ ID NO: 2; DTLR2 is SEQ ID NO: 4; DTLR3 is SEQ ID NO: 6; DTLR4 is SEQ ID NO: 8; DTLR5 is SEQ ID NO: 10; and DTLR6 is SEQ ID NO: 12. Particularly important and conserved, e.g., characteristic, residues correspond, across the DTLRs, to SEQ ID NO: 18 residues tyrl0-tyrl3; trp26; cys46; trp52; pro54-gly55; ser69; lys71; trpl34-prol35; and phel44-trpl45.

DTLR1 QRNLQFHAFISYSGHD SF VKNELLPNLEKEG MQICLHERNF DTLR9 KENLQFHAFISYSEHD SA VKSELVPYLEKED IQICLHERNF

DTLR8 NELIPNLEKEDGS ILICLYESYF

DTLR2 SRNICYDAFVSYSERD AY VENLMVQELENFNPP FKLCLHKRDF

DTLR6 SPDCCYDAFIVYDTKDPAVTEWVLAELVAKLEDPREK—HFNLCLEERDW

DTLR7 TSQTFYDAYISYDTKDASVTDWVINELRYHLEESRDK—NVLLCLEERDW DTLRIO EDALPYDAFVVFDKTXSAVADWVYNELRGQLEECRGRW-ALRLCLEERDW

DTLR4 RGENIYDAFVIYSSQD ED VRNELVKNLEEGVPP FQLCLHYRDF

DTLR5 PDMYKYDAYLCFSSKD FT VQNALLKHLDTQYSDQNRFNLCFEERDF

DTLR3 TEQFEYAAYIIHAYKD KDWVWEHFSSMEKEDQS LKFCLEERDF

DTLR1 VPGKSIVENIITC-IEKSYKSIFVLSPNFVQSE CH-YELYFAHHNLFHE

DTLR9 VPGKSIVENIINC-IEKSYKSIFVLSPNFVQSEWCH-YELYFAHHNLFHE

DTLR8 DPGKSISENIVSF-IEKSYKSIFVLSPNFVQNE CH-YEFYFAHHNLFHE

DTLR2 IPGK IIDNIIDS-IEKSHKTVFVLSENFVKSEWCK-YELDFSHFRLFEE

DTLR6 LPGQPVLENLSQS-IQLSKKTVFVMTDKYAKTENFK-IAFYLSHQRLMDE

DTLR7 DPGLAIIDNLMQS-INQSKKTVFVLTKKYAKSWNFK-TAFYLXLQRLMGE

DTLRIO LPGKTLFENL AS-VYGSRKTLFVLAHTDRVSGLLR-AIFLLAQQRLLE-

DTLR4 IPGVAIAANIIHEGFHKSRKVIVVVSQHFIQSRWCI-FEYEIAQTWQFLS

DTLR5 VPGENRIANIQDA-I NSRKIVCLVSRHFLRDG CL-EAFSYAQGRCLSD

DTLR3 EAGVFELEAIVNS-IKRSRKHFVITHHLLKDPLCKRFKVHHAVQQAIEQ

DTLR1 GSNSLILILLEPIPQYSIPSSYHKLKSLMARRTYLEWPKEKSKRGLFWAN

DTLR9 GSNNLILILLEPIPQNSIPNKYHKLKALMTQRTYLQWPKEKSKRGLFWA- DTLR8 NSDHIILILLEPIPFYCIPTRYHKLEALLEKKAYLEWPKDRRKCGLFWAN

DTLR2 NNDAAILILLEPIEKKAIPQRFCKLRKIMNTKTYLE PMDEAQREGFWVN

DTLR6 KVDVHLIFLEKPFQK SKFLQLRKRLCGSSVLE PTNPQAHPYF QC

DTLR7 NMDVHFILLEPVLQH SPYLRLRQRICKSSILQWPDNPKAERLFWQT

DTLRIO DTLR4 SRAGI I FIVLQKVEKT-LLRQQVELYRLLSRNTYLE EDSVLGRHIF RR

DTLR5 LNSALIMVWGSLSQY-QLMKHQSIRGFVQKQQYLRWPEDLQDVGWFLHK

DTLR3 NLDSIILVFLEEI PDYKLNHALCLRRGMFKSHCILNWPVQKERIGAFRHK

DTLRl LRAAINIKLTEQAKK

DTLR9

DTLR8 LRAAVNVNVLATREMYELQTFTELNEESRGSTISLMRTDCL

DTLR2 LRAAIKS

DTLR6 LKNALATDNHVAYSQVFKETV

DTLR7 LXNVVLTENDSRYNNMYVDSIKQY

DTLRIO

DTLR4 LRKALLDGKSWNPEGTVGTGCNWQEATSI

DTLR5 LSQQILKKEKEKKKDNNI PLQTVATIS

DTLR3 LQVALGSKNSVH Transmembrane segments correspond approximately to 802-818 (791-823) of primate DTLR7 SEQ ID NO: 37; 559-575 (550-586) of DTLR8 SEQ ID NO: 39; 553-569 (549-582) of DTLR9 SEQ ID NO: 41; 796-810 (790-814) of DTLRIO SEQ ID NO: 43; and 481-497 (475-503) of DTLRIO SEQ ID NO: 45. As used herein, the term DNAX Toll like receptor 2 (DTLR2) shall be used to describe a protein comprising a protein or peptide segment .having or sharing the amino acid sequence shown in Table 2, or a substantial fragment thereof. Similarly, with a DTLR3 and Table 3; DTLR4 and Table 4; DTLR5 and Table 5; DTLR6 and Table 6; DTLR7 and Table 7; DTLR8 and Table 8; DTLR9 and Table 9; and DTLRIO and Table 10. Rodent, e.g., mouse, DTLR11 sequence is provided, e.g., in EST AA739083; DTLR13 in ESTAI019567; DTLR14 in ESTs AI390330 and AA244663.

The invention also includes a protein variations of the respective DTLR allele whose sequence is provided, e.g., a mutein agonist or antagonist. Typically, such agonists or antagonists will exhibit less than about 10% sequence differences, and thus will often have between 1- and 11-fold substitutions, e.g., 2-, 3-, 5-, 7-fold, and others. It also encompasses allelic and other variants, e.g., natural polymorphic, of the protein described. Typically, it will bind to its corresponding biological receptor with high affinity, e.g., at least about 100 nM, usually better than about 30 nM, preferably better than about 10 nM, and more preferably at better than about 3 nM. The term shall also be used herein to refer to related naturally occurring forms, e.g., alleles, polymorphic variants, and metabolic variants of the mammalian protein.

This invention also encompasses proteins or peptides having substantial amino acid sequence identity with the amino acid sequence in Table 2. It will include sequence variants with relatively few substitutions, e.g., preferably less than about 3-5. Similar features apply to the other DTLR sequences provided in Tables 3, 4, 5, 6, 7, 8, 9, or 10.

A substantial polypeptide "fragment", or "segment", is a stretch of amino acid residues of at least about 8 amino acids, generally at least 10-amino acids, more generally at least 12 amino acids, often at least 14 amino acids, more often at least 16 amino acids, typically at least 18 amino acids, more typically at least 20 amino acids, usually at least 22 amino acids, more usually at least 24 amino acids, preferably at least 26 amino acids, more preferably at least 28 amino acids, and, in particularly preferred embodiments, at least about 30 or more amino acids. Sequences of segments of different proteins can be compared to one another over appropriate length stretches.

Amino acid sequence homology, or sequence identity, is determined by optimizing residue matches, if necessary, by introducing gaps as required. See, e.g., Needleham, et al., (1970) J. Mol. Biol. 48:443-453; Sankoff, et al., (1983) chapter one in Time Warps, String Edits, and Macromolecules : The Theory and Practice of Sequence Comparison, Addison-Wesley, Reading, MA; and software packages from IntelliGenetics, Mountain View, CA; the University of Wisconsin Genetics Computer Group (GCG) , Madison, WI; and the NCBI (NIH) ; each of which is incorporated herein by reference. This changes when considering conservative substitutions as matches. Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid; asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine. Homologous amino acid sequences are intended to include natural allelic and interspecies variations in the cytokine sequence. Typical homologous proteins or peptides will have from 50-100% homology (if gaps can be introduced), to 60-100% homology (if conservative substitutions are included) with an amino acid sequence segment of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10. Homology measures will be at least about 70%, generally at least 76%, more generally at least 81%, often at least 85%, more often at least 88%, typically at least 90%, more typically at least 92%, usually at least 94%, more usually at least 95%, preferably at least 96%, and more preferably at least 97%, and in particularly preferred embodiments, at least 98% or more. The degree of homology will vary with the length of the compared segments. Homologous proteins or peptides, such as the allelic variants, will share most biological activities with the embodiments described in Table 2, 3, 4, 6, 7, 8, 9, or 10. Particularly interesting regions of comparison, at the amino acid or nucleotide levels, correspond to those within each of the blocks 1-10, or intrablock regions, corresponding to those indicated in Figures 2A- 2B.

As used herein, the term "biological activity" is used to describe, without limitation, effects on inflammatory responses, innate immunity, and/or morphogenic development by respective ligands. For example, these receptors should, like IL-1 receptors, mediate phosphatase or phosphorylase activities, which activities are easily measured by standard procedures.

See, e.g., Hardie, et al. (eds. 1995) The Protein Kinase FactBook vols. I and II, Academic Press, San Diego, CA; Hanks, et al. (1991) Meth. Enzymol. 200:38-62; Hunter, et al. (1992) Cell 70:375-388; Lewin (1990) Cell 61:743-752; Pines, et al. (1991) Cold Spring Harbor Symp. Quant. Biol. 56:449-463; and Parker, et al. (1993) Nature 363:736-738. The receptors exhibit biological activities much like regulatable enzymes, regulated by ligand binding. However, the enzyme turnover number is more close to an enzyme than a receptor complex. Moreover, the numbers of occupied receptors necessary to induce such enzymatic activity is less than most receptor systems, and may number closer to dozens per cell, in contrast to most receptors which will trigger at numbers in the thousands per cell. The receptors, or portions thereof, may be useful as phosphate labeling enzymes to label general or specific substrates.

The terms ligand, agonist, antagonist, and analog of, e.g., a DTLR, include molecules that modulate the characteristic cellular responses to Toll ligand like proteins, as well as molecules possessing the more standard structural binding competition features of ligand-receptor interactions, e.g., where the receptor is a natural receptor or an antibody. The cellular responses likely are mediated through binding of various Toll ligands to cellular receptors related to, but possibly distinct from, the type I or type II IL-1 receptors. See, e.g., Belvin and Anderson (1996) Ann. Rev. Cell Dev. Biol. 12:393-416; Morisato and Anderson (1995) Ann. Rev. Genetics 29:371-3991 and Hultmark (1994) Nature 367:116- 117.

Also, a ligand is a molecule which serves either as a natural ligand to which said receptor, or an analog thereof, binds, or a molecule which is a functional analog of the natural ligand. The functional analog may be a ligand with structural modifications, or may be a wholly unrelated molecule which has a molecular shape which interacts with the appropriate ligand binding determinants. The ligands may serve as agonists or antagonists, see, e.g., Goodman, et al. (eds. 1990) Goodman & Gilman's: The Pharmacological Bases of Therapeutics, Pergamon Press, New York.

Rational drug design may also be based upon structural studies of the molecular shapes of a receptor or antibody and other effectors or ligands. Effectors may be other proteins which mediate other functions in response to ligand binding, or other proteins which normally interact with the receptor. One means for determining which sites interact with specific other proteins is a physical structure determination, e.g., x- ray crystallography or 2 dimensional^' NMR techniques. These will provide guidance as to which amino acid residues form molecular contact regions. For a detailed description of protein structural determination, see, e.g., Blundell and Johnson (1976) Protein Crystallography, Academic Press, New York, which is hereby incorporated herein by reference.

II. Activities

The Toll like receptor proteins will have a number of different biological activities, e.g., in phosphate metabolism, being added to or removed from specific substrates, typically proteins. Such will generally result in modulation of an inflammatory function, other innate immunity response, or a morphological effect. The DTLR2, 3, 4, 5, 6, 7, 8, 9, or 10 proteins are homologous to other Toll like receptor proteins, but each have structural differences. For example, a human DTLR2 gene coding sequence probably has about 70% identity with the nucleotide coding sequence of mouse DTLR2. At the amino acid level, there is also likely to be reasonable identity.

The biological activities of the DTLRs will be related to addition or removal of phosphate moieties to substrates, typically in a specific manner, but occasionally in a non specific manner. Substrates may be identified, or conditions for enzymatic activity may be assayed by standard methods, e.g., as described in Hardie, et al. (eds. 1995) The Protein Kinase FactBook vols. I and II, Academic Press, San Diego, CA; Hanks, et al. (1991) Meth. Enzymol. 200:38-62; Hunter, et al. (1992) Cell 70:375-388; Lewin (1990) Cell 61:743-752; Pines, et al. (1991) Cold Spring Harbor Symp. Quant. Biol. 56:449-463; and Parker, et al. (1993) Nature 363:736-738.

III. Nucleic Acids This invention contemplates use of isolated nucleic acid or fragments, e.g., which encode these or closely related proteins, or fragments thereof, e.g., to encode a corresponding polypeptide, preferably one which is biologically active. In addition, this invention covers isolated or recombinant DNA which encodes such proteins or polypeptides having characteristic sequences of the respective DTLRs, individually or as a group. Typically, the nucleic acid is capable of hybridizing, under appropriate conditions, with a nucleic acid sequence segment shown in Tables 2-10, but preferably not with a corresponding segment of Table 1. Said biologically active protein or polypeptide can be a full length protein, or fragment, and will typically have a segment of amino acid sequence highly homologous to one shown in Tables 2-10. Further, this invention covers the use of isolated or recombinant nucleic acid, or fragments thereof, which encode proteins having fragments which are equivalent to the DTLR2-10 proteins. The isolated nucleic acids can have the respective regulatory sequences in the 5' and 3' flanks, e.g., promoters, enhancers, poly-A addition signals, and others from the natural gene.

An "isolated" nucleic acid is a nucleic acid, e.g., an RNA, DNA, or a mixed polymer, which is substantially pure, e.g., separated from other components which naturally accompany a native sequence, such as ribosomes, polymerases, and flanking genomic sequences from the originating species. The term embraces a nucleic acid sequence which has been removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates, which are thereby distinguishable from naturally occurring compositions, and chemically synthesized analogs or analogs biologically synthesized by heterologous systems. A substantially pure molecule includes isolated forms of the molecule, either completely or substantially pure. An isolated nucleic acid will. generally be a homogeneous composition of molecules, but will, in some embodiments, contain heterogeneity, preferably minor. This heterogeneity is typically found at the polymer ends or portions not critical to a desired biological function or activity.

A " recombinant" nucleic acid is typically defined either by its method of production or its structure. In reference to its method of production, e.g., a product made by a process, the process is use of recombinant nucleic acid techniques, e.g., involving human intervention in the nucleotide sequence. Typically this intervention involves in vitro manipulation, although under certain circumstances it may involve more classical animal breeding techniques. Alternatively, it can be a nucleic acid made by generating a sequence 'comprising fusion of two fragments which are not naturally contiguous to each other, but is meant to exclude products of nature, e.g., naturally occurring mutants as found in their natural state. Thus, for example, products made by transforming cells with any unnaturally occurring vector is encompassed, as are nucleic acids comprising sequence derived using any synthetic oligonucleotide process. Such a process is often done to replace a codon with a redundant codon encoding the same or a conservative amino acid, while typically introducing or removing a restriction enzyme sequence recognition site. Alternatively, the process is performed to join together nucleic acid segments of desired functions to generate a single genetic entity comprising a desired combination of functions not found in the commonly available natural forms, e.g., encoding a fusion protein. Restriction enzyme recognition sites are often the target of such artificial manipulations, but other site specific targets, e.g., promoters, DNA replication sites, regulation sequences, control sequences, or other useful features may be incorporated by design. A similar concept is intended for a recombinant, e.g., fusion, polypeptide. This will include a dimeric repeat. Specifically included are synthetic nucleic acids which, by genetic code redundancy, encode equivalent polypeptides to fragments of DTLR2-5 and fusions of sequences from various different related molecules, e.g., other IL-1 receptor family members.

A " fragment" in a nucleic acid context is a contiguous segment of at least about 17 nucleotides, generally at least 21 nucleotides, more generally at least 25 nucleotides, ordinarily at least 30 nucleotides, more ordinarily at least 35 nucleotides, often at least 39 nucleotides, more often at least 45 nucleotides, typically at least 50 nucleotides, more typically at least 55 nucleotides, usually at least 60 nucleotides, more usually at least 66 nucleotides, preferably at least 72 nucleotides, more preferably at least 79 nucleotides, and in particularly preferred embodiments will be at least 85 or more nucleotides. Typically, fragments of different genetic sequences can be compared to one another over appropriate length stretches, particularly defined segments such as the domains described below.

A nucleic acid which codes for a DTLR2-10 will be particularly useful to identify genes, mRNA, and cDNA species which code for itself or closely related proteins, as well as DNAs which code for polymorphic, allelic, or other genetic variants, e.g., from different individuals or related species. Preferred probes for such screens are those regions of the interleukin which are conserved between different polymorphic variants or which contain nucleotides which lack specificity, and will preferably be full length or nearly so. In other situations, polymorphic variant specific sequences will be more useful.

This invention further covers recombinant nucleic acid molecules and fragments having/a nucleic acid sequence identical to or highly homologous to the isolated DNA set forth herein. In particular, the sequences will often be operably linked to DNA segments which control transcription, translation, and DNA replication. These additional segments typically assist in expression of the desired nucleic acid segment.

Homologous, or highly identical, nucleic acid sequences, when compared to one another or Table 2-10 sequences, exhibit significant -similarity. The standards for homology in nucleic acids are either measures for homology generally used in the art by sequence comparison or based upon hybridization conditions. Comparative hybridization conditions are described in greater detail below.

Substantial identity in the nucleic acid sequence comparison context means either that the segments, or their complementary strands, when compared, are identical when optimally aligned, with appropriate nucleotide insertions or deletions, in at least about 60% of the nucleotides, generally at least 66%, ordinarily at least 71%, often at least 76%, more often at least 80%, usually at least 84%, more usually at least 88%, typically at least 91%, more typically at least about 93%, preferably at least about 95%, more preferably at least about 96 to 98% or more, and in particular embodiments, as high at about 99% or more of the nucleotides, including, e.g., segments encoding structural domains such as the segments described below. Alternatively, substantial identity will exist when the segments will hybridize under selective hybridization conditions, to a strand or its complement, typically using a sequence derived from Tables 2-10.

Typically, selective hybridization will occur when there is at least about 55% homology over a stretch of at least about 14 nucleotides, more typically at least about 65%, preferably at least about 75%, and more preferably at least about 90%. See, Kanehisa (1984) Nucl. Acids Res. 12:203-213, which is incorporated herein by reference. The length of homology comparison, as described, may be over longer stretches, and in certain embodiments will be over a stretch of at least about 17 nucleotides, generally at least about 20 nucleotides, ordinarily at least about 24 nucleotides, usually at least about 28 nucleotides, typically at least about 32 nucleotides, more typically at least about 40 nucleotides, preferably at least about 50 nucleotides, and more preferably at least about 75 to 100 or more nucleotides. Stringent conditions, in referring to homology in the hybridization context, will be stringent combined conditions of salt, temperature, organic solvents, and other parameters typically controlled in hybridization reactions. Stringent temperature conditions will usually include temperatures in excess of about 30° C, more usually in excess of about 37° C, typically in excess of about 45° C, more typically- in excess of about 55° C, preferably in excess of about 65° C, and more preferably in excess of about 70° C. Stringent salt conditions will ordinarily be less than about 500 M, usually less than about 400 mM, more usually less than about 300 mM, typically less than about 200 mM, preferably less than about 100 mM, and ^'more preferably less than about 80 mM, even down to less than about 20 mM. However, the combination of parameters is much more important than the measure of any single parameter. See, e.g., Wetmur and Davidson (1968) J. Mol. Biol. 31:349-370, which is hereby incorporated herein by reference.

Alternatively, for sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison^' algorithm then calculates the percent sequence identity for the test sequence (s) relative to the reference sequence, based on the designated program parameters.

Optical alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2:482, by the homology alignment algorithm of Needlman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat'l Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the

Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI) , or by visual inspection (see generally Ausubel et al . , supra).

One example of a useful algorithm is PILEUP. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments to show relationship and percent sequence identity. It also plots a tree or dendrogram showing the clustering relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng and Doolittle (1987) J. Mol. Evol. 35:351-360. The method used is similar to the method described by Higgins and Sharp (1989) CABIPS 5:151-153. The program can align up to 300 sequences, each of a maximum length of 5,000 nucleotides or amino acids. The multiple alignment procedure begins with the pairwise alignment of the two most similar sequences, producing a cluster of two aligned sequences. This cluster is then aligned to the next most related sequence or cluster of aligned sequences. Two clusters of sequences are aligned by a simple extension of the pairwise alignment of two individual sequences. The final alignment is achieved by a series of progressive, pairwise alignments. The program is run by designating specific sequences and their amino acid or nucleotide coordinates for regions of sequence/comparison and by designating the program parameters _t For example, a reference sequence can be compared to other test sequences to determine the percent sequence identity relationship using the following parameters: default gap weight (3.00), default gap length weight (0.10), and weighted end gaps. Another example of algorithm that is suitable for determining percent sequence identity and sequence similarity is the BLAST algorithm, which is described Altschul, et al. (1990) J. Mol. Biol. 215:403-410. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology

Information (http:www.ncbi.nlm.nih.gov/) . This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive- valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul, et al . , supra) . These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are then extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative- scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLAST program uses as defaults a wordlength (W) of 11, the BL0SUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Nat'l Acad. Sci. USA 89:10915) alignments (B) of 50, expectation (E) of 10, M=5, N=4, and a comparison of both strands .

In addition to calculating percent sequence identity, the BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Nat'l Acad. Sci. USA 90:5873- 5787) . One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.

A further indication that two nucleic acid sequences of polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross reactive with the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, e.g., where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under stringent conditions, as described below. The isolated DNA can be readily modified by nucleotide substitutions, nucleotide deletions, nucleotide insertions, and inversions of nucleotide stretches. These modifications result in novel DNA sequences which encode this protein or its derivatives. These modified sequences can be used to produce mutant proteins (muteins) or to enhance the expression of variant species. Enhanced expression may involve gene amplification, increased transcription, increased translation, and other mechanisms. Such mutant DTLR-like derivatives include predetermined or site-specific mutations of the protein or its fragments, including silent mutations using genetic code degeneracy.. "Mutant DTLR" as used herein encompasses a polypeptide otherwise falling within the homology definition of the DTLR as set forth above, but having an amino acid sequence which differs from that of other DTLRlike proteins as found in nature, whether by way of deletion, substitution, or insertion. In particular, "site specific mutant DTLR" encompasses a protein having substantial homology with a protein of Tables 2-10, and typically shares most of the biological activities or effects of the forms disclosed herein.

Although site specific mutation sites are predetermined, mutants need not be site specific. Mammalian DTLR mutagenesis can be achieved by making amino acid insertions or deletions in the gene, coupled with expression. Substitutions, deletions, insertions, or any combinations may be generated to arrive at a final construct. Insertions include amino- or carboxy- terminal fusions. Random mutagenesis can be conducted at a target codon and the expressed mammalian DTLR mutants can then be screened for the desired activity. Methods for making substitution mutations at predetermined sites in DNA having a known sequence are well known in the art, e.g., by M13 primer mutagenesis. See also Sambrook, et al. (1989) and Ausubel, et al. (1987 and periodic Supplements) .

The mutations in the DNA normally should not place coding sequences out of reading frames and preferably will not create complementary regions that could hybridize to produce secondary mRNA structure such as loops or hairpins. The phosphoramidite method described by Beaucage and Carruthers (1981) Tetra. Letts. 22:1859-1862, will produce suitable synthetic DNA fragments. A double stranded fragment will often be obtained eitjaer by synthesizing the complementary strand and annealing • the strand together under appropriate conditions or by adding the complementary strand using DNA polymerase with an appropriate primer sequence.

Polymerase chain reaction (PCR) techniques can often be applied in mutagenesis. Alternatively, mutagenesis primers are commonly used methods for generating defined mutations at predetermined sites. See, e.g., Innis, et al. (eds. 1990) PCR Protocols: A Guide to Methods and Applications Academic Press, San Diego, CA; and Dieffenbach and Dveksler (eds. 1995) PCR Primer: A Laboratory Manual Cold Spring Harbor Press, CSH, NY.

IV. Proteins, Peptides

As described above, the present invention encompasses primate DTLR2-10, e.g., whose sequences are disclosed in Tables 2-10, and described above. Allelic and other variants are also contemplated, including, e.g., fusion proteins combining portions of such sequences with others, including epitope tags and functional domains. The present invention also provides recombinant proteins, e.g., heterologous fusion proteins using segments from these rodent proteins. A heterologous fusion protein is ^'a fusion of proteins or segments which are naturally not normally fused in the same manner. Thus, the fusion product of a DTLR with an IL-1 receptor is a continuous protein molecule having sequences fused in a typical peptide linkage, typically made as a single translation product and exhibiting properties, e.g., sequence or antigenicity, derived from each source peptide. A similar concept applies to heterologous nucleic acid sequences. In addition, new constructs may be made from combining similar functional or structural domains from other related proteins, e.g., IL-1 receptors or other DTLRs, including species variants. -For example, ligand- binding or other segments may be " swapped" between different new fusion polypeptides or fragments. See, e.g., Cunningham, 'et al. (1989) Science 243 : 1330-1336; and O'Dowd, et al. (1988) J. Biol. Chem. 263:15985-15992, each of which is incorporated herein by reference. Thus, new chimeric polypeptides exhibiting new combinations of specificities will result from the functional linkage of receptor-binding specificities. For example, the ligand binding domains from other related receptor molecules may be added or substituted for other domains of this or related proteins. The resulting protein will often have hybrid function and properties. For example, a fusion protein may include a targeting domain which may serve to provide sequestering of the fusion protein to a particular subcellular organelle. Candidate fusion partners and sequences can be selected from various sequence data bases, e.g., GenBank, c/o IntelliGenetics, Mountain View, CA; and BCG, University of Wisconsin Biotechnology Computing Group, Madison, WI, which are each incorporated herein by reference.

The present invention particularly provides muteins which bind Toll ligands, and/or which are affected in signal transduction. Structural alignment of human DTLR1- 10 with other members of the IL-1 family show conserved features/residues. See, e.g., Figure 3A. Alignment of the human DTLR sequences with other members of the IL-1 family indicates various structural and functionally shared features. See also, Bazan, et al. (1996) Nature 379:591; Lodi, et al. (1994) Science 263:1762-1766; Sayle and Milner-White (1995) TIBS 20:374-376; and Gronenberg, et al. (1991) Protein Engineering 4:263-269. The IL-lα and IL-lβ ligands bind an IL-1 receptor type I as the primary receptor and this complex then forms a high affinity receptor complex with the IL-1 receptor type III. Such receptor subunits are probably shared with the new IL-1 family members.

Similar variations in other species counterparts of DTLR2-10 sequences, e.g., in the corresponding regions, should provide similar interactions with ligand or substrate. Substitutions with either mouse sequences or human sequences are particularly preferred. Conversely, conservative substitutions away from the ligand binding interaction regions will probably preserve most signaling activities .

"Derivatives" of the primate DTLR2-10 include amino acid sequence mutants, glycosylation variants, metabolic derivatives and covalent or aggregative conjugates with other chemical moieties. Covalent derivatives can be prepared by linkage of functionalities to groups which are found in the DTLR amino acid side chains or at the N- or C- termini, e.g., by means which are well known in the art. These derivatives can include, without limitation, aliphatic esters or amides of the carboxyl terminus, or of residues containing carboxyl side chains, O-acyl derivatives of hydroxyl group-containing residues, and N-acyl derivatives of the amino terminal amino acid or amino-group containing residues, e.g., lysine or arginine. Acyl groups are selected from the group of alkyl-moieties including C3 to C18 normal alkyl, thereby forming alkanoyl aroyl species. In particular, glycosylation alterations are included, e.g., made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing, or in further processing steps. Particularly preferred means for accomplishing this are by exposing the polypeptide to glycosylating enzymes derived from cells which normally provide such processing, e.g., mammalian glycosylation enzymes. Deglycosylation enzymes are also contemplated. Also embraced are versions of the same primary amino acid sequence which have other minor modifications, including phosphorylated amino acid residues, e.g., phosphotyrosine, phosphoserine, or phosphothreonine.

A major group of derivatives are covalent conjugates of the receptors or fragments thereof with other proteins of polypeptides. These derivatives can be synthesized in recombinant culture such as N- or C-terminal fusions or by the use of agents known in the art for their usefulness in cross-linking proteins through reactive side groups. Preferred derivatization sites with cross-linking agents are at free amino groups, carbohydrate moieties, and cysteine residues.

Fusion polypeptides between the receptors and other homologous or heterologous proteins are also provided. Homologous polypeptides may be fusions between different receptors, resulting in, for instance, a hybrid protein exhibiting binding specificity for multiple different Toll ligands, or a receptor which may have broadened or weakened specificity of substrate effect. Likewise, heterologous fusions may be constructed which would exhibit a combination of properties or activities of the derivative proteins. Typical examples are fusions of a reporter polypeptide, e.g., luciferase, with a segment or domain of a receptor, e.g., a ligand-binding segment, so that the presence or location of a desired ligand may be easily determined. See, e.g., Dull, et al., U.S. Patent No. 4,859,609, which is hereby incorporated herein by reference. Other gene fusion partners include glutathione-S-transferase (GST) , bacterial β- galactosidase, trpE, Protein A, β-lactamase, alpha amylase, alcohol dehydrogenase, and yeast alpha mating factor. See, e.g., Godowski, et al. (1988) Science 241:812-816. The phosphoramidite method described by Beaucage and Carruthers (1981) Tetra. Letts. 22:1859-1862, will produce suitable synthetic DNA fragments. A double stranded fragment will often be obtained either by synthesizing the complementary strand and annealing -the strand together under appropriate conditions or by adding the complementary strand using DNA polymerase with an appropriate primer sequence.

Such polypeptides may also have amino acid residues which have been chemically modified by phosphorylation, sulfonation, biotinylation, or the addition or removal of other moieties, particularly those which have molecular shapes similar to phosphate groups. In some embodiments, the modifications will be useful labeling reagents, or serve as purification targets, e.g., affinity ligands. Fusion proteins will typically be made by either recombinant nucleic acid methods or by synthetic polypeptide methods. Techniques for nucleic acid manipulation and expression are described generally, for example, in Sambrook, et al. (1989) Molecular Cloning: A Laboratory Manual (2d ed. ) , Vols. 1-3, Cold Spring Harbor Laboratory, and Ausubel, et al . (eds. 1987 and periodic supplements) Current Protocols in Molecular Biology, ^"" Greene/Wiley, New York, which are each incorporated herein by reference. Techniques for synthesis of polypeptides are described, for example, in Merrifield (1963) J. Amer. Chem. Soc. 85:2149-2156; Merrifield ^' (1986) Science 232: 341-347; and Atherton, et al . (1989) 'Solid Phase Peptide Synthesis: A Practical Approach, IRL Press, Oxford; each of which is incorporated herein by reference. See also Dawson, et al. (1994) Science 266:776-779 for methods to make larger polypeptides.

This invention also contemplates the use of derivatives of a DTLR2-10 other than variations in amino acid sequence or glycosylation. Such derivatives may ' involve covalent or aggregative association with chemical moieties. These derivatives generally fall into three classes: (1) salts, (2) side chain and terminal residue covalent modifications, and (3) adsorption complexes, for example with cell membranes. Such covalent or aggregative derivatives are useful as immunogens, as reagents in i munoassays, or in purification methods such as for affinity purification of a receptor or other binding molecule, e.g., an antibody. For example, a Toll ligand can be immobilized by covalent bonding to a solid support such as cyanogen bromide-activated Sepharose, by methods which are well known in the art, or adsorbed onto polyolefin surfaces, with or without glutaraldehyde cross-linking, for use in the assay or purification of a DTLR receptor, antibodies, or other similar molecules. The ligand can also be labeled with a detectable group, for example radioiodinated by the chloramine T procedure, covalently bound to rare earth chelates, or conjugated to another fluorescent moiety for use in diagnostic assays. A DTLR of this invention can be used as an immunogen for the production of antisera or antibodies specific, e.g., capable of distinguishing between other IL-1 receptor family members, for the DTLR or various fragments thereof. The purified DTLR can be used to screen monoclonal antibodies or antigen-binding fragments prepared by immunization with various forms of impure preparations containing the protein. In particular, the term "antibodies" also encompasses antigen binding fragments of natural antibodies, e.g., Fab, Fab2, Fv, etc. The purified DTLR can also be used as a reagent to detect antibodies generated in response to the presence of elevated levels of expression, or immunological disorders which lead to antibody production to the endogenous receptor. Additionally, DTLR fragments may also serve as immunogens to produce the antibodies of the present invention, as described immediately below. For example, this invention contemplates antibodies having binding affinity to or being raised against the amino acid sequences shown in Tables 2-10, fragments thereof, or various homologous peptides. In particular, this invention contemplates antibodies having binding affinity to, or having been raised against, 'Specific fragments which are predicted to be, or actually are, exposed at the exterior protein surface of the native DTLR.

The blocking of physiological response to the receptor ligands may result from the inhibition of binding of the ligand to the receptor, likely through competitive inhibition. Thus, in vitro assays of the present invention will often use antibodies or antigen binding segments of these antibodies, or fragments attached to solid phase substrates. These assays will also allow for the diagnostic determination of the effects of either ligand binding region mutations and modifications, or other mutations and modifications, e.g., which affect signaling or enzymatic function.

This invention also contemplates the use of competitive drug screening assays, e.g., where neutralizing antibodies to the receptor or fragments compete with a test compound for binding to a ligand or other antibody. In this manner, the neutralizing antibodies or fragments can be used to detect the presence of a polypeptide which shares one or more binding sites to a receptor and can also be used to occupy binding sites on a receptor that might otherwise bind a ligand.

V. Making Nucleic Acids and Protein DNA which encodes the protein or fragments thereof can be obtained by chemical synthesis, screening cDNA libraries, or by screening genomic libraries prepared from a wide variety of cell lines or tissue samples. Natural sequences can be isolated using standard methods and the sequences provided herein, e.g., in Tables 2-10. Other species counterparts can be identified by hybridization techniques, or by various PCR techniques, combined with or by searching in sequence databases, e.g., GenBank.

This DNA can be expressed in a wide variety of host cells for the synthesis of a full-length receptor or fragments which can in turn, for example, be used to generate polyclonal or monoclonal antibodies; for binding studies; for construction and expression of modified ligand binding or kinase/phosphatase domains; and for structure/function studies. Variants or fragments can be expressed in host cells that are transformed or transfected with appropriate expression vectors. These molecules can be substantially free of protein or cellular contaminants, other than those derived from the recombinant host, and therefore are particularly useful in pharmaceutical compositions when combined with a pharmaceutically acceptable carrier and/or diluent. The protein, or portions thereof, may be expressed as fusions with other proteins.

Expression vectors are typically self-replicating DNA or RNA constructs containing the desired receptor gene or its fragments, usually operably linked to suitable genetic control elements that are recognized in a suitable host cell. These control elements are capable of effecting expression within a suitable host. The specific type of control elements necessary to effect expression will depend upon the eventual host cell used. Generally, the genetic control elements can include a prokaryotic promoter system or a eukaryotic promoter expression control system, and typically include a transcriptional promoter, an optional operator to control the onset of transcription, transcription enhancers to elevate the level of mRNA expression, a sequence that encodes a suitable ribosome binding site, and sequences that terminate transcription and translation. Expression vectors also usually contain an origin of replication that allows the vector to replicate independently of the host cell.

The vectors of this invention include those which contain DNA which encodes a protein/ as described, or a fragment thereof encoding a biologically active equivalent polypeptide. The DNA can be under the control of a viral promoter and can encode a selection marker. This invention further contemplates use of such expression vectors which are capable of expressing eukaryotic cDNA coding for such a protein in a prokaryotic or eukaryotic host, where the vector is compatible with the host and where the eukaryotic cDNA coding for the receptor is inserted into the vector such that growth of the host containing the vector expresses the cDNA in question. Usually, expression vectors are designed for stable replication in their host cells or for amplification to greatly increase the total number of copies of the desirable gene per cell. It is not always necessary to require that an expression vector replicate in a host cell, e.g., it is possible to effect transient expression of the protein or its fragments in various hosts using vectors that do not contain a replication origin that is recognized by the host cell. It is also possible to use vectors that cause integration of the protein encoding portion or its fragments into the host DNA by recombination.

Vectors, as used herein, comprise plasmids, viruses, bacteriophage, integratable DNA fragments, and other vehicles which enable the integration of DNA fragments into the genome of the host. Expression vectors are specialized vectors which contain genetic control elements that effect expression of operably linked genes. Plasmids are the most commonly used form of vector but all other forms of vectors which serve an equivalent function and which are, or become, known in the art are suitable for use herein. See, e.g., Pouwels, et al. (1985 and Supplements) Cloning Vectors: A Laboratory Manual, Elsevier, N.Y., and Rodriquez, et al . (eds.) Vectors: A Survey of Molecular Cloning Vectors and Their Uses, Buttersworth, Boston, 1988, which are incorporated herein by reference.

Transformed cells are cells, preferably mammalian, that have been transformed or transfected with receptor vectors constructed using recombinant DNA techniques. Transformed host cells usually express the desired protein or its fragments, but for purposes of cloning, amplifying, and manipulating its DNA, do not need to express the subject protein. This invention further contemplates culturing transformed cells in a nutrient medium, thus permitting the receptor to accumulate in the cell membrane. The protein can be recovered, either from the culture or, in certain instances, from the culture medium. For purposes of this invention, nucleic sequences are operably linked when they are functionally related to each other. For example, DNA for a presequence or secretory leader is operably linked to a polypeptide if it is expressed as a preprotein or participates in directing the polypeptide to the cell membrane or in secretion of the polypeptide. A promoter is operably linked to a coding sequence if it controls the transcription of the polypeptide; a ribosome binding site is operably linked to a coding sequence if it is positioned to permit translation. Usually, operably linked means contiguous and_ in reading frame, however, certain genetic elements such as repressor genes are not contiguously linked but still bind to operator sequences that in turn control expression.

Suitable host cells include prokaryotes, lower eukaryotes, and higher eukaryotes. Prokaryotes include both gram negative and gram positive organisms, e.g., E^ coli and B. subtilis. Lower eukaryotes include yeasts, e.g., S. cerevisiae and Pichia, and species of the genus Dictyostelium. Higher eukaryotes include established tissue culture cell lines from animal cells, both of non-mammalian origin, e.g., insect cells, and birds, and of mammalian origin, e.g., human, primates, and rodents. Prokaryotic host-vector systems include a wide variety of vectors for many different species. As used herein, E. coli and its vectors will be used generically to include equivalent vectors used in other prokaryotes. A representative vector for amplifying DNA is pBR322 or many of its derivatives. Vectors that can be used to express the receptor or its fragments include, but are not limited to, such vectors as those containing the lac promoter (pUC-series) ; trp promoter (pBR322-trp) ; Ipp promoter (the. pIN-series) ; lambda-pP or pR promoters (pOTS) ; or hybrid promoters such as ptac (pDR540) . See Brosius, et al. (1988) "Expression Vectors Employing Lambda-, trp-, lac-, and Ipp-derived Promoters", in Vectors: A Survey of Molecular Cloning Vectors and Their Uses, (eds. Rodriguez and Denhardt) , Buttersworth, Boston, Chapter 10, pp. 205-236, which is incorporated herein by reference.

Lower eukaryotes, e.g., yeasts and Dictyostelium, may be transformed with DTLR sequence containing vectors. For purposes of this invention, the most common lower eukaryotic host is the baker's yeast, Saccharomyces cerevisiae . It will be used to generically represent lower eukaryotes although a number of other strains and species are also available. Yeast vectors typically consist of a replication origin (unless of the integrating type) , a selection gene, a promoter, DNA encoding the receptor or its fragments, and sequences for translation termination, polyadenylation, and transcription termination. Suitable expression vectors for yeast include such constitutive promoters as 3-phosphoglycerate kinase and various other glycolytic enzyme gene promoters or such inducible promoters as the alcohol dehydrogenase 2 promoter or metallothionine promoter. Suitable vectors include derivatives of the following types: self-replicating low copy number (such as the YRp-series) , self-replicating high copy number (such as the YEp-series) ; integrating types (such as the Ylp-series) , or mini-chromosomes (such as the YCp-series) .

Higher eukaryotic tissue culture cells are normally the preferred host cells for expression of the functionally active interleukin protein. In principle, any higher eukaryotic tissue culture cell line is workable, e.g., insect baculovirus expression systems, whether from an invertebrate or vertebrate source. However, mammalian cells are preferred. Transformation or transfection and propagation of such cells has become a routine procedure. Examples of useful cell lines include HeLa cells, Chinese hamster ovary (CHO) cell lines, baby rat kidney (BRK) cell lines, insect cell lines, bird cell lines, and monkey (COS) cell lines. Expression vectors for such cell lines usually include an origin of replication, a promoter, a translation initiation site, RNA splice sites (if genomic DNA is used) , a polyadenylation site, and a transcription termination site. These vectors also usually contain a selection gene or amplification gene. Suitable expression vectors may be plasmids, viruses, or retroviruses carrying promoters derived, e.g., from such sources as from adenovirus, SV40, parvoviruses, vaccinia virus, or cytomegalovirus . Representative examples of suitable expression vectors include pCDNAl; pCD, see Okayama, et al. (1985) Mol. Cell Biol. 5:1136-1142; pMClneo PolyA, see Thomas, et al.

(1987) Cell 51:503-512; and a baculovirus vector such as pAC 373 or pAC 610.

For secreted proteins, an open reading frame usually encodes a polypeptide that consists of a mature or secreted product covalently linked at its N-terminus to a signal peptide. The signal peptide is cleaved prior to secretion of the mature, or active, polypeptide. The cleavage site can be predicted with a high degree of accuracy from empirical rules, e.g., von-Heijne (1986) Nucleic Acids Research 14:4683-4690/ and the precise amino acid composition of the signal peptide does not appear to be critical to its function, e.g., Randall, et al. (1989) Science 243:1156-1159; Kaiser, et al. (1987) Science 235:312-317.

It will often be desired to express these polypeptides in a system which provides a specific or defined glycosylation pattern. In this case, the usual pattern will be that provided naturally by the expression system. However, the pattern will be modifiable by exposing the polypeptide, e.g., an unglycosylated form, to appropriate glycosylating proteins introduced into a heterologous expression system. For example, the receptor gene may be co-transformed with one or more genes encoding mammalian or other glycosylating enzymes. Using this approach, certain mammalian glycosylation patterns will be achievable in prokaryote or other cells.

The source of DTLR can be a eukaryotic or prokaryotic host expressing recombinant DTLR, such as is described above. The source can also be a cell line such as mouse Swiss 3T3 fibroblasts, but other mammalian cell lines are also contemplated by this invention, with the preferred cell line being from the human species.

Now that the sequences are known, the primate DTLRs, fragments, or derivatives thereof can be prepared by conventional processes for synthesizing peptides. These include processes such as are described in Stewart and Young (1984) Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, IL; Bodanszky and Bodanszky (1984) The Practice of Peptide Synthesis, Springer-Verlag, New York; and Bodanszky (1984) The Principles of Peptide Synthesis, Springer-Verlag, New York; all of each which are incorporated herein by reference. For example, an azide process, an acid chloride process, an acid anhydride process, a mixed anhydride process, an active ester process (e.g., p-nitrophenyl ester, N-hydroxysuccinimide ester, or cyanomethyl ester), a carb diimidazole process, an oxidative-reductive process, or -a dicyclohexylcarbodiimide (DCCD) /additive process can be used. Solid phase and solution phase syntheses are both applicable to the foregoing processes. Similar techniques can be used with partial DTLR sequences. The DTLR proteins, fragments, or derivatives are suitably prepared in accordance with the above processes as typically employed in peptide synthesis, generally either by a so-called stepwise process which comprises condensing an amino acid to the terminal amino acid, one by one in sequence, or by coupling peptide fragments to the terminal amino acid. Amino groups that are not being used in the coupling reaction typically must be protected to prevent coupling at an incorrect location.

If a solid phase synthesis is adopted, the C-terminal amino acid is bound to an insoluble carrier or support through its carboxyl group. The insoluble carrier is not particularly limited as long as it has a binding capability to a reactive carboxyl group. Examples of such insoluble carriers include halomethyl resins, such as chloromethyl resin or bromomethyl resin, hydroxymethyl resins, phenol resins, tert-alkyloxycarbonylhydrazidated resins, and the like.

An amino group-protected amino acid is bound in sequence through condensation of its activated carboxyl group and the reactive amino group of the previously formed peptide or chain, to synthesize the peptide step by step. After synthesizing the complete sequence, the peptide is split off from the insoluble carrier to produce the peptide. This solid-phase approach is generally described by Merrifield, et al. (1963) in J. Am. Chem. Soc. 85:2149-2156, which is incorporated herein by reference .

The prepared protein and fragments thereof can be isolated and purified from the reaction mixture by means of peptide separation, for example,- by extraction, precipitation, electrophoresis, various forms of chromatography, and the like. The receptors of this invention can be obtained in varying degrees of purity depending upon desired uses. Purification can be accomplished by use of the protein purification techniques disclosed herein, see below, or by the use of the antibodies herein described in methods of immunoabsorbant affinity chromatography. This immunoabsorbant affinity chromatography is carried out by first linking the antibodies to a solid support and then contacting the linked antibodies with solubilized lysates of appropriate cells, lysates of other cells expressing the receptor, or lysates or supernatants of cells producing the protein as a result of DNA techniques, see below. Generally, the purified protein will be at least about 40% pure, ordinarily at least about 50% pure, usually at least about 60% pure, typically at least about 70% pure, more typically at least about 80% pure, preferable at least about 90% pure and more preferably at least about 95% pure, and in particular embodiments, 97%- 99% or more. Purity will usually be on a weight basis, but can also be on a molar basis. Different assays will be applied as appropriate.

VI. Antibodies

Antibodies can be raised to the various mammalian, e.g., primate DTLR proteins and fragments thereof, both in naturally occurring native forms and in their recombinant forms, the difference being that antibodies to the active receptor are more likely to recognize epitopes which are only present in the native conformations. Denatured antigen detection can also be useful in, e.g., Western analysis. Anti-idiotypic antibodies are also contemplated, which would be useful as agonists or antagonists of a natural receptor or^' an antibody. Preferred antibodies will exhibit properties of both affinity and selectivity. High affinity is generally preferred, while selectivity will allow distinction between various embodiment subsets. In particular, it will be desirable to possess antibody preparations characterized to bind, e.g., various specific combinations of related members while not binding others. Such various combinatorial subsets are specifically enabled, e.g., these reagents may be generated or selected using standard methods of immunoaffinity, selection, etc. Antibodies, including binding fragments and single chain versions, against predetermined fragments of the protein can be raised by immunization of animals with conjugates of the fragments with immunogenic proteins. Monoclonal antibodies are prepared from cells secreting the desired antibody. These antibodies can be screened for binding to normal or defective protein, or screened for agonistic or antagonistic activity. These monoclonal antibodies will usually bind with at least a K_D of about 1 mM, more usually at least about 300 μM, typically at least about lOOμM, more typically at least about 30 μM, preferably at least about 10 μM, and more preferably at least about 3 μM or better.

The antibodies, including antigen binding fragments, of this invention can have significant diagnostic or therapeutic value. They can be potent antagonists that bind to the receptor and inhibit binding to ligand or inhibit the ability of the receptor to elicit a biological response, e.g., act on its substrate. They also can be useful as non-neutralizing antibodies and can be coupled to toxins or radionuclides to bind producing cells, or cells localized to the source of the interleukin. Further, these antibodies can be conjugated to drugs or other therapeutic agents, either directly or indirectly by means of a linker.

The antibodies of this invention can also be useful in diagnostic applications. As capture or non-neutralizing antibodies, they might bind to the receptor without inhibiting ligand or substrate binding. As neutralizing antibodies, they can be useful in competitive binding assays. They will also be useful in detecting or quantifying ligand. They may be used as reagents for Western blot analysis, or for immunoprecipitation or immunopurification of the respective protein.

Protein fragments may be joined to other materials, particularly polypeptides, as fused or covalently joined polypeptides to be used as immunogens. Mammalian DTLR and its fragments may be fused or covalently linked to a variety of immunogens, such as keyhole limpet hemocyanin, bovine serum albumin, tetanus toxoid, etc. See Microbiology, Hoeber Medical Division, Harper and Row, 1969; Landsteiner (1962) Specificity of Serological Reactions, Dover Publications, New York; and Williams, et al. (1967) Methods in Immunology and Immunochemistry, Vol. 1, Academic Press, New York; each of which are incorporated herein by reference, for descriptions of methods of preparing polyclonal antisera. A typical method involves hyperimmunization of an animal with an antigen. The blood of the animal is then collected shortly after the repeated immunizations and the gamma globulin is isolated.

In some instances, it is desirable to prepare monoclonal antibodies from various mammalian hosts, such as mice, rodents, primates, humans, etc. Description of techniques for preparing such monoclonal antibodies may be found in, e.g., Stites, et al. (eds.) Basic and Clinical Immunology (4th ed.), Lange Medical Publications, Los Altos, CA, and references cited therein; Harlow and Lane (1988) Antibodies: A Laboratory Manual, CSH Press; Goding (1986) Monoclonal Antibodies: Principles and Practice (2d ed) Academic Press, New York; and particularly in Kohler and Milstein (1975) in Nature 256: .495-497, which discusses one method of generating monoclonal antibodies. Each of these references is incorporated herein by reference. Summarized briefly, this method involves injecting an animal with an immunogen. The animal is then sacrificed and cells taken from its spleen, which are then fused with myeloma cells. The result is a hybrid cell or "hybridoma" that is capable of reproducing in vitro. The population of hybridomas is then screened to isolate individual clones, each of which secrete a single antibody species to the immunogen. In this manner, the individual antibody species obtained are the products of immortalized and cloned single B cells from the immune animal generated in response to a specific site recognized on the immunogenic substance. Other suitable techniques involve in vitro exposure of lymphocytes to the antigenic polypeptides or alternatively to selection of libraries of antibodies in phage or similar vectors. See, Huse, et al. (1989) "Generation of a Large Combinatorial Library of the Immunoglobulin Repertoire in Phage Lambda," Science

246:1275-1281; and Ward, et al. (1989) Nature 341:544-546, each of which is hereby incorporated herein by reference. The polypeptides and antibodies of the present invention may be used with or without modification, including chimeric or humanized antibodies. Frequently, the polypeptides and antibodies will be labeled by joining, either covalently or non-covalently, a substance which provides for a detectable signal. A wide variety of labels and conjugation techniques are known and are reported extensively in both the scientific and patent literature. Suitable labels include radionuclides, enzymes, substrates, cofactors, inhibitors, fluorescent moieties, chemiluminescent moieties, magnetic particles, and the like. Patents, teaching the use of such labels include U.S. Patent Nos . 3, 817, 837; - 3, 850, 752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241. Also, recombinant or chimeric im unoglobulins may be produced, see Cabilly, U.S. Patent No. 4,816,567; or made in transgenic mice, see Mendez, et al. (1997) Nature Genetics 15:146-156. These references are incorporated herein by reference.

The antibodies of this invention can also be used for affinity chromatography in isolating the DTLRs. Columns can be prepared where the antibodies are linked to a solid support, e.g., particles, such as agarose, Sephadex, or the like, where a cell lysate may be passed through the column, the column washed, followed by increasing concentrations of a mild denaturant, whereby the purified protein will be released. The protein may be used to purify antibody. The antibodies may also be used to screen expression libraries for particular expression products. Usually the antibodies used in such a procedure will be labeled with a moiety allowing easy detection of presence of antigen by antibody binding. Antibodies raised against a DTLR will also be used to raise anti-idiotypic antibodies. These will be useful in detecting or diagnosing various immunological conditions related to expression of the protein or cells which express the protein. They also will be useful as agonists or antagonists of the ligand, which may be competitive inhibitors or substitutes for naturally occurring ligands. A DTLR protein that specifically binds to or that is specifically immunoreactive with an antibody generated against a defined immunogen, such as an immunogen consisting of the amino acid sequence of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24, is typically determined in an immunoassay. The immunoassay typically uses a polyclonal antiserum which was raised, e.g., to a protein of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24. This antiserum is selected to have low crossreactivity against other IL-IR family members, e.g., DTLR1, preferably from the same species, and any such crossreactivity is removed by immunoabsorption prior to use in the immunoassay.

In order to produce antisera for use in an immunoassay, the protein of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24, or a combination thereof, is isolated as described herein. For example, recombinant protein may be produced in a mammalian cell line. An appropriate host, e.g., an inbred strain of mice such as Balb/c, is immunized with the selected protein, typically using a standard adjuvant, such as Freund's adjuvant, and a standard mouse immunization protocol (see Harlow and Lane, supra) . Alternatively, a synthetic peptide derived from the sequences disclosed herein and conjugated to a carrier protein can be used an immunogen. Polyclonal sera are collected and titered against the immunogen protein in an immunoassay, e.g., a solid phase immunoassay with the immunogen immobilized on a solid support. Polyclonal antisera with a titer of 10⁴ or greater are selected and tested for their cross reactivity against other IL-IR family members, e.g., mouse DTLRs or human DTLR1, using a competitive binding immunoassay such as the one described in Harlow and Lane, supra, at pages 570-573. Preferably at least two DTLR family members are used in this determination in conjunction with either or some of the human DTLR2-10. These IL-IR family members can be produced as recombinant proteins and isolated using standard molecular biology and protein chemistry techniques as described herein. Immunoassays in the competitive binding format can be used for the crossreactivity determinations. For example, the proteins of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and/or 24, or various fragments thereof, can be immobilized to a solid support. Proteins added to the assay compete with the binding of the antisera to the immobilized antigen. The ability of the above proteins to compete with the binding of the antisera to the immobilized protein is compared to the protein of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and/or 24. The percent crossreactivity for the above proteins is calculated, using standard calculations. Those antisera with less than 10% crossreactivity with each of the proteins listed above are selected and pooled. The cross- reacting antibodies are then removed from the pooled antisera by immunoabsorption with the above-listed proteins.

The immunoabsorbed and pooled antisera are then used in a competitive binding immunoassay as described above to compare a second protein to the immunogen protein (e.g., the IL-IR like protein of SEQ ID NO: 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and/or 24). In order to make this comparison, the two proteins are each assayed at a wide range of concentrations and the amount of each protein required to inhibit 50% of the binding of the antisera to the immobilized protein is determined. If the amount of the second protein required is less than twice the amount of the protein of the selected protein or proteins that is required, then the second protein is said to specifically bind to an antibody generated to the immunogen.

It is understood that these DTLR proteins are members of a family of homologous proteins that comprise at least 10 so far identified genes. For a particular gene product, such as the DTLR2-10, the term refers not only to the amino acid sequences disclosed herein, but also to other proteins that are allelic, non-allelic or species variants. It also understood that the terms include nonnatural mutations introduced by deliberate mutation using conventional recombinant technology such as single site mutation, or by excising short sections of DNA encoding the respective proteins, or by substituting new amino acids, or adding new amino acids. Such minor alterations must substantially maintain the immunoidentity of the original .molecule and/or its biological activity. Thus, these alterations include proteins that are specifically immunoreactive- with a designated naturally occurring IL-IR related protein, for example, the DTLR proteins shown in SEQ ID NO: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24. The biological properties of the altered proteins can be determined by expressing the protein in an appropriate cell line and measuring the appropriate effect upon lymphocytes. Particular protein modifications considered minor would include conservative substitution of amino acids with similar chemical properties, as described above for the IL-IR family as a whole. By aligning a protein optimally with the protein of DTLR2-10 and by using the conventional immunoassays described herein to determine immunoidentity, one can determine the protein compositions of the invention.

VII. Kits and quantitation

Both naturally occurring and recombinant forms of the IL-IR like molecules of this invention are particularly useful in kits and assay methods. For example, these methods would also be applied to screening for binding activity, e.g., ligands for these proteins. Several methods of automating assays have been developed in recent years so as to permit screening of tens of thousands of compounds per year. See, e.g., a BIOMEK automated workstation, Beckman Instruments, Palo Alto, California, and Fodor, et al. (1991) Science 251:767-773, which is incorporated herein by reference. The latter describes means for testing binding by a plurality of defined polymers synthesized on a solid substrate. The development of suitable assays to screen for a ligand or agonist/antagonist homologous proteins can be greatly facilitated by the availability of large amounts of purified, soluble DTLRs in an active^' state such as is provided by this invention.

Purified DTLR can be coated directly onto plates for use in the aforementioned ligand screening techniques. However, non-neutralizing antibodies to these proteins can be used as capture antibodies to immobilize the respective receptor on the, solid phase, useful, e.g., in diagnostic uses .

This invention also contemplates use of DTLR2-10, fragments thereof, peptides, and their fusion products in a variety of diagnostic kits and methods for detecting the presence of the protein or its ligand. Alternatively, or additionally, antibodies against the molecules may be incorporated into the kits and methods. Typically the kit will have a compartment containing either a defined DTLR peptide or gene segment or a reagent which recognizes one or the other. Typically, recognition reagents, in the case of peptide, would be a receptor or antibody, or in the case of a gene segment, would usually be a hybridization probe.

A preferred kit for determining the concentration of, e.g., DTLR4 , a sample would typically comprise a labeled compound, e.g., ligand or antibody, having known binding affinity for DTLR4, a source of DTLR4 (naturally occurring or recombinant) as a positive control, and a means for separating the bound from free labeled compound, for example a solid phase for immobilizing the DTLR4 in the test sample. Compartments containing reagents, and instructions, will normally be provided.

Antibodies, including antigen binding fragments, specific for mammalian DTLR or a peptide fragment, or receptor fragments are .useful in diagnostic applications to detect the presence of elevated levels of ligand and/or its fragments. Diagnostic assays may be homogeneous (without a separation step between free reagent and antibody-antigen complex) or heterogeneous (with a separation step) . Various commercial assays exist, such as radioimmunoassay (RIA) , enzyme-linked immunosorbent assay (ELISA) , enzyme immunoassay (EIA) , enzyme-multiplied immunoassay technique (EMIT) , substrate-labeled fluorescent immunoassay (SLFIA) and the like. For example, unlabeled antibodies can be employed by using a second antibody which is labeled and which recognizes the antibody to DTLR4 or to a particular fragment thereof. These assays have also been extensively discussed in the literature. See, e.g., Harlow and Lane (1988) Antibodies: A Laboratory Manual, CSH., and Coligan (ed. 1991 and periodic supplements) Current Protocols In Immunology Greene/Wiley, New York.

Anti-idiotypic antibodies may have similar use to serve as agonists or antagonists of DTLR . These should be useful as therapeutic reagents under appropriate circumstances.

Frequently, the reagents for diagnostic assays are supplied in kits, so as to optimize the sensitivity of the assay. For the subject invention, depending upon the nature of the assay, the protocol, and the label, either labeled or unlabeled antibody, or labeled ligand is provided. This is usually in conjunction with other additives, such as buffers, stabilizers, materials necessary for signal production such as substrates for enzymes, and the like. Preferably, the kit will also contain instructions for proper use and disposal of the contents after use. Typically the kit has compartments for each useful reagent, and will contain instructions for proper use and disposal of reagents. Desirably, the reagents are provided as a dry lyophilized powder, where the reagents may be reconstituted in an aqueous medium having appropriate concentrations for performing the assay.

The aforementioned constituents of the diagnostic assays may be used without modification or may be modified in a variety of ways. For example,' labeling may be achieved by covalently or non-covalently joining a moiety which directly or indirectly provides a detectable signal. In any of these assays, a. test compound, DTLR, or antibodies thereto can be labeled either directly or indirectly. Possibilities for direct labeling include label groups: radiolabels such as 125j._f enzymes (U.S. Pat. No. 3,645,090) such as peroxidase and alkaline phosphatase, and fluorescent labels (U.S. Pat. No. 3,940,475) capable of monitoring the change in fluorescence intensity, wavelength shift, or fluorescence polarization. Both of the patents are incorporated herein by reference. Possibilities for indirect labeling include biotinylation of one constituent followed by binding to avidin coupled to one of the above label groups. There are also numerous methods of separating the bound from the free ligand, or alternatively the. bound from the free test compound. The DTLR can be immobilized on various matrixes followed by washing. Suitable matrices include plastic such as an ELISA plate, filters, and beads. Methods of immobilizing the receptor to a matrix include, without limitation, direct adhesion to plastic, use of a capture antibody, chemical coupling,, and biotin-avidin. The last step in this approach involves the precipitation of antibody/antigen complex by any of several methods including those utilizing, e.g., an organic solvent such as polyethylene glycol or a salt such as ammonium sulfate. Other suitable separation techniques include, without limitation, the fluorescein antibody magnetizable particle method described in Rattle, et al. (1984) Clin. Chem. 30 (9) : 1457-1461, and the double antibody magnetic particle separation as described in' U.S. Pat. No. 4,659,678, each of which is incorporated herein by reference.

The methods for linking protein or fragments to various labels have been extensively^' reported in the literature and do not require detailed discussion here. Many of the techniques involve the use of activated carboxyl groups either through the use of carbodiimide or active esters to form peptide bonds, the formation of thioethers by reaction of a mercapto group with an activated halogen such as chloroacetyl, or an activated olefin such as maleimide, for linkage, or the like. Fusion proteins will also find use in these applications.

Another diagnostic aspect of this invention involves^" use of oligonucleotide or polynucleotide sequences taken from the sequence of a DTLR. These sequences can be used as probes for detecting levels of the respective DTLR in patients suspected of having an immunological disorder. The preparation of both RNA and DNA nucleotide sequences, the labeling of the sequences, and the preferred size of the sequences has received ample description and discussion in the literature. Normally an oligonucleotide probe should have at least about 14 nucleotides, usually at least about 18 nucleotides, and the polynucleotide probes may be up to several kilobases. Various labels may be employed, most commonly radionuclides, particularly

32p. However, other techniques may also be employed, such as using biotin modified nucleotides for introduction into a polynucleotide. The biotin then serves as the site for binding to avidin or antibodies, which may be labeled with a wide variety of labels, such as radionuclides, fluorescers, enzymes, or the like. Alternatively, antibodies may be employed which can recognize specific duplexes, including DNA duplexes, RNA duplexes, DNA-RNA hybrid duplexes, or DNA-protein duplexes. The antibodies in turn may be labeled and the assay carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected. The use of probes to the novel anti-sense RNA may be carried out in any conventional techniques such as nucleic acid hybridization, plus and minus screening, recombinational probing, hybrid .released translation (HRT) , and hybrid arrested translation (HART) . This also includes amplification techniques such as polymerase chain reaction (PCR) . Diagnostic kits which also test for the qualitative or quantitative presence of other markers are also contemplated. Diagnosis or prognosis may depend on the combination of multiple indications used as markers. Thus, kits may test for combinations of markers. See, e.g., Viallet, et al. (1989) Progress in Growth Factor Res. 1:89-97.

VIII. Therapeutic Utility

This invention provides reagents with significant therapeutic value. The DTLRs (naturally occurring or recombinant), fragments thereof, mutein receptors, and antibodies, along with compounds identified as having binding affinity to the receptors or antibodies, should be useful in the treatment of conditions exhibiting abnormal expression of the receptors of their ligands. Such abnormality will typically be manifested by immunological disorders. Additionally, this invention should provide therapeutic value in various diseases or disorders associated with abnormal expression or abnormal triggering of response to the ligand. The Toll ligands have been suggested to be involved in morphologic development, e.g., dorso-ventral polarity determination, and immune responses, particularly the primitive innate responses. See, e.g., Sun, et al. (1991) Eur. J. Biochem. 196:247- 254; Hultmark (1994) Nature 367:116-117. Recombinant DTLRs, muteins, agonist or antagonist antibodies thereto, or antibodies can be purified and then administered to a patient. These reagents can be combined for therapeutic use with additional ..active ingredients, e.g., in conventional pharmaceutically acceptable carriers or diluents, along with physiologically innocuous stabilizers and excipients. These combinations can be sterile, e.g., filtered, and placed into dosage forms as by lyophilization in dosage vials or storage in stabilized aqueous preparations. This invention also contemplates use of antibodies or binding fragments thereof which are not complement binding.

Ligand screening using DTLR or fragments thereof can be performed to identify molecules having binding affinity to the receptors. Subsequent biological assays can then be utilized to determine if a putative ligand can provide competitive binding, which can block intrinsic stimulating activity. Receptor fragments can be used as a blocker or antagonist in that it blocks the activity of ligand. Likewise, a compound having intrinsic stimulating activity can activate the receptor and is thus an agonist in that it simulates the activity of ligand, e.g., inducing signaling. This invention further contemplates the ™ therapeutic use of antibodies to DTLRs as antagonists. The quantities of reagents necessary for effective therapy will depend upon many different factors, including means of administration, target site, physiological state of the patient, and other medicants administered. Thus, treatment dosages should be titrated to optimize safety and efficacy. Typically, dosages used in vitro may provide useful guidance in the amounts useful for in situ administration of these reagents. Animal testing of effective doses for treatment of particular disorders will provide further predictive indication of human dosage. Various considerations are described, e.g., in Gilman, et al. (eds. 1990) Goodman and Gilman' s: The Pharmacological Bases of Therapeutics, 8th Ed., Pergamon Press; and Remington's Pharmaceutical Sciences, (current edition) , Mack Publishing Co., Easton, Penn.; each of which is hereby incorporated herein by reference. Methods for administration are discussed therein and below, e.g., for oral, intravenous, intraperitoneal, or intramuscular administration, transdermal diffusion, and others. Pharmaceutically acceptable carriers will include water, saline, buffers, and other compounds described, e.g., in the Merck Index, Merck & Co., Rahway, New Jersey. Because of the likely high affinity binding, or turnover numbers, between a putative ligand and its receptors, low dosages of these reagents would be initially expected to be effective. And the signaling pathway suggests extremely low amounts of ligand may have effect. Thus, dosage ranges would ordinarily be expected to be in amounts lower than 1 mM concentrations, typically less than about 10 μM concentrations, usually less than about 100 nM, preferably less than about 10 pM (picomolar) , and most preferably less than about 1 fM (femtomolar), with an appropriate carrier. Slow release formulations, or slow release apparatus will often be utilized for continuous administration .

DTLRs, fragments thereof, and antibodies or its fragments, antagonists, and agonists, may be administered directly to the host to be treated or, depending on the size of the compounds, it may be desirable to conjugate them to carrier proteins such as ovalbumin or serum albumin prior to their administration. Therapeutic formulations may be administered in any conventional dosage formulation. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. Formulations comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof. Each carrier must be both pharmaceutically and physiologically acceptable in the sense of being compatible with the other ingredients and not injurious to the patient. Formulations include those suitable for oral, rectal, nasal, or parenteral (-including subcutaneous, intramuscular, intravenous and intradermal) administration. . The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. See, e.g., Gilman, et al. (eds. 1990) Goodman and Gilman' s: The Pharmacological Bases of Therapeutics, 8th Ed., Pergamon Press; and Remington's Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Penn.; Avis, et al. (eds. 1993) Pharmaceutical Dosage Forms: Parenteral Medications Dekker, NY; Lieber an, et al. (eds. 1990) Pharmaceutical Dosage Forms: Tablets Dekker, NY; and

Lieberman, et al. (eds. 1990) Pharmaceutical Dosage Forms: Disperse Systems Dekker, NY. The therapy of this invention may be combined with or used in association with other therapeutic agents, particularly agonists or antagonists of other IL-1 family members.

IX. Ligands

The description of the Toll receptors herein provide means to identify ligands, as described above. Such ligand should bind specifically to the respective receptor with reasonably high affinity. Various constructs are made available which allow either labeling of the receptor to detect its ligand. For example, directly labeling DTLR, fusing onto it markers for secondary labeling, e.g., FLAG or other epitope tags, etc., will allow detection of receptor. This can be histological, as an affinity method for biochemical purification, or labeling or selection in an expression cloning approach. A two-hybrid selection system may also be applied making appropriate constructs with the available DTLR sequences. See, e.g., Fields and Song (1989) Nature 340:245-246. Generally, descriptions of DTLRs will be analogously applicable to individual specific embodiments directed to DTLR2, DTLR3, DTLR , DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, and/or DTLRIO reagents and compositions. The broad scope of this invention is best understood with reference to the following examples, which are not intended to limit the inventions to the specific embodiments .

EXAMPLES

I. General Methods

Some of the standard methods are described or referenced, e.g., in Maniatis, et al. (1982) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor Press; Sambrook, et al. (1989) Molecular Cloning: A Laboratory Manual, (2d ed.), vols. 1-3, CSH Press, NY; Ausubel, et al., Biology, Greene Publishing Associates, Brooklyn, NY; or Ausubel, et al. (1987 and Supplements) Current Protocols in Molecular Biology, Greene/Wiley, New York. Methods for protein purification include such methods as ammonium sulfate precipitation, column chromatography, electrophoresis, centrifugation, crystallization, and others. See, e.g., Ausubel, et al. (1987 and periodic supplements); Coligan, et al. (ed. 1996) and periodic supplements, Current Protocols In Protein Science Greene/Wiley, New York; Deutscher (1990) "Guide to Protein Purification" in Methods in Enzymology, vol. 182, and other volumes in this series; and manufacturer's literature on use of protein purification products, e.g., Pharmacia, Piscataway, N.J., or Bio-Rad, Richmond, CA. Combination with recombinant techniques allow fusion to appropriate segments, e.g., to a FLAG sequence or an equivalent which can be fused via a protease-re ovable sequence. See, e.g., Hochuli (1989) Chemische Industrie 12:69-70; Hochuli (1990) "Purification of Recombinant Proteins with Metal Chelate Absorbent" in Setlow (ed.) Genetic Engineering, Principle and Methods 12:87-98, Plenum Press, N.Y.; and Crowe, et al. (1992) QIAexpress: The High Level Expression and Protein Purification System QUIAGEN, Inc., Chatsworth, CA.

Standard immunological techniques and assays are described, e.g., in Hertzenberg, et al. (eds. 1996) Weir' s Handbook of Experimental Immunology vols. 1-4, Blackwell Science; Coligan (1991) Current Protocols in Immunology Wiley/Greene, NY; and Methods in Enzymology volumes. 70, 73, 74, 84, 92, 93, 108, 116, 121, 132, 150, 162, and 163.

Assays for vascular biological activities are well known in the art. They will cover angiogenic and angiostatic activities in tumor, or other tissues, e.g., arterial smooth -muscle proliferation (see, e.g., Koyo a, et al. (1996) Cell 87:1069-1078), monocyte adhesion to vascular epithelium (see McEvoy, et al. (1997) J. Exp. Med. 185:2069-2077), etc. See also Ross (1993) Nature 362:801-809; Rekhter and Gordon (1995) Am. J. Pathol. 147:668-677; Thyberg, et al. (1990) Atherosclerosis 10:966-990; and Gumbiner (1996) Cell 84:345-357.

Assays for neural cell biological activities are described, e.g., in Wouterlood (ed. 1995) Neuroscience Protocols modules 10, Elsevier; Methods in Neurosciences Academic Press; and Neuromethods Humana Press, Tptowa, NJ. Methodology of developmental systems is described, e.g., in Meisami (ed.) Handbook of Human Growth and Developmental Biology CRC Press; and Chrispeels (ed.) Molecular Techniques and Approaches in Developmental Biology Interscience .

Computer sequence analysis is performed, e.g., using available software programs, including those from the"~GCG (U. Wisconsin) and GenBank sources. Public sequence databases were also used, e.g., from GenBank, NCBI, EMBO, and others. Determination of transmembrane and other important motifs may be predicted using such bioinformatics tools.

Many techniques applicable to IL-10 receptors may be applied to DTLRs, as described, e.g., in USSN 08/110,683 (IL-10 receptor) , which is incorporated herein by reference for all purposes.

II. Novel Family of Human Receptors Abbreviations: DTLR, DNAX Toll-like receptor; IL-IR, interleukin-1 receptor; TH, Toll homology; LRR, leucine- rich repeat; EST, expressed sequence tag; STS, sequence tagged site; FISH, fluorescence in situ hybridization.

The discovery of sequence homology between the cytoplasmic domains of Drosophila Toll and human interleukin-1 (IL-1) receptors has sown the conviction that both molecules trigger related signaling pathways tied to the nuclear translocation of Rel-type transcription factors. This conserved signaling scheme governs an evolutionarily ancient immune response in both insects and vertebrates. We report the molecular cloning' of a novel class of putative human receptors with a protein architecture that is closely similar to Drosophila Toll in both intra- and extra-cellular segments. Five human Toll-like receptors, designated DTLRs 1-5, are likely the direct homologs of the fly molecule_', and as such could constitute an important and unrecognized component of innate immunity in humans; intriguingly, the evolutionary retention of DTLRs in vertebrates may indicate another role, akin to Toll in the dorso- ventralization of the Drosophila embryo, as regulators of early morphogenetic patterning. Multiple tissue mRNA blots indicate markedly different patterns of expression for the human DTLRs. Using fluorescence in situ hybridization and Sequence-Tagged Site database analyses, we also show that the cognate DTLR genes reside on chromosomes 4 (DTLRs 1, 2, and 3), 9 (DTLR4), and 1 (DTLR5) . Structure prediction of the aligned Toll- homology (TH) domains from varied insect and human DTLRs, vertebrate IL-1 receptors, and MyD88 factors, and plant disease resistance proteins, recognizes a parallel β/α fold with an acidic active site; a similar structure notably recurs in a class of response regulators broadly involved in transducing sensory information in bacteria. The seeds of the morphogenetic gulf that so dramatically separates flies from humans are planted in familiar embryonic shapes and patterns, but give rise to very different cell complexities. -DeRobertis and Sasai

(1996) Nature 380:37-40; and Arendt and Nϋbler-Jung (1997) Mech. Develop. 61:7-21. This divergence of developmental plans between insects and vertebrates is choreographed by remarkably similar signaling pathways, underscoring a greater conservation of protein networks and biochemical mechanisms from unequal gene repertoires. Miklos and Rubin (1996) Cell 86:521-529; and Chothia (1994) Develop. 1994 Suppl., 27-33. A powerful way to chart the evolutionary design of these regulatory pathways is by inferring their likely molecular components (and biological functions) through interspecies comparisons of protein sequences and structures. Miklos and Rubin (1996) Cell 86:521-529; Chothia (1994) Develop. 1994 Suppl., 27- 33 (3-5); and Banfi, et al. (1996) Nature Genet. 13:167- 174.

A universally critical step in embryonic development is the specification of body axes, either born from innate asymmetries or triggered by external cues. DeRobertis and Sasai (1996) Nature 380:37-40; and Arendt and Nϋbler-Jung (1997) Mech. Develop. 61:7-21. As a model system, particular attention has been focused on the phylogenetic basis and cellular mechanisms of dorsoventral polarization. DeRobertis and Sasai (1996) Nature 380:37- 40; and Arendt and Nϋbler-Jung (1997) Mech. Develop. 61:7- 21. A prototype molecular strategy for this transformation has emerged from the Drosophila embryo, where the sequential action of a small number of genes results in a ventralizing gradient of the transcription factor Dorsal. St. Johnston and Nϋsslein-Volhard (1992) Cell 68:201-219; and Morisato-and Anderson (1995) Ann- Rev. Genet. 29:371-399. This signaling pathway centers on Toll, a transmembrane receptor that transduces the binding of a maternally-secreted ventral factor, Spatzle, into the cytoplasmic engagement of Tube, an accessory molecule, and the activation of Pelle, a Ser/Thr • kinase that catalyzes the dissociation of Dorsal from the inhibitor Cactus and allows migration of Dorsal to ventral nuclei (Morisato and Anderson (1995) Ann. Rev. Genet. 29:371-399; and Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393- 416. The Toll pathway also controls the induction of potent antimicrobial factors in the adult fly (Lemaitre, et al. (1996) Cell 86:973-983); this role in Drosophila immune defense strengthens mechanistic parallels to IL-1 pathways that govern a host of immune and inflammatory responses in vertebrates. Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393-416; and Wasserman (1993) Molec. Biol. Cell 4:767-771. A Toll-related cytoplasmic domain in IL-1 receptors directs the binding of a Pelle- like kinase, IRAK, and the activation of a latent NF-KB/I- KB complex that mirrors the embrace of Dorsal and Cactus. Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393-416; and Wasserman (1993) Molec. Biol. Cell 4:767- 771.

We describe the cloning and molecular characterization of four new Toll-like molecules in humans, designated DTLRs 2-5 (following Chiang and Beachy (1994) Mech. Develop. 47:225-239), that reveal a receptor family more closely tied to Drosophila Toll homologs than to vertebrate IL-1 receptors. The DTLR sequences are derived from human ESTs; these partial cDNAs were used to draw complete expression profiles in human tissues for the five DTLRs, map the chromosomal locations of cognate genes, and narrow the choice of cDNA libraries for full- length cDNA retrievals. Spurred by other efforts (Banfi, et al. (1996) Nature Genet. 13:167-174; and Wang, et al . (1996) J. Biol. Chem. 271:4468-4476), we are assembling, by structural conservation and molecular parsimony, a biological system in humans that is the counterpart of a compelling regulatory scheme in Drosophila. In addition, a biochemical mechanism driving Toll signaling is suggested by the proposed tertiary fold of the Toll- homology (TH) domain, a core module shared by DTLRs, a broad family of IL-1 receptors, mammalian MyD88 factors and plant disease resistance proteins. Mitcham, et al. (1996) J. Biol. Chem. 271:5777-5783; and Hardiman, et al. (1996) Oncoqene 13:2467-2475. We propose that a signaling route coupling morphogenesis and primitive immunity in insects, plants, and animals (Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393-416; and Wilson, et al. (1997) Curr. Biol. 7:175-178) may have roots in bacterial two-component pathways.

Computational Analysis.

Human sequences related to insect DTLRs were identified from the EST database (dbEST) at the National Center for Biotechnology Information (NCBI) using the

BLAST server (Altschul, et al . (1994) Nature Genet. 6:119- 129) . More sensitive pattern- and profile-based methods (Bork and Gibson (1996) Meth . Enzymol. 266:162-184) were used to isolate the signaling domains of the DTLR family that are shared with vertebrate and plant proteins present in nonredundant databases. The progressive alignment of DTLR intra- or extracellular domain sequences was carried out by ClustalW (Thompson, et al. (1994) Nucleic Acids Res . 22:4673-4680); this program also calculated the branching order of aligned sequences by the Neighbor- Joining algorithm (5000 bootstrap replications provided confidence values for the tree groupings) .

Conserved alignment patterns, discerned at several degrees of stringency, were drawn by the Consensus program (internet URL http://www.bork.embl- heidelberg.de/Alignment/ consensus.html). The PRINTS library of protein fingerprints

(http: //www. biochem. ucl.ac.uk/bsm/dbbrowser/PRINTS/ PRINTS.html) (Attwood, et al. (1997) Nucleic Acids Res. 25:212-217) reliably identified the. myriad leucine-rich repeats (LRRs) present in the extracellular segments of DTLRs with a compound motif (PRINTS code Leurichrpt) that flexibly matches N- and C-terminal features of divergent LRRs. Two prediction algorithms whose three-state accuracy is above 72% were used to derive a consensus secondary structure for the intracellular domain alignment, as a bridge to fold recognition efforts (Fischer, et al. (1996) FASEB J. 10:126-136). Both the neural network program PHD (Rost and Sander (1994) Proteins 19:55-72) and the statistical prediction method DSC (King and Sternberg (1996) Protein Sci. 5:2298-2310) have internet servers (URLs http://www.embl- heidelberg .de/predictprotein/phd_pred.html and http: //bonsai . lif . icnet.uk/bmm/dsc/dsc_read_align.html, respectively) . The intracellular region encodes the THD region discussed, e.g., in Hardiman, et al. (1996)

Oncoqene 13:2467-2475; and Rock, et al. (1998) Proc. Nat'l Acad. Sci. USA 95:588-593, each of which is incorporated herein by reference. This domain is very important ϊή the mechanism of signaling by the receptors, which transfers a phosphate group to a substrate.

Cloning of full-length human DTLR cDNAs.

PCR primers derived from the Toll-like Humrsc786 sequence (GenBank accession code D13637) (Nomura, et al. (1994) DNA Res. 1:27-35) were used to probe a human erythroleukemic, TF-1 cell line-derived cDNA library (Kitamura, et al. (1989) Blood 73:375-380) to yield the DTLR1 cDNA sequence. The remaining DTLR sequences were flagged from dbEST, and the relevant EST clones obtained from the I.M.A.G.E. consortium (Lennon, et al- (1996)

Genomics 33:151-152) via Research Genetics (Huntsville, AL) : CloneID#'s 80633 and 117262 (DTLR2), 144675 (DTLR3), 202057 (DTLR4) and 277229 (DTLR5) . Full length cDNAs for human DTLRs 2-4 were cloned by DNA hybridization screening of λgtlO phage, human adult lung, placenta, and fetal liver 5 '-Stretch Plus cDNA libraries (Clontech) , respectively; the DTLR5 sequence is derived from a human multiple-sclerosis plaque EST. All positive clones were sequenced and aligned to identify individual DTLR ORFs: DTLR1 (2366 bp clone, 786 aa ORF) , DTLR2 (2600 bp, 784 aa), DTLR3 (3029 bp, 904 aa) , DTLR4 (3811 bp, 879 aa) and DTLR5 (1275 bp, 370 aa) . Similar methods are used for DTLRs 6-10. Probes for DTLR3 and DTLR4 hybridizations were generated by PCR using human placenta (Stratagene) and adult liver (Clontech) cDNA libraries as templates, respectively; primer pairs were derived from the respective EST sequences. PCR reactions were conducted using T. aquaticus Taqplus DNA polymerase (Stratagene) under the following conditions: 1 x (94° C, 2 min) 30 x (55° C, 20 sec; 72° C 30 sec; 94° C 20 sec), 1 x (72° C, 8 min) . For DTLR2 full-length cDNA screening, a 900 bp fragment generated by EcoRI/Xbal digestion of the first EST clone (ID# 80633) was used as a probe.

mRNA blots and chromosomal localization. Human multiple tissue (Cat# 1, 2) and cancer cell line blots (Cat# 7757-1) , containing approximately 2 μg of poly (A) ⁺ RNA per lane, were purchased from Clontech (Palo Alto, CA) . For DTLRs 1-4, the isolated full-length cDNAs served as probes, for DTLR5 the EST clone (ID #277229) plasmid insert was used. Briefly, the probes were radiolabeled with [ α-³²P] dATP using the Amersham Rediprime random primer labeling kit (RPN1633) . Prehybridization and hybridizations were performed at 65° C in 0.5 M Na2HP04, 7% SDS, 0.5 M EDTA (pH 8.0). All stringency washes were conducted at 65° C with two initial washes in 2 x SSC, 0.1% SDS for 40 min followed by a subsequent wash in 0.1 x SSC, 0.1% SDS for 20 min. Membranes were then exposed at -70° C to X-Ray film (Kodak) in the presence of intensifying screens. More detailed studies by cDNA library Southerns (14) were performed with selected human DTLR -clones to examine their expression in hemopoietic cell subsets.

Human chromosomal mapping was conducted by the method of fluorescence in situ hybridization (FISH) as described in Heng and Tsui (1994) Meth. Molec. Biol. 33:109-122, using the various full-length (DTLRs 2-4) or partial (DTLR5) cDNA clones as probes. These analyses were performed as a service by SeeDNA Biotech Inc. (Ontario, Canada) . A search for human syndromes (or mouse defects in syntenic loci) associated with the mapped DTLR genes was conducted in the Dysmorphic Human-Mouse Homology Database by internet server

(http://www.hgmp.mrc.ac.uk/DHMHD/ hum_chromel.html) . Similar methods nare applicable to DTLRs 6-10.

Conserved architecture of insect and human DTLR ectodomains .

The Toll family in Drosophila comprises at least four distinct gene products: Toll, the prototype receptor involved in dorsoventral patterning of the fly embryo (Morisato and Anderson (1995) Ann. Rev.ft Genet. 29:371-399) and a second named '18 Wheeler' (18w) that may also be involved in early embryonic development (Chiang and Beachy (1994) Mech. Develop. 47:225-239; Eldon, et al. (1994) Develop. 120:885-899); two additional receptors are predicted by incomplete, Toll-like ORFs downstream of the male-specific-transcript (Mst) locus (GenBank code X67703) or encoded by the 'sequence-tagged-site¹ (STS) Dm2245 (GenBank code G01378) (Mitcha , et al. (1996) J. Biol. Chem. 271:5777-5783). The extracellular segments of Toll and 18w are distinctively composed of imperfect, -24 amino acid LRR motifs (Chiang and Beachy (1994) Mech. Develop. 47:225-239; and Eldon, et al. (1994) Develop. 120:885- 899) . Similar tandem arrays of LRRs commonly form the adhesive antennae of varied cell surface molecules and their generic tertiary structure is /presumed to mimic the horseshoe-shaped cradle of a ribonuclease inhibitor fold, where seventeen .LRRs show a repeating β/α-hairpin, 28 residue motif (Buchanan and Gay (1996) Prog. Biophys. Molec. Biol. 65:1-44). The specific recognition of Spatzle by Toll may follow a model proposed for the binding of cystine-knot fold glycoprotein hormones by the multi-LRR ectodomains of serpentine receptors, using the concave side of the curved β-sheet (Kajava, et al. (1995) Structure 3:867-877); intriguingly, the pattern of cysteines in Spatzle, and an orphan Drosophila ligand, Trunk, predict a similar cystine-knot tertiary structure (Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393-416; and Casanova, et al . (1995) Genes Develop. 9:2539-2544) .

The 22 and 31 LRR ectodomains of Toll and 18w, respectively (the Mst ORF fragment displays 16 LRRs) , are most closely related to the comparable 18, 19, 24, and 22 LRR arrays of DTLRs 1-4 (the incomplete DTLR5 chain presently includes four membrane-proximal LRRs) by sequence and pattern analysis (Altschul, et al. (1994) Nature Genet. 6:119-129; and Bork and Gibson (1996) Meth. Enzymol. 266:162-184) (Fig. 1). However, a striking difference in the human DTLR chains is the common loss of a -90 residue cysteine-rich region that is variably embedded in the ectodomains of Toll, 18w and the Mst ORF (distanced four, six and two LRRs, respectively, from the membrane boundary) . These cysteine clusters are bipartite, with distinct 'top' (ending an LRR) and 'bottom' (stacked atop an LRR) halves (Chiang and Beachy (1994) Mech. Develop. 47:225-239; Eldon, et al. (1994) Develop. 120:885-899; and Buchanan and Gay (1996) Prog.

Biophys. Molec. Biol. 65:1-44); the 'top' module recurs in both Drosophila and human DTLRs as a conserved juxtamembrane spacer (Fig. 1) . We suggest that the flexibly located cysteine clusters in Drosophila receptors (and other LRR proteins), when mated 'top' to 'bottom', form a compact module with paired termini that can be inserted between any pair of LRRs without altering the overall fold of DTLR ectodomains; analogous 'extruded' domains decorate the structures of other proteins (Russell (1994) Protein Engin. 7:1407-1410).

Molecular design of the TH signaling domain.

Sequence comparison of Toll and IL-1 type-I (IL-1R1) receptors has disclosed a distant resemblance of a -200 amino acid cytoplasmic domain that presumably mediates signaling by similar Rel-type transcription factors.

Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393-416; and (Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393-416; and Wasserman (1993) Molec. Biol. Cell 4:767-771). More recent additions to this functional paradigm include a pair of plant disease resistance proteins from tobacco and flax that feature an N-terminal TH module followed by nucleotide-binding (NTPase) and LRR segments (Wilson, et al . (1997) Curr. Biol . 7:175-178); by contrast, a 'death domain' precedes the TH chain of MyD88, an intracellular myeloid differentiation marker (Mitcham, et al. (1996) J. Biol. Chem. 271:5777-5783; and Hardiman, et al. (1996) Oncogene 13:2467-2475) (Fig. 1) . New IL-1-type receptors include IL-1R3, an accessory signaling molecule, and orphan receptors IL-1R4 (also called ST2/Fit-1/Tl) , IL-1R5 (IL- lR-related protein), and IL-1R6 (IL-lR-related protein-2) (Mitcham, et al. (1996) J. Biol. Chem. 271:5777- 5783,-Hardiman, et al. (1996) Oncogene 13:2467-2475). With the new human DTLR sequences, we have sought a structural definition of this evolutionary thread by analyzing the conformation of the common TH module: ten blocks of conserved sequence comprising 128 amino acids form the minimal TH domain fold; gaps in the alignment mark the likely location of sequence and length-variable loops (Fig. 2A-2B) . Two prediction algorithms that take advantage of the patterns of conservation and variation in multiply aligned sequences, PHD (Rost and Sander (1994) Proteins 19:55-72) and DSC (King and Sternberg (1996) Protein Sci. 5:2298- 2310) , produced strong, concordant results for the TH signaling module (Fig. 2A-2B) . Each block contains a discrete secondary structural element: the imprint of alternating β-strands (labeled A-E) and α-helices (numbered 1-5) is diagnostic of a β/α-class fold with - helices on both faces of a parallel β-sheet. Hydrophobic β-strands A, C and D are predicted to form 'interior' staves in the β-sheet, while the shorter, amphipathic β- strands B and E resemble typical 'edge' units (Fig. 2A- 2B) . This assignment is consistent with a strand order of B-A-C-D-E in the core β-sheet (Fig. 2C) ; fold comparison ('mapping') and recognition ('threading') programs

(Fischer, et al. (1996) FASEB J. 10:126-136) strongly return this doubly wound β/ topology. A surprising, functional prediction of this outline structure for tHe TH domain is that many of the conserved, charged residues in the multiple alignment map to the C-terminal end of the β- sheet: residue Aspl6 (block numbering scheme - Fig. 2A-2B) at the end of βA, Arg39 and Asp40 following βB, Glu75 in the first turn of α3, and the more loosely conserved Glu/Asp residues in the βD-α4 loop, or after βE (Fig. 2A- 2B) . The location of four other conserved residues (Asp7, Glu28, and the Arg57-Arg/Lys58 pair) is compatible with a salt bridge network at the opposite, N-terminal end of the β-sheet (Fig. 2A-2B) . Alignment of the other DTLR embodiments exhibit similar features, and peptide segments comprising these feataures, e.g., 20 amino acid segments containing them, are particularly important. Signaling function depends on the structural integrity of the TH domain. Inactivating mutations or deletions within the module boundaries (Fig. 2A-2B) have been catalogued for IL-1R1 and Toll.. Heguy, et al. (1992) J. Biol. Chem. 267:2605-2609; Croston, et al. (1995) J_ Biol. Chem. 270:16514-16517; Schneider, et al. (1991) Genes Develop. 5:797-807; Norris and Manley. (1992) Genes Develop. 6:1654-1667; Norris and Manley (1995) Genes Develop. 9:358-369; and Norris and Manley (1996) Genes Develop. 10:862-872. The human DTLRl-5 chains extending past the minimal TH domain (8, 0, 6, 22 and 18 residue lengths, respectively) are most closely similar to the stubby, 4 aa 'tail' of the Mst ORF. Toll and 18w display ' unrelated 102 and 207 residue tails (Fig. 2A-2B) that may negatively regulate the signaling of the fused TH domains. Norris and Manley (1995) Genes Develop. 9:358-369; and Norris and Manley (1996) Genes Develop. 10:862-872.

The evolutionary relationship between the disparate proteins that carry the TH domain can best be discerned by a phylogenetic tree derived from the multiple alignment (Fig. 3) . Four principal branches segregate the plant proteins, the MyD88 factors, IL-1 receptors, and Toll-like molecules; the latter branch clusters the Drosophila and human DTLRs.

Chromosomal dispersal of human DTLR genes.

In order to investigate the genetic linkage of the nascent human DTLR gene family, we mapped the chromosomal loci of four of the five genes by FISH (Fig. 4) . The DTLRl gene has previously been charted by the human genome project: an STS database locus (dbSTS accession number G06709, corresponding to STS WI-7804 or SHGC-12827) exists for the Humrsc786 cDNA ^' (Nomura, et al. (1994) DNA Res. 1:27-35) and fixes the gene to chromosome 4 marker interval D4S1587-D42405 (50-56 cM) circa 4pl4. This assignment has recently been corroborated by FISH analysis. Taguchi, et al. (1996) Genomics 32:486-488. In the present work, we reliably assign the remaining DTLR genes to loci on chromosome 4q32 (DTLR2), 4q35 (DTLR3), 9q32-33 (DTLR4) and lq33.3 (DTLR5)./ During the course of this work, an STS for the parent DTLR2 EST (clonelD #

80633) has been .generated (dbSTS accession number T57791 for STS SHGC-33147) and maps to the chromosome 4 marker interval D4S424-D4S1548 (143-153 cM) at 4q32 -in accord with our findings. There is a -50 cM gap between DTLR2 and DTLR3 genes on the long arm of chromosome 4.

DTLR genes are differentially expressed.

Both Toll and 18w have complex spatial and temporal patterns of expression in Drosophila that may point to functions beyond embryonic patterning. St. Johnston and Nusslein-Volhard (1992) Cell 68:201-219; Morisato and Anderson (1995) Ann. Rev. Genet. 29:371-399; Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393-416; Lemaitre, et al. (1996) Cell 86:973-983; Chiang and Beachy (1994) Mech. Develop. 47:225-239; and Eldon, et al. (1994) Develop. 120:885-899. We have examined the spatial distribution of DTLR transcripts by mRNA blot analysis with varied human tissue and cancer cell lines using radiolabeled DTLR cDNAs (Fig. 5) . DTLRl is found to be ubiquitously expressed, and at higher levels than the other receptors. Presumably reflecting alternative splicing, 'short' 3.0 kB and 'long' 8.0 kB DTLRl transcript forms are present in ovary and spleen, respectively (Fig. 5, panels A and B) . A cancer cell mRNA panel also shows the prominent overexpression of DTLRl in a Burkitt's Lymphoma Raji cell line (Fig. 5, panel C) . DTLR2 mRNA is less widely expressed than DTLRl, with a 4.0 kB species detected in lung and a 4.4 kB transcript evident in heart, brain and muscle. The tissue distribution pattern of DTLR3 echoes that of DTLR2 (Fig. 5, panel E) . DTLR3 is also present as two major transcripts of approximately 4.0 and 6.0 kB in size, and the highest levels of expression are observed in placenta and pancreas. By contrast, DTLR4 and DTLR5 messages appear to be extremely tissue-specific. DTLR4 was detected only in placenta as a single transcript of -7.0 kB in size. A faint .0 kB signal was observed for DTLR5 in ovary and peripheral blood monocytes.

Components of an evolutionarily ancient regulatory system. The original molecular blueprints and divergent fates of signaling pathways can be reconstructed by comparative genomic approaches. Miklos and Rubin (1996) Cell 86:521- 529; Chothia (1994) Develop. 1994 Suppl., 27-33; Banfi, et al. (1996) Nature Genet. 13:167-174; and Wang, et al. (1996) J. Biol. Chem. 271:4468-4476. We have used this logic to identify an emergent gene family in humans, encoding five receptor paralogs at present, DTLRs 1-5, that are the direct evolutionary counterparts of a Drosophila gene family headed by Toll (Figs. 1-3). The conserved architecture of human and fly DTLRs, conserved LRR ectodomains and intracellular TH modules (Fig. 1) , intimates that the robust pathway coupled to Toll in Drosophila (6, 7) survives in vertebrates. The best evidence borrows from a reiterated pathway: the manifold IL-1 system and its repertoire of receptor-fused TH domains, IRAK, NF-KB and I-KB homologs (Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393-416; Wasserman (1993) Molec. Biol. Cell 4:767-771; Hardiman, et al. (1996) Oncogene 13:2467-2475; and Cao, et al . (1996) Science 271:1128-1131); a Tube-like factor has also been characterized. It is not known whether DTLRs can productively couple to the IL-IR signaling machinery, or instead, a parallel set of proteins is used. Differently from IL-1 receptors, the LRR cradle of human DTLRs is predicted to retain an affinity for Spatzle/Trunk-related cystine-knot factors; candidate DTLR ligands (called PENs) that fit this mold have been isolated.

Biochemical mechanisms of signal transduction can be gauged by the conservation of interacting protein folds in a pathway. Miklos and Rubin (1996) Cell 86:521-529;

Chothia (1994) Develop. 1994 Suppl., 27-33. At present, the Toll signaling paradigm involves some molecules whose roles are narrowly defined by their structures, actions or fates: Pelle is a Ser/Thr kinase (phosphorylation), Dorsal is an NF-KB-like transcription factor (DNA-binding) and Cactus is an ankyrin-repeat inhibitor (Dorsal binding, degradation) . Belvin and Anderson (1996) Ann. Rev. Cell Develop. Biol. 12:393-416. By contrast, the functions of ^' the Toll TH domain and Tube remain enigmatic. Like other cytokine receptors (Heldin (1995) Cell 80:213-223), ligand-mediated dimerization of Toll appears to be the triggering event: free cysteines in the juxtamembrane region of Toll create constitutively active receptor pairs (Schneider, et al . (1991) Genes Develop. 5:797-807), and chimeric Torso-Toll receptors signal as dimers (Galindo, et al. (1995) Develop. 121:2209-2218); yet, severe truncations or wholesale loss of the Toll ectodomain results in promiscuous intracellular signaling (Norris and Manley (1995) Genes Develop. 9:358-369; and Winans and Hashimoto (1995) Molec. Biol. Cell 6:587-596), reminiscent of oncogenic receptors with catalytic domains (Heldin (1995) Cell 80:213-223). Tube is membrane-localized, engages the N-terminal (death) domain of Pelle and is phosphorylated, but neither Toll-Tube or Toll-Pelle interactions are registered by two-hybrid analysis (Galindo, et al. (1995) Develop. 121:2209-2218; and Groβhans, et al. (1994) Nature 372:563-566); this latter result suggests that the conformational 'state' of the Toll TH domain somehow affects factor recruitment. Norris and Manley (1996) Genes Develop. 10:862-872; and Galindo, et al. (1995) Develop. 121:2209-2218. At the heart of these vexing issues is the structural nature of the Toll TH module. To address this question, we have taken advantage of the evolutionary diversity of TH sequences from insects, plants and vertebrates, incorporating the human DTLR chains, and extracted the minimal, conserved protein core for structure prediction and fold recognition (Fig. 2) . The strongly predicted (β/α)5 TH domain fold with its asymmetric cluster of acidic residues is topologically identical to the structures of response regulators in bacterial two-component signaling pathways (Volz (1993) Biochemistry 32:11741-11753; and Parkinson (1993) Cell 73:857-871) (Fig. 2A-2C) . The prototype chemotaxis regulator CheY transiently binds a divalent cation in an 'aspartate pocket' at the C-end of the core β-sheet; this cation provides electrostatic stability and facilitates the activating phosphorylation of an invariant Asp. Volz (1993) Biochemistry 32:11741- 11753. Likewise, the TH domain may capture cations in its acidic nest, but activation, and downstream signaling, could depend on the specific binding of a negatively charged moiety: anionic ligands can overcome intensely negative binding-site potentials by locking into precise hydrogen-bond networks. Ledvina, et al. (1996) Proc. Natl. Acad. Sci. USA 93:6786-6791. Intriguingly, the TH domain may not simply act as a passive scaffold for the assembly of a Tube/Pelle complex for Toll, or homologous systems in plants and vertebrates, but instead actively participate as a true conformational trigger in the signal transducing machinery. Perhaps explaining the conditional binding of a Tube/Pelle complex, Toll dimerization could promote unmasking, by regulatory receptor tails (Norris and Manley (1995) Genes Develop. 9:358-369; Norris and Manley (1996) Genes Develop. 10:862-872), or binding by small molecule activators of the TH pocket. However, 'free' TH modules inside the cell (Norris and Manley (1995) Genes Develop. 9:358-369; Winans and Hashimoto (1995) Molec. Biol. Cell 6:587-596) could act as catalytic, CheY-like triggers by activating and docking with errant Tube/Pelle complexes.

Morphogenetic receptors and immune -defense.

The evolutionary link between insect and vertebrate immune systems is stamped in DNA: genes encoding antimicrobial factors in insects display upstream motifs similar to acute phase response elements known to bind NF- KB transcription factors in mammals. Hultmark (1993)

Trends Genet. 9:178-183. Dorsal, and two Dorsal-related factors, Dif and Relish, help induce these defense proteins after bacterial challenge (Reichhart, et al. (1993) C. R. Acad. Sci. Paris 316:1218-1224; Ip, et al . (1993) Cell 75:753-763; and Dushay, et al. (1996) Proc. Natl. Acad. Sci. USA 93:10343-10347); Toll, or other DTLRs, likely modulate these rapid immune responses in adult Drosophila (Lemaitre, et al. (1996) Cell 86:973-983; and Rosetto, et al. (1995) Biochem. Biophys. Res. Commun. 209:111-116). These mechanistic parallels to the IL-1 inflammatory response in vertebrates are evidence of the functional versatility of the Toll signaling pathway, and suggest an ancient synergy between embryonic patterning and innate immunity (Belvin and Anderson (1996) Ann . Rev. Cell Develop. Biol. 12:393-416; Lemaitre, et al. (1996)

Cell 86:973-983; Wasserman (1993) Molec. Biol. Cell 4:767- 771; Wilson, et al. (1997) Curr. Biol. 7:175-178; Hultmark (1993) Trends Genet. 9:178-183; Reichhart, et al. (1993) C. R. Acad. Sci. Paris 316:1218-1224; Ip, et al. (1993) Cell 75:753-763; Dushay, et al. (1996) Proc. Natl. Acad. Sci. USA 93:10343-10347; Rosetto, et al. (1995) Biochem. Biophys. Res. Commun. 209:111-116; Medzhitov and Janeway (1997) Curr. Qpin. Immunol. 9:4-9; and Medzhitov and Janeway (1997) Curr. Qpin. Immunol. 9:4-9). The closer homology of insect and human DTLR proteins invites an even stronger overlap of biological functions that supersedes the purely immune parallels to IL-1 systems, and lends potential molecular regulators to dorso-ventral and other transformations of vertebrate embryos. DeRobertis and Sasai (1996) Nature 380:37-40; and A^'rendt and Nϋbler-Jung (1997) Mech. Develop. 61:7-21.

The present description of an emergent, robust receptor family in humans mirrors the recent discovery of the vertebrate Frizzled receptors for Wnt patterning factors. Wang, et al. (1996) J. Biol. Chem. 271:4468- 4476. As numerous other cytokine-receptor systems have roles in early development (Lemaire and Kodjabachian (1996) Trends Genet. 12:525-531), perhaps the distinct cellular contexts of compact embryos and gangly adults simply result in familiar signaling pathways and their diffusible triggers having different biological outcomes at different times, e.g., morphogenesis versus immune defense for DTLRs. For insect, plant, and human Toll- related systems (Hardiman, et al. (1996) Oncogene 13:2467- 2475; Wilson, et al. (1997) Curr. Biol. 7:175-178), these signals course through a regulatory TH domain that intriguingly resembles a bacterial transducing engine (Parkinson (1993) Cell 73 : 857-871) .

In particular, the DTLR6 exhibits structural features which establish its membership in the family. Moreover, members of the family have been implicated in a number of significant developmental disease conditions and with function of the innate immune system. In particular, the DTLR6 has been mapped to the X chromosome to a location which is a hot spot for major developmental abnormalities. See, e.g., The Sanger Center: human X chromosome website http://www.sanger.ac.uk/HGP/ChrX/index.shtml; and the Baylor College of Medicine Human Genome Sequencing website http: //gc.bcm. tmc. edu: 8088/cgi-bin/seq/home.

The accession number for the deposited PAC is AC003046. This accession number contains sequence from two PACs: RPC-164K3 and RPC-263P4. These two PAC sequences mapped on human chromosome Xp22 at the Baylor web site between STS markers DXS704 and DXS7166. This region is a "hot spot" for severe developmental abnormalities .

III. Amplification of DTLR fragment by PCR

Two appropriate primer sequences are selected (see Tables 1 through 10) . RT-PCR is used on an appropriate mRNA sample selected for the presence of message to produce a partial or full length cDNA, e.g., a sample which expresses the gene. See, e.g., Innis, et al. (eds. 1990) PCR Protocols: A Guide to Methods and Applications Academic Press, San Diego, CA; .and Dieffenbach and Dveksler (eds. 1995) PCR Primer: A Laboratory Manual Cold Spring Harbor Press, CSH, NY. Such will allow determination of a useful sequence to probe for_. a full length gene in a cDNA library. The DTLR6 is a contiguous sequence in the genome, which may suggest that the other DTLRs are also. Thus, PCR on geno ic DNA may yield full length contiguous sequence, and chromosome walking methodology would then be applicable. Alternatively, sequence databases will contain sequence corresponding to portions of the described embodiments, or closely rel"ated forms, e.g., alternative splicing, etc. Expression cloning techniques also may be applied on cDNA libraries.

IV. Tissue distribution of DTLRs

Message for each gene encoding these DTLRs has been detected. See Figures 5A-5F. Other cells and tissues will be assayed by appropriate technology, e.g., PCR, immunoassay, hybridization, or otherwise. Tissue and organ cDNA preparations are available, e.g., from Clontech, Mountain View, CA. Identification of sources of natural expression are useful, as described. Southern Analysis: DNA (5 μg) from a primary a plifie cDNA library is digested with appropriate restriction enzymes to release the inserts, run on a 1% agarose gel and transferred to a nylon membrane (Schleicher and Schuell, Keene, NH) .

Samples for human mRNA isolation would typically include, e.g.: peripheral blood mononuclear cells

(monocytes, T cells, NK cells, granulocytes, B cells), resting (T100) ; peripheral blood mononuclear cells, activated with anti-CD3 for 2, 6, 12 h pooled (T101); T cell, THO clone Mot 72, resting (T102); T cell, THO clone Mot 72, activated with anti-CD28 and anti-CD3 for 3, 6, 12 h pooled (T103) ; T cell, THO clone Mot 72, anergic treated with specific peptide for 2, 7, 12 h pooled (T104); T cell, THl clone HY06, resting (T107) ; T cell, THl clone HY06, activated with anti-CD28 and anti-CD3 for 3, 6, 12 h pooled (T108) ; T cell, THl clone HY06, anergic treated with specific peptide for 2, 6, 12 h pooled (T109) ; T cell, TH2 clone HY935, resting (THO) ; T cell, TH2 clone HY935, activated with anti-CD28 and anti-CD3 for 2, 7, 12 h pooled (Till) ; T cells CD4+CD45RO- T cells polarized 27 days in anti-CD28, IL-4, and anti IFN-γ, TH2 polarized, activated with anti-CD3 and anti-CD28 4 h (T116) ; T cell tumor lines Jurkat and Hut78, resting (T117) ; T cell clones, pooled AD130.2, Tc783.12, Tc783.13, Tc783.58, Tc782.69, resting (T118); T cell random γδ T cell clones, resting (T119) ; Splenocytes, resting (BlOO) ; Splenocytes, activated with anti-CD40 and IL-4 (B101) ; B cell EBV lines pooled WT49, RSB, JY, CVIR, 721.221, RM3, HSY, resting (B102) ; B cell line JY, activated with PMA and ionomycin for 1, 6 h pooled (B103) ; NK 20 clones pooled, resting (K100); NK 20 clones pooled, activated with PMA and ionomycin for 6 h (K101) ; NKL clone, derived from peripheral blood of LGL leukemia patient, IL-2 treated (K106) ; NK cytotoxic clone 640-A30-1, resting (K107); hematopoietic precursor line TF1, activated with PMA and ionomycin for 1, 6 h pooled (C100) ; U937 premonocytic line, resting (M100) ; U937 premonocytic line, activated with PMA and ionomycin for 1, 6 h pooled (M101) ; elutriated monocytes, activated with LPS, IFNγ, anti-IL-10 for 1, 2, 6, 12, 24 h pooled (M102) ; elutriated monocytes, activated with LPS, IFNγ, IL-10 for ,1, 2, 6, 12, 24 h pooled (M103) ; elutriated monocytes, activated with LPS, IFNγ, anti-IL-10. for 4, 16 h pooled (M106) ; elutriated monocytes, activated with LPS, IFNγ, IL-10 for 4, 16 h pooled (M107); elutriated monocytes, activated LPS for 1 h (M108); elutriated monocytes, activated LPS for 6 h (M109); DC 70% CDla+, from CD34+ GM-CSF, TNFα 12 days, resting (D101) ; DC 70% CDla+, from CD34+ GM-CSF, TNFα 12 days, activated with PMA and ionomycin for 1 hr (D102); DC 70% CDla+, from CD34+ GM-CSF, TNFα 12 days, activated with PMA and ionomycin for 6 hr (D103) ; DC 95% CDla+, from CD34+ GM-CSF, TNFα 12 days FACS sorted, activated with PMA and ionomycin for 1, 6 h pooled (D104); DC 95% CD14+, ex CD34+ GM-CSF, TNFα 12 days FACS sorted, activated with PMA and ionomycin 1, 6 hr pooled (D105) ; DC CDla+ CD86+, from CD34+ GM-CSF, TNFα 12 days FACS sorted, activated with PMA and ionomycin for 1, 6 h pooled (D106) ; DC from monocytes GM-CSF, IL-4 5 days, resting (D107); DC from monocytes GM- CSF, IL-4 5 days, resting (D108); DC from monocytes GM- CSF, IL-4 5 days, activated LPS 4, 16 h pooled (D109) ; DC from monocytes GM-CSF, IL-4 5 days, activated TNFα, monocyte supe for 4, 16 h pooled (DUO); leiomyoma Lll benign tumor (X101) ; normal myometrium M5 (0115); malignant leiomyosarcoma GS1 (X103) ; lung fibroblast sarcoma line MRC5, activated with PMA and ionomycin for 1, 6 h pooled (C101) ; kidney epithelial carcinoma cell line CHA, activated with PMA and ionomycin for 1, 6 h pooled (C102); kidney fetal 28 wk male (O100) ; lung fetal 28 wk male (O101) ; liver fetal 28 wk male (O102) ; heart fetal 28 wk male (O103) ; brain fetal 28 wk male (O104); gallbladder fetal 28 wk male (O106) ; small intestine fetal 28 wk male (O107); adipose tissue fetal 28 wk male (0108); ovary fetal 25 wk female (O109) ; uterus fetal 25 wk female (OHO) ; testes fetal 28 wk male (0111) ; spleen fetal 28 wk male (0112); adult placenta 28 wk (0113); and tonsil inflamed, from 12 year old (X100) .

Samples for mouse mRNA isolation can include, e.g.: resting mouse fibroblastic L cell line (C200); Braf:ER (Braf fusion to .estrogen receptor) transfected cells, control (C201) ; T cells, THl polarized (Mell4 bright, CD4+ cells from spleen, polarized for 7 days with IFN-γ and anti IL-4; T200) ; T cells, TH2 polarized (Mell4 bright, CD4+ cells from spleen, polarized for 7 days with IL-4 and anti-IFN-γ; T201) ; T cells, highly THl polarized (see Openshaw, et al. (1995) J. Exp. Med. 182:1357-1367; activated with anti-CD3 for 2, 6, 16 h pooled; T202); T cells, highly TH2 polarized (see Openshaw, et al. (1995) J. Exp. Med. 182:1357-1367; activated with anti-CD3 for 2, 6, 16 h pooled; T203) ; CD44- CD25+ pre T cells, sorted from thymus (T204); THl T cell clone Dl.l, resting for 3 weeks after last stimulation with antigen (T205) ; THl T cell clone Dl.l, 10 μg/ml ConA stimulated 15 h (T206) ; TH2 T cell clone CDC35, resting for 3 weeks after last stimulation with antigen (T207); TH2 T cell clone CDC35, 10 μg/ml ConA stimulated 15 h (T208); Mell4+ naive T cells from spleen, resting (T209) ; Mell4+ T cells, polarized to Thl with IFN-γ/IL-12/anti-IL-4 for 6, 12, 24 h pooled (T210); Mell4+ T cells, polarized to Th2 with IL-4/anti- IFN-γ for 6, 13, 24 h pooled (T211) ; unstimulated mature B cell leukemia cell line A20 (B200) ; unstimulated B cell line CH12 (B201) ; unstimulated large B cells from spleen (B202); B cells from total spleen, LPS activated (B203); metrizamide enriched dendritic cells from spleen, resting (D200) ; dendritic cells from bone marrow, resting (D201) ; monocyte cell line RAW 264.7 activated with LPS 4 h (M200) ; bone-marrow macrophages derived with GM and M-CSF (M201) ; macrophage cell line J774, resting (M202) ; macrophage cell line J774 + LPS + anti-IL-10 at 0.5, 1, 3, 6, 12 h pooled (M203); macrophage cell line J774 + LPS + IL-10 at 0.5, 1, 3, 5, 12 h pooled (M204) ; aerosol challenged mouse lung tissue, Th2 primers, aerosol OVA challenge 7, 14, 23 h pooled (see Garlisi, et al. (1995) Clinical Immunology and Immunopatholόgy 75:75-83; X206) ; Nippostrongulus-infected lung tissue (see Coffman, et al. (1989) Science 245:308-310; X200) ; total adult lung, normal (O200) ; total lung, rag-1 (see Schwarz, et al. (1993) Immunodeficiency 4:249-252; O205) ; IL-10 K.O. spleen (see Kuhn, et al. (1991) Cell 75:263-274; X201) ; total adult spleen, normal (O201) ; total spleen, rag-1

(O207); IL-10 K.O. Peyer's patches (O202) ; total Peyer's patches, normal (O210) ; IL-10 K.O. mesenteric lymph nodes (X203) ; total mesenteric lymph nodes, normal (0211); IL- 10 K.O. colon (X203); total colon, normal (0212); NOD mouse pancreas (see Makino, et al. (1980) Jikken Dobutsu 29:1-13; X205) ; total thymus, rag-1 (O208); total kidney, rag-1 (O209) ; total heart, rag-1 (O202); total brain, rag- 1 (O203); total testes, rag-1 (O204); total liver, rag-1 (O206) ; rat normal joint tissue (O300) ; and rat arthritic joint tissue (X300) .

The DTLRIO has been found to be highly expressed in precursor dendritic cell type 2 (pDC2). See, e.g., Rissoan, et al. (1999) Science 283:1183-1186; and Siegal, et al. (1999) Science 284:1835-1837. However, it is not expressed on monocytes. The restricted expression of DTLRIO reinforces the suggestions of a role for the receptor in host immune defense. The pDC2 cells are natural interferon producing cells (NIPC) , which produce large amounts of IFNα in response to Herpes simplex virus infection.

V. Cloning of species counterparts of DTLRs

Various strategies are used to obtain species counterparts of these DTLRs, preferably from other primates. One method is by cross hybridization using closely related species DNA probes. It may be useful to go into evolutionarily similar species as intermediate steps. Another method is by using specific PCR primers based on the identification of blocks of similarity or difference between particular species, e.g., human, genes, e.g., areas of highly conserved or ήonconserved polypeptide or nucleotide sequence; Alternatively, antibodies may be used for expression cloning.

VI. Production of mammalian DTLR protein

An appropriate, e.g., GST, fusion construct is engineered for expression, e.g., in E. coli. For example, a mouse IGIF pGex plasmid is constructed and transformed into E. coli. Freshly transformed cells are grown in LB medium containing 50 μg/ml ampicillin and induced with IPTG (Sigma, St. Louis, MO). After overnight induction, the bacteria are harvested and the pellets containing the DTLR protein are isolated. The pellets are homogenized in TE buffer (50 mM Tris-base pH 8.0, 10 mM EDTA and 2 mM pefabloc) in 2 liters. This material is passed through a microfluidizer (Microfluidics, Newton, MA) three times. The fluidized supernatant is spun down on a Sorvall GS-3 rotor for 1 h at 13,000 rp . The resulting supernatant containing the DTLR protein' is filtered and passed over a glutathione-SEPHAROSE column equilibrated in 50 mM Tris- base pH 8.0. The fractions containing the DTLR-GST fusion protein are pooled and cleaved with thro bin (Enzyme

Research Laboratories, Inc., South Bend, IN). The cleaved pool is then passed over a Q-SEPHAROSE column equilibrated in 50 mM Tris-base. Fractions containing DTLR are pooled and diluted in cold distilled H2θ, to lower the conductivity, and passed back over a fresh Q-Sepharose column, alone or in succession with an immunoaffinity antibody column.. Fractions containing the DTLR protein are pooled, aliquoted, and stored in the -70° C freezer. Comparison of the CD spectrum with DTLRl protein may suggest that the protein is correctly folded. See Hazuda, et al. (1969) J. Biol. Chem. 264:1689-1693. VII. Biological Assays with DTLRs

Biological assays will generally be directed to the ligand binding feature of the protein or to the kinase/phosphatase activity of the- receptor. The activity will typically be reversible, as are many other enzyme actions, and will mediate phosphatase or phosphorylase activities, which activities are easily measured by standard procedures. See, e.g., Hardie, et al. (eds. 1995) The Protein Kinase FactBook vols. I and II, Academic Press, San Diego, CA; Hanks, et al. (1991) Meth. Enzymol. 200:38-62; Hunter, et al. (1992) Cell 70:375-388; Lewin (1990) Cell 61:743-752; Pines, et al. (1991) Cold Spring Harbor Symp. -Quant. Biol. 56:449-463; and Parker, et al . (1993) Nature 363:736-738.

The family of interleukin Is contains molecules, each of which is an important mediator of inflammatory disease. For a comprehensive review, see Dinarello (1996) "Biologic basis for interleukin-1 in disease" Blood 87:2095-2147. There are suggestions that the various Toll ligands may play important roles in the initiation of disease, particularly inflammatory responses. The finding of novel proteins related to the IL-1 family furthers the identification of molecules that provide the molecular basis for initiation of disease and allow for the development of therapeutic strategies of increased range and efficacy.

VIII. Preparation of antibodies specific for, e.g., DTLR4 Inbred Balb/c mice are immunized intraperitoneally with recombinant forms of the protein, e.g., purified DTLR4 or stable transfected NIH-3T3 cells. Animals are boosted at appropriate time points with protein, with or without additional adjuvant, to further stimulate antibody production. Serum is collected, or hybridomas produced with harvested spleens. Alternatively, Balb/c mice are immunized with cells transformed with the gene or fragments thereof, either endogenous or exogenous cells, or with isolated membranes enriched for expression of the antigen. Serum is collected at the appropriate time, • typically after numerous further administrations. Various gene therapy techniques may be useful, e.g., in producing protein in situ, for generating an immune response.

Monoclonal antibodies may be made. For example, splenocytes are fused with an appropriate fusion partner and hybridomas are selected in growth medium by standard procedures. Hybridoma supernatants are screened for the presence of antibodies which bind to the desired DTLR, e.g., by ELISA or other assay. Antibodies which specifically recognize specific DTLR embodiments may also be selected or prepared.

In another method, synthetic peptides or purified protein are presented to an immune system to generate monoclonal or polyclonal antibodies. See, e.g., Coligan (1991) Current Protocols in Immunology Wiley/Greene; and Harlow and Lane (1989) Antibodies: A Laboratory Manual Cold Spring Harbor Press. In appropriate situations, the binding reagent is either labeled as described above, e.g., fluorescence or otherwise, or immobilized to a substrate for panning methods. Nucleic acids may also be introduced into cells in an animal to produce the antigen, which serves to elicit an immune response. See, e.g., Wang, et al . (-1993) Proc. Nat'l. Acad. Sci. 90:4156-4160; Barry, et al. (1994) BioTechniques 16:616-619; and Xiang, et al. (1995) Immunity 2: 129-135.

IX. Production of fusion proteins with, e.g., DTLR5

Various fusion constructs are made with DTLR5. This portion of the gene is fused to an epitope tag, e.g., a FLAG tag, or to a two hybrid system construct. See, e.g., Fields and Song (1989) Nature 340:245-246. The epitope tag may be used in an expression cloning procedure with detection with anti-FLAG antibodies to detect a binding partner, e.g., ligand for the respective DTLR5. The two hybrid system may also be used to isolate proteins which specifically bind to DTLR5.

X. Chromosomal mapping of DTLRs

Chromosome spreads are prepared. In situ hybridization is performed on chromosome preparations obtained from phytohemagglutinin-stimulated lymphocytes cultured for 72 h. 5-bromodeoxyuridine is added for the final seven hours of culture (60 μg/ml of medium), to ensure a posthybridization chromosomal banding of good quality. An appropriate fragment, e.g., a PCR fragment, amplified with the help of primers on total B cell cDNA template, is cloned into an appropriate vector. The vector is labeled by nick-translation with ^H . The radiolabeled probe is hybridized to metaphase spreads as described in Mattel, et al . (1985) Hum. Genet. 69:327-331. After coating with nuclear track emulsion (KODAK NTB2), slides are exposed, e.g., for 18 days at 4° C. To avoid any slipping of silver grains during the banding procedure, chromosome spreads are first stained with buffered Giemsa solution and metaphase photographed. R- banding is then performed by the fluorochrome-photolysis- Giemsa (FPG) method and metaphases rephotographed before analysis.

Alternatively, FISH can be performed, as described above. The DTLR genes are located on different chromosomes. DTLR2 and DTLR3 are localized to human chromosome 4; DTLR4 is localized to human chromosome 9, and DTLR5 is localized to human chromosome 1. See Figures 4A-4D. XI. Structure activity relationship

Information on the criticality of particular residues is determined using standard procedures and analysis. Standard mutagenesis analysis is performed, e.g., by generating many different variants- at determined positions, e.g., at the positions identified above, and evaluating biological activities of the variants. This may be performed to the extent of determining positions which modify activity, or to focus on specific positions to determine the residues which can be substituted to either retain, block, or modulate biological activity.

Alternatively, analysis of natural variants can indicate what positions tolerate natural mutations. This may result from populational analysis of variation among individuals, or across strains or species. Samples from selected individuals are analyzed, e.g., by PCR analysis and sequencing. This allows evaluation of population polymorphisms .

XI. Isolation of a ligand for a DTLR

A DTLR can be used as a specific binding reagent to identify its binding partner, by taking advantage of its specificity of binding, much like an antibody would be used. A binding reagent is either labeled as described above, e.g., fluorescence or otherwise, or immobilized to a substrate for panning methods.

The binding composition is used to screen an expression library made from a cell line which expresses a binding partner, i.e., ligand, preferably membrane associated. Standard staining techniques are used to detect or sort surface expressed ligand, or surface expressing transformed cells are screened by panning. Screening of intracellular expression is performed by various staining or immunofluorescence procedures. See also McMahan, et al. (1991) EMBO J. 10:2821-2832. For example, on day 0, precoat 2-chamber permanox slides with 1 ml per chamber of fibronectin, 10 ng/ml in PBS, for 30 min at room temperature. Rinse once with PBS. Then plate COS cells at 2-3 x 10⁵ cells per chamber in 1.5 ml of growth media. Incubate overnight at 37° C. On day 1 for each sample, prepare 0.5 ml of a solution of 66 μg/ml DEAE-dextran, 66 μM chloroquine, and 4 μg DNA in serum free DME. For each set, a positive control is prepared, e.g., of DTLR-FLAG cDNA at 1 and 1/200 dilution, and a negative mock. Rinse cells with serum free DME. Add the DNA solution and incubate 5 hr at 37° C. Remove the medium and add 0.5 ml 10% DMSO in DME for 2.5 min. Remove and wash once with DME. Add 1.5 ml growth medium and incubate overnight. On day 2, change the medium. On days 3 or 4, the cells are fixed and stained. Rinse the cells twice with Hank's Buffered Saline Solution (HBSS) and fix in 4% paraformaldehyde (PFA) /glucose for 5 min. Wash 3X with HBSS. The slides may be stored at -80° C after all liquid is removed. For each chamber, 0.5 ml incubations are performed as follows. Add HBSS/saponin (0.1%) with 32 μl/ml of 1 M NaN3 for 20 min. Cells are then washed with

HBSS/saponin IX. Add appropriate DTLR or DTLR/antibo y complex to cells and incubate for 30 min. Wash cells twice with HBSS/saponin. If appropriate, add first antibody for 30 min. Add second antibody, e.g., Vector anti-mouse antibody, at 1/200 dilution, and incubate for 30 min. Prepare ELISA solution, e.g., Vector Elite ABC horseradish peroxidase solution, and preincubate for 30 min. Use, e.g., 1 drop of solution A (avidin) and 1 drop solution B (biotin) per 2.5 ml HBSS/saponin. Wash cells twice with HBSS/saponin. Add ABC HRP solution and incubate for 30 min. Wash cells twice with HBSS, second wash for 2 min, which closes cells. Then add Vector diaminobenzoic acid (DAB) for 5 to 10 min. Use 2 drops of buffer plus 4 drops DAB plus 2 drops of H2O2 P^er 5 ml of glass distilled water. Carefully remove chamber and rinse slide in water. Air dry for a few minutes, then add 1 drop of Crystal Mount and a cover slip. Bake for 5 min at 85-90° C. Evaluate positive staining of- pools and progressively subclone to isolation of single genes responsible for the binding .

Alternatively, DTLR reagents are used to affinity purify or sort out cells expressing a putative ligand. See, e.g., Sambrook, et al. or Ausubel, et al.

Another strategy is to screen for a membrane bound receptor by panning. The receptor cDNA is constructed as described above. The ligand can be immobilized and used to immobilize expressing cells. Immobilization may be achieved by use of appropriate antibodies which recognize, e.g., a FLAG sequence of a DTLR fusion construct, or by use of antibodies raised against the first antibodies. Recursive cycles of selection and amplification lead to enrichment of appropriate clones and eventual isolation of receptor expressing clones.

Phage expression libraries can be screened by mammalian DTLRs. Appropriate label techniques, e.g., anti-FLAG antibodies, will allow specific labeling of appropriate clones.

All citations herein are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only, and the invention is to be limited by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled; and the invention is not to be limited by the specific embodiments that have been presented herein by way of example.

Humans have two distinct types of dendritic cell (DC) precursors. Peripheral blood monocytes (pDCl) give rise to immature yeloid DCs after culturing with GMCSF and IL- 4. These immature cells become mature myeloid DCs (DC1) after stimulation with CD40 ligand (CD40L) . The CD4+CD3- CDllc- plasmacytoid cells (pDC2) from blood or tonsils give rise to a distinct type of immature DC after culture with IL-3, and differentiate into mature DCs (DC2) after CD40L stimulation. Rissoan, et al . (1999) Science 283:1183-1186. Siegal, et al. (1999) Science 284:1835-1837, show that pDC2 is the "Natural Interferon Producing Cell" (IPC) . Interferons (IFNs) are the most important cytokines in antiviral immune responses. "Natural IFN- producing cells" (NIPCs) in human blood express CD4 and major histocompatibility complex class II proteins, but have not been isolated and further characterized because of their rarity, rapid apoptosis, and lack of lineage markers. Purified NIPCs are here shown to be the CD4(+)CDllc- type 2 dendritic cell precursors (pDC2s), which produce 200 to 1000 times more IFN than other blood cells after microbial challenge. pDC2s are thus an effector cell type of the immune system, critical for antiviral and antitumor immune responses. They are implicated as important cells in HIV infected patients Toll-like receptor (TLR) molecules belong to the IL- 1/Toll receptor family. Ligands for TLR2 and TLR4 have been identified, and their functions are related to the host immune response to microbial antigen or injury. Takeuchi, et al. (1999) Immunity 11:443-451; and Noshino, et al. (1999) J. Immunol. 162:3749-3752. The pattern of expression of TLRs seem to be restricted. Muzio, et al. (2000) J. Immunol. 164:5998-6004. With these findings that: i) TLR10 is highly expressed and restricted in pDC2s, and ii) pDC2 is the NIPC, it is likely that TLR10 will play an important role in the host's innate immune response .

Claims (1)

1. WHAT IS CLAIMED IS:

   1. A composition of matter selected from the group consisting of: a) a substantially pure or recombinant DTLR2 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 4; b) a natural sequence DTLR2 of SEQ ID NO: 4; c) a fusion protein comprising DTLR2 sequence; d) a substantially pure or recombinant DTLR3 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 6; e) a natural sequence DTLR3 of SEQ ID NO: 6; f) a fusion protein comprising DTLR3 sequence; g) a substantially pure or recombinant DTLR4 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 8; h) a natural sequence DTLR4 of SEQ ID NO: 8; i) a fusion protein comprising DTLR4 sequence; j) a substantially pure or recombinant DTLR5 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 10; k) a natural sequence DTLR5 comprising SEQ ID NO: 10; 1) a fusion protein comprising DTLR5 sequence; m) a substantially pure or recombinant DTLR6 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 12, 28, or 30; n) a natural sequence DTLR6 comprising SEQ ID NO: 12, 28, or 30; o) a fusion protein comprising DTLR6 sequence; p) a substantially pure or recombinant DTLR7 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 16,

   18, or 37; q) a natural sequence DTLR7 comprising SEQ ID NO:

   16, 18, or 37; r) a fusion protein comprising DTLR7 sequence; s) a substantially pure or recombinant DTLR8 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 32 or 39; t) a natural sequence DTLR8 comprising SEQ ID NO: 32 or 39; u) a fusion protein comprising DTLR8 sequence; v) a substantially pure or recombinant DTLR9 protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ ID NO: 22 or 41; w) a natural sequence DTLR9 comprising SEQ ID NO: 22 or 41; x) a fusion protein comprising DTLR9 sequence; y) a substantially pure or recombinant DTLRIO protein or peptide exhibiting identity over a length of at least about 12 amino acids to SEQ

   ID NO: 34, 43, or 45; z) a natural sequence DTLRIO comprising SEQ ID NO:

   34, 43, or 45; zz) a fusion protein comprising DTLRIO sequence.

   2. A substantially pure or isolated protein comprising a segment exhibiting sequence identity to a corresponding portion of a: a) DTLR2 of Claim 1, and said identity is over at least: a) about 15 amino acids; b) about 19 amino acids; or c) about 25 amino acids; b) DTLR3 of Claim 1, and said identity is over at least: a) about 15 amino acids; b) about 19 amino acids; or c) about 25 amino acids; c) DTLR4 of Claim 1, and said identity is over at least: a) about 15 amino acids; b) about 19 amino acids; or c) about 25 amino acids; d) DTLR5 of Claim 1, and said identity is over at least : a) about 15 amino acids; b) about 19 amino acids; or c) about 25 amino acids; e) DTLR6 of Claim 1, and said identity is over at least : a) about 15 amino acids; b) about 19 amino acids; or c) about 25 amino acids; f) DTLR7 of Claim 1, and said identity is over at least: a) about 15 amino acids; b) about 19 amino acids; or c) about 25 amino acids; g) DTLR8 of Claim 1, and said identity is over ^"at least : a) about 15 amino acids; b) about 19 amino acids; or c) about 25 amino acids; h) DTLR9 of Claim 1, and said identity is over at least : a) about 15 amino acids; b) about 19 amino acids; or c) about 25 amino acids; or i) DTLRIO of Claim 1, and said identity is over at least : a) about 15 amino acids; b) about 19 amino acids; or c) aboμt 25 amino_ acids.

   3. The composition of matter of Claim 1, wherein said: a) DTLR2: i ) comprises a mature sequence of Table 2 ; or ii ) lacks post-translational modification ; b) DTLR3 : i ) comprises a mature sequence of Table 3 ; or ii ) lacks post-translational modification ; c) DTLR4: i) comprises a mature sequence of Table 4; or ii) lacks post-translational modification; d) DTLRS: i) comprises a mature sequence of Table 5; or ii) lacks post-translational modification; e) DTLR6: i) comprises a mature sequence of Table 6; or ii) lacks post-translational modification; f) DTLR7: i) comprises a sequence of Table 7; or ii) lacks post-translational modification; g) DTLR8: i) comprises a sequence of Table 8; or ii) lacks post-translational modification; h) DTLR9: i) comprises a sequence of Table 9; or ii) lacks post-translational modification; i) DTLRIO: i) comprises a sequence of Table 10; or ii) lacks post-translational modification; or j) protein or peptide: i) is from a warm blooded animal selected from a mammal, including a primate, such as a human; ii) comprises at least one polypeptide segment of SEQ ID NO: 4, 6, 26, 10, 12, 28, 30, 16, 18, 37, 39, 32, 22, 34, 43, or 45; iii) exhibits a plurality of said segments of identity; iv) is a natural allelic variant of DTLR2,

   DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO; v) has a length at least about 30 amino acids; vi) exhibits at least two non-overlapping epitopes which are specific for a primate DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO; vii) exhibits sequence identity over a length of at least about 35 amino acids to a primate DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7, DTLR8, DTLR9. or DTLRl0; viii) further exhibits at least two non- overlapping epitopes which are specific for a primate DTLR2, DTLR3, DTLR4 , DTLR5,

   DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO; ix) exhibits identity over a length of at least about 20 amino acids to a rodent DTLR6; x) is glycosylated; xi) has a molecular weight of at least 100 kD with natural glycosylation; xii) is a synthetic polypeptide; xiii) is attached to a solid substrate; xiv) is conjugated to another chemical moiety; xv) is a 5-fold or less substitution from natural sequence; or xvi) is a deletion or insertion variant from a natural sequence.

   A composition comprising: sterile DTLR2 protein or peptide of Claim 1, b) said DTLR2 protein or peptide of Claim 1 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral> rectal, nasal, topical, or parenteral administration; c) a sterile DTLR3 protein or peptide of Claim 1; d) said DTLR3 protein or peptide of Claim 1 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral, rectal, nasal, topical, or parenteral administration; e) a sterile DTLR4 protein or peptide of Claim 1, f) said DTLR4 protein or peptide of Claim 1 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral, rectal, nasal, topical, or parenteral administration; g) a sterile DTLR5 protein or peptide of Claim 1; h) said DTLR5 protein or peptide of Claim 1 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral, rectal, nasal, topical, or parenteral administration; i) a sterile DTLR6 protein or peptide of Claim 1; j) said DTLR6 protein or peptide of Claim 1 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral, rectal, nasal, topical, or parenteral administration; k) a sterile DTLR7 protein or peptide of Claim 1; 1) said DTLR7 protein or peptide of Claim 1 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral, rectal, nasal, topical, or parenteral administration; m) a sterile DTLR8 protein or peptide of Claim 1; n) said DTLR8 protein or peptide of Claim 1 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral, rectal, nasal, topical, or parenteral administration; o) a sterile DTLR9 protein or peptide of Claim 1; p) said DTLR9 protein or peptide of Claim 1 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral, rectal, nasal, topical, or parenteral administration; q) a sterile DTLRIO protein or peptide of Claim 1; r) said DTLRIO protein or peptide of Claim 1 and a carrier, wherein said carrier is: i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral, rectal, nasal, topical, or parenteral administration;

   5. The fusion protein of Claim 1, comprising: a) mature protein comprising sequence of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; b) a detection or purification tag, including a

   FLAG, His6, or Ig sequence; or c) sequence of another receptor protein.

   6. A kit comprising a protein or polypeptide of Claim 1, and: a) a compartment comprising said protein or polypeptide; and/or b) instructions for use or disposal of reagents in said kit.

   7. A binding compound comprising an antigen binding site from an antibody, which specifically binds to a natural DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO protein of Claim 1, wherein: a) said protein is a primate protein; b) said binding compound is an Fv, Fab, or Fab2 fragment; c) said binding compound is conjugated to another chemical moiety; or d) said antibody: i) is raised against a peptide sequence of a mature polypeptide of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; ii) is raised against a mature DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7 , DTLR8, DTLR9, or DTLRIO; iii) is raised to a purified human DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7 , DTLR8,

   DTLR9, or DTLRIO; iv) is immunoselected; v) is a polyclonal antibody; vi) binds to a denatured DTLR2, DTLR3, DTLR4, DTLR5, DTLR6, DTLR7, DTLR8, DTLR9, or

   DTLRIO; vii) exhibits a Kd to antigen of at least 30 μM; viii) is attached to a solid substrate, including a bead or plastic membrane; ix) is in a sterile composition; or x) is detectably labeled, including a radioactive or fluorescent label.

   8. A kit comprising, said binding compound of Claim 7, and: a) a compartment comprising said binding compound; and/or b) instructions for use or disposal of reagents in said kit.

   9. A method of:

   A) making an antibody of Claim 7, comprising immunizing an immune system with an immunogenic amount of: a) a primate DTLR2 , b) a primate DTLR3_; c) a primate DTLR , d) a primate DTLR5, e) a primate DTLR6, f) a primate DTLR7 , g) a primate DTLR8 , h) a primate DTLR9; or i) a primate DTLRIO; thereby causing said antibody to be produced; or B) producing an antigen: antibody complex, comprising' contacting an antibody of Claim 7 with: a) a mammalian DTLR2 protein or peptide; b) a mammalian DTLR3 protein or peptide; c) a mammalian DTLR4 protein or peptide; d) a mammalian DTLR5 protein or peptide; e) a mammalian DTLR6 protein or peptide; f) a mammalian DTLR7 protein or peptide; g) a mammalian DTLR8 protein or peptide; h) a mammalian DTLR9 protein or peptide; or i) a mammalian DTLRIO protein or peptide; thereby allowing said complex to form.

   10. A composition comprising: a) a sterile binding compound of Claim 7, or b) said binding compound of Claim 7 and a carrier, wherein said carrier is:- i) an aqueous compound, including water, saline, and/or buffer; and/or ii) formulated for oral, rectal, nasal, topical, or parenteral administration.

   11. An isolated or recombinant nucleic acid encoding a protein or peptide or fusion protein of Claim 1, wherein: a) said DTLR is from a mammal; or b) said nucleic acid: i) encodes an antigenic peptide sequence of

   Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; ii) encodes a plurality of antigenic peptide sequences of Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; iii) exhibits at least about 80% identity to a natural cDNA encoding said segment; iv) is an expression vector; v) further comprises an origin of replication; vi) is from a natural source; vii) comprises a detectable label; viii) comprises synthetic nucleotide sequence; ix) is less than 6 kb, preferably less than 3 kb; x) is from a mammal, including a primate; xi) comprises a natural full length coding sequence; xii) is a hybridization probe for a gene encoding said DTLR; xiii) comprises at least 17 contiguous nucleotides from Table 2, 3, 4, 5, 6, 7, 8,

   9, or 10; xiv) comprises at plurality of nonoverlapping segments of least 17 contiguous nucleotides from Table 2, 3, 4, 5, 6, 7, 8, 9, or 10; or xv) is a PCR primer, PCR product, or mutagenesis primer.

   12. A cell, tissue, or organ comprising a recombinant nucleic acid of Claim 11.

   13. The cell of Claim 12, wherein said cell is: a) a prokaryotic cell; b) a eukaryotic cell; c) a bacterial cell; d) a yeast cell; e) an insect cell; f) a mammalian cell; g) a mouse cell; h) a primate cell; or i) a human cell.

   14. A kit comprising said nucleic acid of Claim 11, and: a) a compartment comprising said nucleic acid; b) a compartment further comprising a primate

   DTLR2, DTLR3, DTLR4 , DTLR5, DTLR6, DTLR7, DTLR8 , DTLR9, or DTLRIO protein or polypeptide; and/or c) instructions for use or disposal of reagents in said kit.

   15. A method of: A) making a polypeptide, comprising expressing said nucleic acid of Claim 11, thereby producing said polypeptide; or

   B) making a duplex nucleic acid, comprising contacting said nucleic acid of Claim 11 with a complementary nucleic acid, thereby allowing said duplex to form.

   16. A nucleic acid which: a) hybridizes under wash conditions of 30° C and less than 2M salt to SEQ ID NO: 3; b) hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 5; c) hybridizes under wash conditions of 30° C and less than 2M salt to SEQ ID NO: 25; d) hybridizes under wash conditions of 30° -C and less than 2 M salt to SEQ ID NO: 9; e) hybridizes under wash conditions of 30° C and less than 2M salt to SEQ ID NO: 11, 27, or 29; f) hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 15, 17, or 36; g) hybridizes under wash conditions of 30° C and less than 2M salt to SEQ ID NO: 31 or 38; ^"~ h) hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 21 or 40; i) hybridizes under wash conditions of 30° C and less than 2 M salt to SEQ ID NO: 33, 35, 42, or

   44; j) exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLR2; k) exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLR3; 1) exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLR4 ; m) exhibits at least about 85,%^' identity over a stretch of at least about 30 nucleotides to a primate DTLR5; n) exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLR6; o) exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLR7; p) exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLR8; q) exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLR9; or r) exhibits at least about 85% identity over a stretch of at least about 30 nucleotides to a primate DTLRIO.

   17. The nucleic acid of Claim 16, wherein: a) said wash conditions are at 45° C and/or 500 mM salt; or b) said identity is at least 90% and/or said stretch is at least 55 nucleotides.

   18. The nucleic acid of Claim 17, wherein: a) said wash conditions are at 55° C and/or 150 mM salt; or b) said identity is at least 95% and/or said stretch is at least 75 nucleotides.

   19. A method of producing a ligand: receptor complex, comprising contacting: a) a substantially pure primate DTLR2, including a recombinant or synthetically produced protein, with candidate Toll ligand; b) a substantially pure primate DTLR3, including a recombinant or synthetically produced protein, with candidate Toll ligand; c) a substantially pure primate DTLR4 , including a recombinant or synthetically produced protein, with candidate Toll ligand; d) a substantially pure primate DTLR5, including a recombinant or synthetically produced protein, with candidate Toll ligand; e) a substantially pure primate DTLR6, including a recombinant or synthetically produced protein, with candidate Toll ligand; f) a substantially pure primate DTLR7 , including a recombinant or synthetically produced protein, with candidate Toll ligand; g) a substantially pure primate DTLR8 , including a recombinant or synthetically produced protein, with candidate Toll ligand; h) a substantially pure primate DTLR9, including a recombinant or synthetically produced protein, with candidate Toll ligand; i) a substantially pure primate DTLRIO, including a recombinant or synthetically produced protein, with candidate- Toll ligand; thereby allowing said complex to form.

   20. A method of modulating physiology or development of a cell or tissue culture cells comprising contacting said cell with an agonist or antagonist of a mammalian DTLR2, DTLR3, DTLR , DTLR5; DTLR6, DTLR7, DTLR8, DTLR9, or DTLRIO.

   21. The method of Claim 20, wherein said agonist or antagonist is of DTLRIO, and said cell is a pDC2 cell.

   SEQUENCE SUBMISSION

   SEQ ID NO: 1 provides primate DTLRl nucleotide sequence. SEQ ID NO: 2 provides primate DTLRl polypeptide sequence. SEQ ID NO : 3 provides primate DTLR2 nucleotide sequence . SEQ ID NO : 4 provides primate DTLR2 polypeptide sequence . SEQ ID NO: 5 provides primate DTLR3 nucleotide sequence. SEQ ID NO: 6 provides primate DTLR3 polypeptide sequence. SEQ ID NO: 7 provides primate DTLR4 nucleotide sequence. SEQ ID NO: 8 provides primate DTLR4 polypeptide sequence. SEQ ID NO : 9 provides primate DTLR5 nucleotide sequence . SEQ ID NO: 10 provides primate DTLR5 polypeptide sequence. SEQ ID NO: 11 provides primate DTLR6 nucleotide sequence. SEQ ID NO: 12 provides primate DTLR6 polypeptide sequence. SEQ ID NO: 13 provides rodent DTLR6 nucleotide sequence. SEQ ID NO: 14 provides rodent DTLR6 polypeptide sequence. SEQ ID NO: 15 provides primate DTLR7 nucleotide sequence. SEQ ID NO: 16 provides primate DTLR7 polypeptide sequence. SEQ ID NO: 17 provides primate DTLR7 nucleotide sequence. SEQ ID NO: 18 provides primate DTLR7 polypeptide sequence. SEQ ID NO: 19 provides primate DTLR8 nucleotide sequence. SEQ ID NO: 20 provides primate DTLR8 polypeptide sequence. SEQ ID NO: 21 provides primate DTLR9 nucleotide sequence. SEQ ID NO: 22 provides primate DTLR9 polypeptide sequence. SEQ ID NO: 23 provides primate DTLRIO nucleotide sequence. SEQ ID NO: 24 provides primate DTLRIO polypeptide sequence. SEQ ID NO: 25 provides primate DTLR4 nucleotide sequence. SEQ ID NO: 2S provides primate DTLR4 polypeptide sequence. SEQ ID NO: 27 provides rodent DTLR6 nucleotide sequence. SEQ ID NO: 28 provides rodent DTLR6 polypeptide sequence. SEQ ID NO: 29 provides rodent DTLR6 nucleotide sequence. SEQ ID NO: 30 provides rodent DTLRS polypeptide sequence. SEQ ID NO: 31 provides primate DTLR8 nucleotide sequence. SEQ ID NO: 32 provides primate DTLR8 polypeptide sequence. SEQ ID NO: 33 provides primate DTLRIO nucleotide sequence. SEQ ID NO: 34 provides primate DTLRIO polypeptide sequence. SEQ ID NO: 35 provides rodent DTLRIO nucleotide sequence. SEQ ID NO: 36 provides primate DTLR7 nucleotide sequence. SEQ ID NO: 37 provides primate DTLR7 polypeptide sequence. SEQ ID NO: 38 provides primate DTLR8 nucleotide sequence. SEQ ID NO: 39 provides primate DTLR8 polypeptide sequence. SEQ ID NO: 40 provides primate DTLR9 nucleotide sequence. SEQ ID NO: 41 provides primate DTLR9 polypeptide sequence. SEQ ID NO: 42 provides primate DTLRIO nucleotide sequence. SEQ ID NO: 43 provides primate DTLRIO polypeptide sequence. SEQ ID NO: 44 provides rodent DTLRIO nucleotide sequence. SEQ ID NO: 45 provides rodent DTLRIO polypeptide sequence.

   <110> Sc ering Corp. < 120> Human Receptor Proteins ; Related Reagents and Methods

   < 130> DX0724 P

   < 140> <141>

   < 160> 45

   < 170> Patent ln Ver . 2 . 0

   <210> 1 <211> 2367 <212> DNA

   <213> Unknown

   <220>

   <223> Description of Unknown Organism: primate; surmised Homo sapiens

   <220> <221> CDS <222> (1)..{2358)

   <220>

   <221> mat_peptide

   <222> (67) .. (2358) <400> 1 atg act age ate ttc cat ttt gcc att ate ttc atg tta ata ctt cag 48

   Met Thr Ser He Phe His Phe Ala He He Phe Met Leu He Leu Gin -20 -15 -10 ate aga ata caa tta tct gaa gaa agt gaa ttt tta gtt gat agg tea 96 He Arg He Gin Leu Ser Glu Glu Ser Glu Phe Leu Val Asp Arg Ser -5 -1 1 5 10 aaa aac ggt etc ate cac gtt cct aaa gac eta tec cag aaa aca aca 144 Lys Asn Gly Leu He His Val Pro Lys Asp Leu Ser Gin Lys Thr Thr

   15 20 25 ate tta aat ata teg caa aat tat ata tct gag ctt tgg act tct gac 192 He Leu Asn He Ser Gin Asn Tyr He Ser Glu Leu Trp Thr Ser Asp 30 35 40 ate tta tea ctg tea aaa ctg agg att ttg ata att tct cat aat aga 240 He Leu Ser Leu Ser Lys Leu Arg He Leu He He Ser His Asn Arg 45 50 55 ate cag tat ctt gat ate agt gtt ttc aaa ttc aac cag gaa ttg gaa 288 He Gin Tyr Leu Asp He Ser Val Phe Lys Phe Asn Gin Glu Leu Glu 60 65 70 tac ttg gat ttg tec cac aac aag ttg gtg aag att tct tgc cac cct 336

   Tyr Leu Asp Leu Ser His Asn Lys Leu Val Lys He Ser Cys His Pro

   75 80 85 90 act gtg aac etc aag cac ttg gac ctg tea ttt aat gca ttt gat gcc 384

   Thr Val Asn Leu Lys His Leu Asp Leu Ser Phe Asn Ala Phe Asp Ala

   95 100 105 ctg cct ata tgc aaa gag ttt ggc aat atg tct caa eta aaa ttt ctg 432

   Leu Pro He Cys Lys Glu Phe Gly Asn Met Ser Gin Leu Lys Phe Leu

   110 115 ^'' 120 ggg ttg age ace aca cac tta gaa aaa tct agt gtg ctg cca att get 480 ' Gly Leu Ser Thr Thr His Leu Glu Lys Ser Ser Val Leu Pro He Ala

   125 130 135 cat ttg aat ate age aag gtc ttg ctg gtc tta gga gag act tat ggg 528

   His Leu Asn He Ser Lys Val Leu Leu Val Leu Gly Glu Thr Tyr Gly 140 145 150 gaa aaa gaa gac cct gag ggc ctt caa gac ttt aac act gag agt ctg 576

   Glu Lys Glu Asp Pro Glu Gly Leu Gin Asp Phe Asn Thr Glu Ser Leu

   155 160 165 170 cac att gtg ttc ccc aca aac aaa gaa ttc cat ttt att ttg gat gtg 624

   His He Val Phe Pro Thr Asn Lys Glu Phe His Phe He Leu Asp Val

   175 180 185 tea gtc aag act gta gca aat ctg gaa eta tct aat ate aaa tgt gtg 672

   Ser Val Lys Thr Val Ala Asn Leu Glu Leu Ser Asn He Lys Cys Val

   190 195 200 eta gaa gat aac aaa tgt tct tac ttc eta agt att ctg gcg aaa ctt 720 Leu Glu Asp Asn Lys Cys Ser Tyr Phe Leu Ser He Leu Ala Lys Leu

   205 210 215 caa aca aat cca aag tta tea agt ctt ace tta aac aac att gaa aca 768

   Gin Thr Asn Pro Lys Leu Ser Ser Leu Thr Leu Asn Asn He Glu Thr 220 225 230 act tgg aat tct ttc att agg ate etc caa eta gtt tgg cat aca act 816

   Thr Trp Asn Ser Phe He Arg He Leu Gin Leu Val Trp His Thr Thr

   235 240 245 250 gta tgg tat ttc tea att tea aac gtg aag eta cag ggt cag ctg gac 864

   Val Trp Tyr Phe Ser He Ser Asn Val Lys Leu Gin Gly Gin Leu Asp

   255 260 265 ttc aga gat ttt gat tat tct ggc act tec ttg aag gcc ttg tct ata 912

   Phe Arg Asp Phe Asp Tyr Ser Gly Thr Ser Leu Lys Ala Leu Ser He

   270 275 280 cac caa gtt gtc age gat gtg ttc ggt ttt ccg caa agt tat ate tat 960 His Gin Val Val Ser Asp Val Phe Gly Phe Pro Gin Ser Tyr He Tyr

   285 290 295 gaa ate ttt teg aat atg aac ate aaa aat ttc aca gtg tct ggt aca 1008

   Glu He Phe Ser Asn Met Asn He Lys Asn Phe Thr Val Ser Gly Thr 300 305 310 cgc atg gtc cac atg ctt tgc cca tec aaa att age ccg ttc ctg cat 1056

   Arg Met Val His Met Leu Cys Pro Ser Lys He Ser Pro Phe Leu His 315 320 325 330 ttg gat ttt tec aat aat etc tta aca gac acg gtt ttt gaa aat tgt 1104

   Leu Asp Phe Ser Asn Asn Leu Leu Thr Asp Thr Val Phe Glu Asn Cys 335 340 345 ggg cac ctt act gag ttg gag aca ^"ctt att tta ^"caa atg aat caa tta 1152

   Gly His Leu Thr Glu Leu Glu Thr Leu He Leu Gin Met Asn Gin Leu 350 355 360 aaa gaa ctt tea aaa ata get gaa atg act aca cag atg aag tct ctg 1200

   Lys Glu Leu Ser Lys He Ala Glu Met Thr Thr Gin Met Lys Ser Leu 365 370 375 caa caa ttg gat att age cag aat tct gta age tat gat gaa aag aaa 1248

   Gin Gin Leu Asp He Ser Gin Asn Ser Val Ser Tyr Asp Glu Lys Lys 380 385 390 gga gac tgt tct tgg act aaa agt tta tta agt tta aat atg tct tea 1296 Gly Asp Cys Ser Trp Thr Lys Ser Leu Leu Ser Leu Asn Met Ser Ser

   395 400 405 410 aat ata ctt act gac act att ttc aga tgt tta cct ccc agg ate aag 1344

   Asn He Leu Thr Asp Thr He Phe Arg Cys Leu Pro Pro Arg He Lys 415 420 425 gta ctt gat ctt cac age aat aaa ata aag age att cct aaa caa gtc 1392

   Val Leu Asp Leu His Ser Asn Lys He Lys Ser He Pro Lys Gin Val 430 435 440 gta aaa ctg gaa get ttg caa gaa etc aat gtt get ttc aat tct tta 1440

   Val Lys Leu Glu Ala Leu Gin Glu Leu Asn Val Ala Phe Asn Ser Leu 445 450 455 act gac ctt cct gga tgt ggc age ttt age age ctt tct gta ttg ate 1488

   Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser Ser Leu Ser Val Leu He 460 465 470 att gat cac aat tea gtt tec cac cca tea get gat ttc ttc cag age 1536 He Asp His Asn Ser Val Ser His Pro Ser Ala Asp Phe Phe Gin Ser 475 480 485 490 tgc cag aag atg agg tea ata aaa gca ggg gac aat cca ttc caa tgt 1584

   Cys Gin Lys Met Arg Se'r He Lys Ala Gly Asp Asn Pro Phe Gin Cys 495 500 505 ace tgt gag etc gga gaa ttt gtc aaa 'aat ata gac caa gta tea agt 1632

   Thr Cys Glu Leu Gly Glu Phe Val Lys Asn He Asp Gin Val Ser Ser 510 515 520 gaa gtg tta gag ggc tgg cct gat tct tat aag tgt gac tac ccg gaa 1680

   Glu Val Leu Glu Gly Trp Pro Asp Ser Tyr Lys Cys Asp Tyr Pro Glu 525 530 535 agt tat aga gga ace eta eta aag gac ttt cac atg tct gaa tta tec 1728

   Ser Tyr Arg Gly Thr Leu Leu Lys Asp Phe His Met Ser Glu Leu Ser 540 545 550 tgc aac ata act ctg ctg ate gtc ace ate gtt gcc ace atg ctg gtg 1776

   Cys Asn He Thr Leu Leu He Val Thr He Val Ala Thr Met Leu Val

   555 560 565 570 ttg get gtg act gtg ace tec etc tgc ate tac ttg gat ctg ccc tgg 1824

   Leu Ala Val Thr Val Thr Ser Leu Cys He Tyr Leu Asp Leu Pro Trp

   575 580 ^'" 585 tat etc agg atg gtg tgc cag tgg ace cag ace egg cgc agg gcc agg 1872 Tyr Leu Arg Met Val' Cys Gin Trp Thr Gin Thr Arg Arg Arg Ala Arg

   590 595 600 aac ata ccc tta gaa gaa etc caa aga aat etc cag ttt cat gca ttt 1920

   Asn He Pro Leu Glu Glu Leu Gin Arg Asn Leu Gin Phe His Ala Phe 605 610 615 att tea tat agt ggg cac gat tct ttc tgg gtg aag aat gaa tta ttg 1968

   He Ser Tyr Ser Gly His Asp Ser Phe Trp Val Lys Asn Glu Leu Leu

   620 625 630 cca aac eta gag aaa gaa ggt atg cag att tgc ctt cat gag aga aac 2016

   Pro Asn Leu Glu Lys Glu Gly Met Gin He Cys Leu His Glu Arg Asn

   635 640 645 650 ttt gtt cct ggc aag age att gtg gaa aat ate ate ace tgc att gag 2064

   Phe Val Pro Gly Lys Ser He Val Glu Asn He He Thr Cys He Glu

   655 660 665 aag agt tac aag tec ate ttt gtt ttg tct ccc aac ttt gtc cag agt 2112 Lys Ser Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Ser

   670 675 680 gaa tgg tgc cat tat gaa etc tac ttt gcc cat cac aat etc ttt cat 2160

   Glu Trp Cys His Tyr Glu Leu Tyr Phe Ala His His Asn Leu Phe His 685 690 695 gaa gga tct aat age tta ate ctg ate ttg ctg gaa ccc att ccg cag 2208

   Glu Gly Ser Asn Ser Leu He Leu He Leu Leu Glu Pro He Pro Gin

   700 705 710 tac tec att cct age agt tat cac aag etc aaa agt etc atg gcc agg 2256

   Tyr Ser He Pro Ser Ser Tyr His Lys Leu Lys Ser Leu Met Ala Arg

   715 720 725 730 agg act tat ttg gaa tgg ccc aag gaa aag age aaa cgt ggc ctt ttt 2304

   Arg Thr Tyr Leu Glu Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe

   735 740 745 tgg get aac tta agg gca gcc att aat att aag ctg aca gag caa gca 2352 Trp Ala Asn Leu Arg Ala Ala He Asn He Lys Leu Thr Glu Gin Ala

   750 755 760 aag aaa tagtctaga 2367

   Lys Lys

   <210> 2 <211> 786 < 212> PRT <213> Unknown

   < 400> 2 Met Thr Ser He Phe His Phe Ala He He Phe Met Leu He Leu Gin -20 -15 _ -10

   He Arg He Gin Leu Ser Glu Glu Ser Glu Phe Leu Val Asp Arg Ser -5 -1 1 5 10

   Lys Asn Gly Leu He His Val Pro Lys Asp Leu Ser Gin Lys Thr Thr 15 20 25

   He Leu Asn He Ser Gin Asn Tyr He Ser Glu Leu Trp Thr Ser Asp 30 35 40

   He Leu Ser Leu Ser Lys Leu Arg He Leu He He Ser His Asn Arg 45 50 55 He Gin Tyr Leu Asp He Ser Val Phe Lys Phe Asn Gin Glu Leu Glu 60 65 70

   Tyr Leu Asp Leu Ser His Asn Lys Leu Val Lys He Ser Cys His Pro 75 80 85 90

   Thr Val Asn Leu Lys His Leu Asp Leu Ser Phe Asn Ala Phe Asp^" Ala 95 100 105

   Leu Pro He Cys Lys Glu Phe Gly Asn Met Ser Gin Leu Lys Phe Leu 110 115 120

   Gly Leu Ser Thr Thr His Leu Glu Lys Ser Ser Val Leu Pro He Ala

   125 130 135 His Leu Asn He Ser Lys Val Leu Leu Val Leu Gly Glu Thr Tyr Gly

   140 145 150

   Glu Lys Glu Asp Pro Glu Gly Leu Gin Asp Phe Asn Thr Glu Ser Leu 155 160 165 170

   His He Val Phe Pro Thr Asn Lys Glu Phe His Phe He Leu Asp Val 175 180 . 185

   Ser Val Lys Thr Val Ala Asn Leu Glu Leu Ser Asn He Lys Cys Val 190 195 200

   Leu Glu Asp Asn Lys Cys Ser Tyr Phe Leu Ser He Leu Ala Lys Leu 205 210 215 Gin Thr Asn Pro Lys Leu Ser Ser Leu Thr Leu Asn Asn He Glu Thr 220 225 230

   Thr Trp Asn Ser Phe He Arg He Leu Gin Leu Val Trp His Thr Thr 235 240 245 250

   Val Trp Tyr Phe Ser He Ser Asn Val Lys Leu Gin Gly Gin Leu Asp 255 260 265 Phe Arg Asp Phe Asp Tyr Ser Gly Thr Ser Leu Lys Ala Leu Ser He 270 275 280

   His Gin Val Val Ser Asp Val Phe Gly Phe Pro Gin Ser Tyr He Tyr 285 290 295

   Glu He Phe Ser Asn Met Asn He Lys Asn Phe^' Thr Val Ser Gly Thr

   300 305 ^• 310 Arg Met Val His Met^' Leu Cys Pro Ser Lys He Ser Pro Phe Leu His 315 320 325 330

   Leu Asp Phe Ser Asn Asn Leu Leu Thr Asp Thr Val Phe Glu Asn Cys 335 340 345

   Gly His Leu Thr Glu Leu Glu Thr Leu He Leu Gin Met Asn Gin Leu 350 355 360

   Lys Glu Leu Ser Lys He Ala Glu Met Thr Thr Gin Met Lys Ser Leu 365 370 375

   Gin Gin Leu Asp He Ser Gin Asn Ser Val Ser Tyr Asp Glu Lys Lys 380 385 390 Gly Asp Cys Ser Trp Thr Lys Ser Leu Leu Ser Leu Asn Met Ser Ser 395 400 405 410

   Asn He Leu Thr Asp Thr He Phe Arg Cys Leu Pro Pro Arg He Lys 415 420 425

   Val Leu Asp Leu His Ser Asn Lys He Lys Ser He Pro Lys Gin Val 430 435 440

   Val Lys Leu Glu Ala Leu Gin Glu Leu Asn Val Ala Phe Asn Ser Leu 445 450 455

   Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser Ser Leu Ser Val Leu He

   460 465 470 He Asp His Asn Ser Val Ser His Pro Ser Ala Asp Phe Phe Gin Ser 475 480 485 490

   Cys Gin Lys Met Arg Ser He Lys Ala Gly Asp Asn Pro Phe Gin Cys 495 500 505

   Thr Cys Glu Leu Gly Glu Phe Val Lys Asn He Asp Gin Val Ser Ser 510 515 520

   Glu Val Leu Glu Gly Trp Pro Asp Ser Tyr Lys Cys Asp Tyr Pro Glu 525 530 535

   Ser Tyr Arg Gly Thr Leu Leu Lys Asp Phe His Met Ser Glu Leu Ser

   540 545 550 Cys Asn He Thr Leu Leu He Val Thr He Val Ala Thr Met Leu Val

   555 560 565 570

   Leu Ala Val Thr Val Thr Ser Leu Cys He Tyr Leu Asp Leu Pro Trp 575 580 585

   Tyr Leu Arg Met Val Cys Gin Trp Thr Gin Thr Arg Arg Arg Ala Arg 590 595 600

   Asn He Pro Leu Glu Glu Leu Gin Arg Asn Leu -Gin Phe His Ala Phe 605 610 ^'" 615

   He Ser Tyr Ser Gly His Asp Ser Phe Trp Val Lys Asn Glu Leu Leu 620 ' 625 630

   Pro Asn Leu Glu Lys Glu Gly Met Gin He Cys Leu His Glu Arg Asn 635 640 645 650 Phe Val Pro Gly Lys Ser He Val Glu Asn He He Thr Cys He Glu

   655 660 665

   Lys Ser Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Ser 670 675 680

   Glu Trp Cys His Tyr Glu Leu Tyr Phe Ala His His Asn Leu Phe His 685 690 695

   Glu Gly Ser Asn Ser Leu He Leu He Leu Leu Glu Pro He Pro Gin 700 705 710

   Tyr Ser He Pro Ser Ser Tyr His Lys Leu Lys Ser Leu Met Ala Arg

   715 720 725 730 Arg Thr Tyr Leu Glu Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe

   ^"735 740 745

   Trp Ala Asn Leu Arg Ala Ala He Asn He Lys Leu Thr Glu Gin Ala 750 755 760

   Lys Lys

   <210> 3

   <211> 2355 <212> DNA <213> Unknown <220>

   <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220> <221> CDS

   <222> (1) .. (2352)

   <220>

   < 221> matjpeptide <222> ( 67 ) . . ( 2352 )

   < 400> 3 atg cca cat act ttg tgg atg gtg tgg gtc ttg ggg gtc ate ate age 48 Met Pro His Thr Leu Trp Met Val Trp Val Leu Gly Val He He Ser -20 ^• -15 • -10 etc tec aag gaa gaa tec tec aat cag get tct ctg tct tgt gac cgc 96 Leu Ser Lys Glu Glu Ser Ser Asn Gin Ala Ser Leu Ser Cys Asp Arg

   -5 -1 1 5;' 10 aat ggt ate tgc aag ggc age tea gga tct tta aac tec att ccc tea 144

   Asn Gly He Cys Lys Gly Ser Ser Gly Ser Leu Asn Ser He Pro Ser 15' 20 25 ggg etc aca gaa get gta aaa age ctt gac ctg tec aac aac agg ate 192

   Gly Leu Thr Glu Ala Val Lys Ser Leu Asp Leu Ser Asn Asn Arg He 30 35 40 ace tac att age aac agt gac eta cag agg tgt gtg aac etc cag get 240

   Thr Tyr He Ser Asn Ser Asp Leu Gin Arg Cys Val Asn Leu Gin Ala 45 50 55 ctg gtg ctg aca tec aat gga att aac aca ata gag gaa gat tct ttt 288

   Leu Val Leu Thr Ser Asn Gly He Asn Thr He Glu Glu Asp Ser Phe 60 . 65 70 tct tec ctg ggc agt ctt gaa cat tta gac tta tec tat aat tac tta 336 Ser Ser Leu Gly Ser Leu Glu His Leu Asp Leu Ser Tyr Asn Tyr Leu

   75 80 85 90 tct aat tta teg tct tec tgg ttc aag ccc ctt tct tct tta aca ttc 384

   Ser Asn Leu Ser Ser Ser Trp Phe Lys Pro Leu Ser Ser Leu Thr Phe 95 100 105 tta aac tta ctg gga aat cct tac aaa ace eta ggg gaa aca tct ctt 432

   Leu Asn Leu Leu Gly Asn Pro Tyr Lys Thr Leu Gly Glu Thr Ser Leu 110 115 120 ttt tct cat etc aca aaa ttg caa ate ctg aga gtg gga aat atg gac 480

   Phe Ser His Leu Thr Lys Leu Gin He Leu Arg Val Gly Asn Met Asp 125 130 135 ace ttc act aag att caa aga aaa gat ttt get gga ctt ace ttc ctt 528

   Thr Phe Thr Lys He Gin Arg Lys Asp Phe Ala Gly Leu Thr Phe Leu 140 145 150 gag gaa ctt gag att gat get tea gat eta cag age tat gag cca aaa 576 Glu Glu Leu Glu He Asp Ala Ser Asp Leu Gin Ser Tyr Glu Pro Lys

   155 160 165 170 agt ttg aag tea att cag aac gta agt cat ctg ate ctt cat atg aag 624

   Ser Leu Lys Ser He Gin Asn Val Ser His Leu He Leu His Met Lys 175 180 185 cag cat att tta ctg ctg gag att ttt gta gat gtt aca agt tec gtg 672 Gin His He Leu Leu Leu Glu He Phe Val Asp Val Thr Ser Ser Val 190 195 200 gaa tgt ttg gaa ctg cga gat act gat ttg gac act ttc cat ttt tea 720 Glu Cys Leu Glu Leu Arg Asp Thr Asp Leu Asp Thr Phe His Phe Ser 205 210 215 gaa eta tec act ggt gaa aca aat tea ttg att aaa aag ttt aca ttt 768

   Glu Leu Ser Thr Gly Glu Thr Asn Ser Leu He Lys Lys Phe Thr Phe

   220 225 230 aga aat gtg aaa ate ace gat gaa agt ttg ttt cag gtt atg aaa ctt 816

   Arg Asn Val Lys He Thr Asp Glu Ser Leu Phe Gin Val Met Lys Leu

   235 240 245 250 ttg aat cag att tct' gga ttg tta gaa tta gag ttt gat gac tgt ace 864 Leu Asn Gin He Ser Gly Leu Leu Glu Leu Glu Phe Asp Asp Cys Thr 255 260 265 ctt aat gga gtt ggt aat ttt aga gca tct gat aat gac aga gtt ata 912 Leu Asn Gly Val Gly Asn Phe Arg Ala Ser Asp Asn Asp Arg Val He 270 275 280 gat cca ggt aaa gtg gaa acg tta aca ate egg agg ctg cat att cca 960 Asp Pro Gly Lys Val Glu Thr Leu Thr He Arg Arg Leu His He Pro 285 290 295 agg ttt tac tta ttt tat gat ctg age act tta tat tea ctt aca gaa 1008

   Arg Phe Tyr Leu Phe Tyr Asp Leu Ser Thr Leu Tyr Ser Leu Thr Glu

   300 305 310 aga gtt aaa aga ate aca gta gaa aac agt aaa gtt ttt ctg gtt cct 1056

   Arg Val Lys Arg He Thr Val Glu Asn Ser Lys Val Phe Leu Val Pro

   315 320 325 330 tgt tta ctt tea caa cat tta aaa tea tta gaa tac ttg gat etc agt 1104 Cys Leu Leu Ser Gin His Leu Lys Ser Leu Glu Tyr Leu Asp Leu Ser 335 340 345 gaa aat ttg atg gtt gaa gaa tac ttg aaa aat tea gcc tgt gag gat 1152 Glu Asn Leu Met Val Glu Glu Tyr Leu Lys Asn Ser Ala Cys Glu Asp 350 355 360 gcc tgg ccc tct eta caa act tta att tta agg caa aat cat ttg gca 1200 Ala Trp Pro Ser Leu Gin Thr Leu He Leu Arg Gin Asn His Leu Ala 365 370 375 tea ttg gaa aaa ace gga gag act ttg etc act ctg aaa aac ttg act 1248

   Ser Leu Glu Lys Thr Gly Glu Thr Leu Leu Thr Leu Lys Asn Leu Thr 380 385 390 aac att gat ate agt aag aat agt ttt cat tct atg cct gaa act tgt 1296

   Asn He Asp He Ser Lys Asn Ser Phe His Ser Met Pro Glu Thr Cys 395 400 405 410 cag tgg cca gaa aag atg aaa tat ttg aac tta tec age aca cga ata 1344 Gin Trp Pro Glu Lys Met Lys Tyr Leu Asn Leu Ser Ser Thr Arg He 415 420 425 cac agt gta aca ggc tgc att ccc aag aca ctg gaa att tta gat gtt 1392 His Ser Val Thr Gly Cys He Pro Lys Thr Leu Glu He Leu Asp Val 430 435 440 age aac aac aat etc aat tta ttt tct ttg aat ttg ccg caa etc aaa 1440

   10 Ser Asn Asn Asn Leu Asn Leu Phe Ser Leu Asn Leu Pro Gin Leu Lys 445 450 455 gaa ctt tat att tec aga aat aag ttg atg act eta cca gat gcc tec 1488 Glu Leu Tyr He Ser Arg Asn Lys Leu Met Thr Leu Pro Asp Ala Ser

   460 465 _--470 etc tta ccc atg tta eta gta ttg aaa ate agt agg aat gca ata act 1536

   Leu Leu Pro Met Leu Leu Val Leu Lys He Ser Arg Asn Ala He Thr 475 ' 480 485 490 acg ttt tct aag gag caa ctt gac tea ttt cac aca ctg aag act ttg 1584

   Thr Phe Ser Lys Glu Gin Leu Asp Ser Phe His Thr Leu Lys Thr Leu 495 500 505 gaa get ggt ggc aat aac ttc att tgc tec tgt gaa ttc etc tec ttc 1632

   Glu Ala Gly Gly Asn Asn Phe He Cys Ser Cys Glu Phe Leu Ser Phe 510 515 520 act cag gag cag caa gca ctg gcc aaa gtc ttg att gat tgg cca gca 1680

   Thr Gin Glu Gin Gin Ala Leu Ala Lys Val Leu He Asp Trp Pro Ala 525 530 535 aat tac ctg tgt gac tct cca tec cat gtg cgt ggc cag cag gtt cag 1728 Asn Tyr Leu Cys Asp Ser Pro Ser His Val Arg Gly Gin Gin Val Gin

   540 545 550 gat gtc cgc etc teg gtg teg gaa tgt cac agg aca gca ctg gtg tct 1776

   Asp Val Arg Leu Ser Val Ser Glu Cys His Arg Thr Ala Leu Val Ser 555 560 565 570 ggc atg tgc tgt get ctg ttc ctg ctg ate ctg etc acg ggg gtc ctg 1824

   Gly Met Cys Cys Ala Leu Phe Leu Leu He Leu Leu Thr Gly Val Leu 575 580 585 tgc cac cgt ttc cat ggc ctg tgg tat atg aaa atg atg tgg gcc tgg "1872

   Cys His Arg Phe His Gly Leu Trp Tyr Met Lys Met Met Trp Ala Trp 590 595 600 etc cag gcc aaa agg aag ccc agg aaa get ccc age agg aac ate tgc 1920

   Leu Gin Ala Lys Arg Lys Pro Arg Lys Ala Pro Ser Arg Asn He Cys 605 610 . 615 tat gat gca ttt gtt tct tac agt gag egg gat gcc tac tgg gtg gag 1968 Tyr Asp Ala Phe Val Ser Tyr Ser Glu Arg Asp Ala Tyr Trp Val Glu

   620 625 630 aac ctt atg gtc cag gag ctg gag aac ttc aat ccc ccc ttc aag ttg 2016

   Asn Leu Met Val Gin Glu Leu Glu Asn Phe Asn Pro Pro Phe Lys Leu 635 640 645 650 - tgt ctt cat aag egg gac ttc att cct ggc aag tgg ate att gac aat 2064

   Cys Leu His Lys Arg Asp Phe He Pro Gly Lys Trp He He Asp Asn 655 660 665 ate att gac tec att gaa aag age cac aaa act gtc ttt gtg ctt tct 2112 He He Asp Ser He Glu Lys Ser His Lys Thr Val Phe Val Leu Ser 670 ^• 675 680

   11 gaa aac ttt gtg aag agt gag tgg tgc aag tat gaa ctg gac ttc tec 2160

   Glu Asn Phe Val Lys Ser Glu Trp Cys Lys Tyr Glu Leu Asp Phe Ser

   685 690 695 cat ttc cgt ctt ttt gaa gag aac aat gat gct 'gcc att etc att ctt 2208

   His Phe Arg Leu Phe Glu Glu Asn^'Asn Asp Ala^' Ala He Leu He Leu

   700 705 ^■ 710 ctg gag ccc att gag' aaa aaa gcc att ccc cag cgc ttc tgc aag ctg 2256 Leu Glu Pro He Glu Lys Lys Ala He Pro Gin Arg Phe Cys Lys Leu 715 720 725 730 egg aag ata atg aac ace aag ace tac ctg gag tgg ccc atg gac gag 2304 Arg Lys He Met Asn Thr Lys Thr Tyr Leu Glu Trp Pro Met Asp Glu

   735 740 745 get cag egg gaa gga ttt tgg gta aat ctg aga get gcg ata aag tec 2352 Ala Gin Arg Glu Gly Phe Trp Val Asn Leu Arg Ala Ala He Lys Ser 750 755 760 tag . 2355

   <210> 4

   <211> 784

   <212> PRT

   <213> Unknown <400> 4

   Met Pro His Thr Leu Trp Met Val Trp Val Leu Gly Val He He Ser -20 -15 -10

   Leu Ser Lys Glu Glu Ser Ser Asn Gin Ala Ser Leu Ser Cys Asp Arg -5 -1 1 5 10

   Asn Gly He Cys Lys Gly Ser Ser Gly Ser Leu Asn Ser He Pro Ser 15 20 25 Gly Leu Thr Glu Ala Val Lys Ser Leu Asp Leu Ser Asn Asn Arg He

   30 35 40 •

   Thr Tyr He Ser Asn Ser Asp Leu Gin Arg Cys Val Asn Leu Gin Ala 45 ^' 50 55

   Leu Val Leu Thr Ser Asn Gly He Asn Thr He Glu Glu Asp Ser Phe 60 65 70

   Ser Ser Leu Gly Ser Leu Glu His Leu Asp Leu Ser Tyr Asn Tyr Leu 75 80 85 90

   Ser Asn Leu Ser Ser Ser Trp Phe Lys Pro Leu Ser Ser Leu Thr Phe 95 100 105 Leu Asn Leu Leu Gly Asn Pro Tyr Lys Thr Leu Gly Glu Thr Ser Leu 110 115 120

   Phe Ser His Leu Thr Lys Leu Gin He Leu Arg Val Gly Asn Met Asp

   12 125 130 135

   Thr Phe Thr Lys He Gin Arg Lys Asp Phe Ala Gly Leu Thr Phe Leu 140 145 150

   Glu Glu Leu Glu He Asp Ala Ser Asp Leu Gln/Ser Tyr Glu Pro Lys 155 160 165^'' 170

   Ser Leu Lys Ser He Gin Asn Val Ser His Leu He Leu His Met Lys 175^' 180 185

   Gin His He Leu Leu Leu Glu He Phe Val Asp Val Thr Ser Ser Val 190 195 200 Glu Cys Leu Glu Leu Arg Asp Thr Asp Leu Asp Thr Phe His Phe Ser 205 210 215

   Glu Leu Ser Thr Gly Glu Thr Asn Ser Leu He Lys Lys Phe Thr Phe 220 225 230

   Arg Asn Val Lys lie Thr Asp Glu Ser Leu Phe Gin Val Met Lys Leu 235 240 245 250

   Leu Asn Gin He Ser Gly Leu Leu Glu Leu Glu Phe Asp Asp Cys Thr 255 260 265

   Leu Asn Gly Val Gly Asn Phe Arg Ala Ser Asp Asn Asp Arg Val He 270 275 280 Asp Pro Gly Lys Val Glu Thr Leu Thr He Arg Arg Leu His He Pro 285 290 295

   Arg Phe Tyr Leu Phe Tyr Asp Leu Ser Thr Leu Tyr Ser Leu Thr Glu 300 305 310

   Arg Val Lys Arg He Thr Val Glu Asn Ser Lys Val Phe Leu Val Pro 315 320 325 330

   Cys Leu Leu Ser Gin His Leu Lys Ser Leu Glu Tyr Leu Asp Leu Ser 335 340 345

   Glu Asn Leu Met Val Glu Glu Tyr Leu Lys Asn Ser Ala Cys Glu Asp

   350 355 360 Ala Trp Pro Ser Leu Gin Thr Leu He Leu Arg Gin Asn His Leu Ala

   365 370 375

   Ser Leu Glu Lys Thr Gly Glu Thr Leu Leu Thr Leu Lys Asn Leu Thr 380 385 390

   Asn He Asp He Ser Lys Asn Ser Phe His Ser Met Pro Glu Thr Cys 395 400 405 410

   Gin Trp Pro Glu Lys Met Lys Tyr Leu Asn Leu Ser Ser Thr Arg He 415 420 425

   His Ser Val Thr Gly Cys He Pro Lys Thr Leu Glu He Leu Asp Val 430 435 440

   13 Ser Asn Asn Asn Leu Asn Leu Phe Ser Leu Asn Leu Pro Gin Leu Lys 445 450 455

   Glu Leu Tyr He Ser Arg Asn Lys Leu Met Thr Leu Pro Asp Ala Ser 460 465 .- 470

   Leu Leu Pro Met Leu Leu Val Leu Lys He Ser Arg Asn Ala He Thr 475 480 485 490

   Thr Phe Ser Lys Glu Gin Leu Asp Ser Phe His Thr Leu Lys Thr Leu 495 500 505

   Glu Ala Gly Gly Asn Asn Phe He Cys Ser Cys Glu Phe Leu Ser Phe 510 515 520

   Thr Gin Glu Gin Gin Ala Leu Ala Lys Val Leu He Asp Trp Pro Ala

   525 530 535 Asn Tyr Leu Cys Asp Ser Pro Ser His Val Arg Gly Gin Gin Val Gin 540 545 550

   Asp Val Arg Leu Ser Val Ser Glu Cys His Arg Thr Ala Leu Val Ser 555 560 565 570

   Gly Met Cys Cys Ala Leu Phe Leu Leu He Leu Leu Thr Gly Val Leu 575 580 585

   Cys His Arg Phe His Gly Leu Trp Tyr Met Lys Met Met Trp Ala Trp 590 595 600

   Leu Gin Ala Lys Arg Lys Pro Arg Lys Ala Pro Ser Arg Asn He Cys 605 610 615 Tyr Asp Ala Phe Val Ser Tyr Ser Glu Arg Asp Ala Tyr Trp Val Glu 620 625 630

   Asn Leu Met Val Gin Glu Leu Glu Asn Phe Asn Pro Pro Phe Lys Leu

   635 640 645 650

   Cys Leu His Lys Arg Asp Phe He Pro Gly Lys Trp He He Asp Asn

   655 660 665

   He He Asp Ser He Glu Lys Ser His Lys Thr Val Phe Val Leu Ser 670 675 680

   Glu Asn Phe Val Lys Ser Glu Trp Cys Lys Tyr Glu Leu Asp Phe Ser 685 690 695 His Phe Arg Leu Phe Glu Glu Asn Asn Asp Ala Ala He Leu He Leu 700 705 710

   Leu Glu Pro He Glu Lys Lys Ala He Pro Gin Arg Phe Cys Lys Leu 715 720 725 730

   Arg Lys He Met Asn Thr Lys Thr Tyr Leu Glu Trp Pro Met Asp Glu 735 740 745

   14 Ala Gin Arg Glu Gly Phe Trp Val Asn Leu Arg Ala Ala He Lys Ser 750 755 760

   <210> 5

   <211> 2715

   <212> DNA

   <213> Unknown <220>

   <223> Description of Unknown Organism:ρrimate; surmised Homo sapiens

   <220> <221> CDS

   <222> (1)..(2712)

   <220>

   <221> mat_peρtide < 222> ( 64 ) . . ( 2712 )

   <400> 5 atg aga cag act ttg cct tgt ate tac ttt tgg ggg ggc ctt ttg ccc 48 Met Arg Gin Thr Leu Pro Cys He Tyr Phe Trp Gly Gly Leu Leu Pro -20 -15 -10 ttt ggg atg ctg tgt gca tec tec ace ace aag tgc act gtt age cat 96

   Phe Gly Met Leu Cys Ala Ser Ser Thr Thr Lys Cys Thr Val Ser His -5 -1 1 5 10 gaa gtt get gac tgc age cac ctg aag ttg act cag gta ccc gat gat 144

   Glu Val Ala Asp Cys Ser His Leu Lys Leu Thr Gin Val Pro Asp Asp

   15 20 25 eta ccc aca aac ata aca gtg ttg aac ctt ace cat aat caa etc aga 192 Leu Pro Thr Asn He Thr Val Leu Asn Leu Thr His Asn Gin Leu Arg 30 35 40 aga tta cca gcc gcc aac ttc aca agg tat age cag eta act age ttg 240 Arg Leu Pro Ala Ala Asn Phe Thr Arg Tyr Ser Gin Leu Thr Ser Leu 45 50 55 gat gta gga ttt aac ace ate tea aaa ctg gag cca gaa ttg tgc cag 288 Asp Val Gly Phe Asn Thr He Ser Lys Leu Glu Pro Glu Leu Cys Gin 60 65 70 75 aaa ctt ccc atg tta aaa gtt ttg aac etc cag cac aat gag eta tct 336 Lys Leu Pro Met Leu Lys Val Leu Asn Leu Gin His Asn Glu Leu Ser 80 85 90 caa ctt tct gat aaa ace ttt gcc ttc tgc acg aat ttg act gaa etc 384 Gin Leu Ser Asp Lys Thr Phe Ala Phe Cys Thr Asn Leu Thr Glu Leu 95 100 105 cat etc atg tec aac tea ate cag aaa att aaa aat aat ccc ttt gtc 432 His Leu Met Ser Asn Ser He Gin Lys He Lys Asn Asn Pro Phe Val 110 115 120

   15 aag cag aag aat tta ate aca tta gat ctg tct cat aat ggc ttg tea 480

   Lys Gin Lys Asn Leu He Thr Leu Asp Leu Ser His Asn Gly Leu Ser

   125 130 135 tct aca aaa tta gga act cag gtt cag ctg gaa aat etc caa gag ctt 528

   Ser Thr Lys Leu Gly Thr Gin Val Gin Leu Glu _ sn Leu Gin Glu Leu

   140 145 150^'' 155 eta tta tea aac aat aaa att caa gcg eta aaa agt gaa gaa ctg gat 576 Leu Leu Ser Asn Asn' Lys He Gin Ala Leu Lys Ser Glu Glu Leu Asp

   160 165 170 ate ttt gcc aat tea tct tta aaa aaa tta gag ttg tea teg aat caa 624

   He Phe Ala Asn Ser Ser Leu Lys Lys Leu Glu Leu Ser Ser Asn Gin 175 180 185 att aaa gag ttt tct cca ggg tgt ttt cac gca att gga aga tta ttt 672

   He Lys Glu Phe Ser Pro Gly Cys Phe His Ala He Gly Arg Leu Phe 190 195 200 ggc etc ttt ctg aac aat gtc cag ctg ggt ccc age ctt aca gag aag 720

   Gly Leu Phe Leu Asn Asn Val Gin Leu Gly Pro Ser Leu Thr Glu Lys

   205 210 215 eta tgt ttg gaa tta gca aac aca age att egg aat ctg tct ctg agt 768

   Leu Cys Leu Glu Leu Ala Asn Thr Ser He Arg Asn Leu Ser Leu^" Ser

   220 225 230 235 aac age cag ctg tec ace ace age aat aca act ttc ttg gga eta aag 816 Asn Ser Gin Leu Ser Thr Thr Ser Asn Thr Thr Phe Leu Gly Leu Lys

   240 245 250 tgg aca aat etc act atg etc gat ctt tec tac aac aac tta aat gtg 864

   Trp Thr Asn Leu Thr Met Leu Asp Leu Ser Tyr Asn Asn Leu Asn Val 255 260 265 gtt ggt aac gat tec ttt get tgg ctt cca caa eta gaa tat ttc ttc 912 Val Gly Asn Asp Ser Phe Ala Trp Leu Pro Gin Leu Glu Tyr Phe Phe 270 275 280 eta gag tat aat aat ata cag cat ttg ttt tct cac tct ttg cac ggg 960

   Leu Glu Tyr Asn Asn He Gin His Leu Phe Ser His Ser Leu His Gly

   285 290 295 ctt ttc aat gtg agg tac ctg aat ttg aaa egg tct ttt act aaa caa 1008

   Leu Phe Asn Val Arg Tyr Leu Asn Leu Lys Arg Ser Phe Thr Lys Gin

   300 305 310 315 agt att tec ctt gcc tea etc ccc aag att gat gat ttt tct ttt cag 1056 Ser He Ser Leu Ala Ser Leu Pro Lys He Asp Asp Phe Ser Phe Gin _

   320 325 330 tgg eta aaa tgt ttg gag cac ctt aac atg gaa gat aat gat att cca 1104

   Trp Leu Lys Cys Leu Glu His Leu Asn Met Glu Asp Asn Asp He Pro 335 340 345 ggc ata aaa age aat atg ttc aca gga ttg ata aac ctg aaa tac tta 1152

   Gly He Lys Ser Asn Met Phe Thr Gly Leu He Asn Leu Lys Tyr Leu

   16 350 355 360 agt eta tec aac tec ttt aca agt ttg cga act ttg aca aat gaa aca 1200

   Ser Leu Ser Asn Ser Phe Thr Ser Leu Arg Thr Leu Thr Asn Glu Thr 365 370 375 ttt gta tea ctt get cat tct ccc ^'tta cac ata etc aac eta ace aag 1248

   Phe Val Ser Leu Ala His Ser Pro Leu His He Leu Asn Leu Thr Lys

   380 385 390 395 aat aaa ate tea aaa ata gag agt gat get ttc tct tgg ttg ggc cac 1296

   Asn Lys He Ser Lys He Glu Ser Asp Ala Phe Ser Trp Leu Gly His

   400 405 410 eta gaa gta ctt gac ctg ggc ctt aat gaa att ggg caa gaa etc aca 1344

   Leu Glu Val Leu Asp Leu Gly Leu Asn Glu He Gly Gin Glu Leu Thr

   415 420 425 ggc cag gaa tgg aga ggt eta gaa aat att ttc gaa ate tat ctt tec 1392 Gly Gin Glu Trp Arg Gly Leu Glu Asn He Phe Glu He Tyr Leu Ser

   430 435 440 tac aac aag tac ctg cag ctg act agg aac tec ttt gcc ttg gtc cca 1440

   Tyr Asn Lys Tyr Leu Gin Leu Thr Arg Asn Ser Phe Ala Leu Val Pro 445 450 455 age ctt caa cga ctg atg etc cga agg gtg gcc ctt aaa aat gtg gat 1488

   Ser Leu Gin Arg Leu Met Leu Arg Arg Val Ala Leu Lys Asn Val Asp

   460 465 470 475 age tct cct tea cca ttc cag cct ctt cgt aac ttg ace att ctg gat 1536

   Ser Ser Pro Ser Pro Phe Gin Pro Leu Arg Asn Leu Thr He Leu Asp

   480 485 490 eta age aac aac aac ata gcc aac ata aat gat gac atg ttg gag ggt 1584

   Leu Ser Asn Asn Asn He Ala Asn He Asn Asp Asp Met Leu Glu Gly

   495 500 505 ctt gag aaa eta gaa att etc gat ttg cag cat aac aac tta gca egg 1632 Leu Glu Lys Leu Glu He Leu Asp Leu Gin His Asn Asn Leu Ala Arg

   510 515 520 etc tgg aaa cac gca aac cct ggt ggt ccc att tat ttc eta aag ggt 1680

   Leu Trp Lys His Ala As'n Pro Gly Gly Pro He Tyr Phe Leu Lys Gly 525 530 535 ctg tct cac etc cac ate ctt aac ttg gag tec aac ggc ttt gac gag 1728

   Leu Ser His Leu His He Leu Asn Leu Glu Ser Asn Gly Phe Asp Glu

   540 545 550 555 ate cca gtt gag gtc ttc aag gat tta ttt gaa eta aag ate ate gat 1776

   He Pro Val Glu Val Phe Lys Asp Leu Phe Glu Leu Lys He He Asp

   560 565 570 tta gga ttg aat aat tta aac aca ctt cca gca tct gtc ttt aat aat 1824

   Leu Gly Leu Asn Asn Leu Asn Thr Leu Pro Ala Ser Val Phe Asn Asn

   575 580 585

   17 cag gtg tct eta aag tea ttg aac ctt cag aag aat etc ata aca tec 1872

   Gin Val Ser Leu Lys Ser Leu Asn Leu Gin Lys Asn Leu He Thr Ser

   590 595 600 gtt gag aag aag gtt ttc ggg cca get ttc agg aac ctg act gag tta 1920

   Val Glu Lys Lys Val Phe Gly Pro Ala Phe Arg-'Asn Leu Thr Glu Leu

   605 610 ^'' 615 gat atg cgc ttt aat ccc ttt gat tgc acg tgt gaa agt att gcc tgg 1968 Asp Met Arg Phe Ash Pro Phe Asp Cys Thr Cys Glu Ser He Ala Trp

   620 625 630 635 ttt gtt aat tgg att aac gag ace -cat ace aac ate cct gag ctg tea 2016

   Phe Val Asn Trp He Asn Glu Thr His Thr Asn He Pro Glu Leu Ser 640 645 650 age cac tac ctt tgc aac act cca cct cac tat cat ggg ttc cca gtg 2064

   Ser His Tyr Leu Cys Asn Thr Pro Pro His Tyr His Gly Phe Pro Val

   655 660 665 aga ctt ttt gat aca tea tct tgc aaa gac agt gcc ccc ttt gaa etc 2112

   Arg Leu Phe Asp Thr Ser Ser Cys Lys Asp Ser Ala Pro Phe Glu Leu

   670 675 680 ttt ttc atg ate aat ace agt ate ctg ttg att ttt ate ttt att gta 2160

   Phe Phe Met He Asn Thr Ser He Leu Leu He Phe He Phe He Val

   685 690 695 ctt etc ate cac ttt gag ggc tgg agg ata tct ttt tat tgg aat gtt 2208 Leu Leu He His Phe Glu Gly Trp Arg He Ser Phe Tyr Trp Asn Val

   700 705 710 715 tea gta cat cga gtt ctt ggt ttc aaa gaa ata gac aga cag aca gaa 2256

   Ser Val His Arg Val Leu Gly Phe Lys Glu He Asp Arg Gin Thr Glu 720 725 730 cag ttt gaa tat gca gca tat ata att cat gcc tat aaa gat aag gat 2304

   Gin Phe Glu Tyr Ala Ala Tyr He He His Ala Tyr Lys Asp Lys Asp

   735 740 745 tgg gtc tgg gaa cat ttc tct tea atg gaa aag gaa gac caa tct etc 2352

   Trp Val Trp Glu His Phe Ser Ser Met Glu Lys Glu Asp Gin Ser Leu

   750 755 760 aaa ttt tgt ctg gaa gaa agg gac ttt gag gcg ggt gtt ttt gaa eta 2400

   Lys Phe Cys Leu Glu Glu Arg Asp Phe Glu Ala Gly Val Phe Glu Leu

   765 770 775 gaa gca att gtt aac age ate aaa aga age aga aaa att att ttt gtt 2448 Glu Ala He Val Asn Ser He Lys Arg Ser Arg Lys He He Phe Val

   780 785 790 795 ata aca cac cat eta tta aaa gac cca tta tgc aaa aga ttc aag gta 2496

   He Thr His His Leu Leu Lys Asp Pro Leu Cys Lys Arg Phe Lys Val 800 805 810 cat cat gca gtt caa caa get att gaa caa aat ctg gat tec att ata 2544

   His His Ala Val Gin Gin Ala He Glu Gin Asn Leu Asp Ser He He

   18 815 820 825 ttg gtt ttc ctt gag gag att cca gat tat aaa ctg aac cat gca etc 2592 Leu Val Phe Leu Glu Glu He Pro Asp Tyr Lys Leu Asn His Ala Leu 830 835 840 tgt ttg cga aga gga atg ttt aaa tct cac tgc ate ttg aac tgg cca 2640

   Cys Leu Arg Arg Gly Met Phe Lys Ser His Cys He Leu Asn Trp Pro 845 850 855 gtt cag aaa gaa egg ata ggt gcc ttt cgt cat aaa ttg caa gta gca 2688

   Val Gin Lys Glu Arg He Gly Ala Phe Arg His Lys Leu Gin Val Ala 860 865 ^• 870 875 ctt gga tec aaa aac tct gta cat taa 2715

   Leu Gly Ser Lys Asn Ser Val His 880

   <210> 6

   <211> 904

   <212> PRT

   <213> Unknown <400> 6

   Met Arg Gin Thr Leu Pro Cys He Tyr Phe Trp Gly Gly Leu Leu Pro -20 -15 -10

   Phe Gly Met Leu Cys Ala Ser Ser Thr Thr Lys Cys Thr Val Ser His -5 -1 1 5 10

   Glu Val Ala Asp Cys Ser His Leu Lys Leu Thr Gin Val Pro Asp Asp 15 20 25 Leu Pro Thr Asn He Thr Val Leu Asn Leu Thr His Asn Gin Leu Arg 30 35 40

   Arg Leu Pro Ala Ala Asn Phe Thr Arg Tyr Ser Gin Leu Thr Ser Leu 45 50 55

   Asp Val Gly Phe Asn Thr He Ser Lys Leu Glu Pro Glu Leu Cys Gin 60 65 70 75

   Lys Leu Pro Met Leu Lys Val Leu Asn Leu Gin His Asn Glu Leu Ser 80- 85 90

   Gin Leu Ser Asp Lys Thr Phe Ala Phe Cys Thr Asn Leu Thr Glu Leu

   95 100 105 His Leu Met Ser Asn Ser He Gin Lys He Lys Asn Asn Pro Phe Val

   110 115 120

   Lys Gin Lys Asn Leu He Thr Leu Asp Leu Ser His Asn Gly Leu Ser 125 130 135

   Ser Thr Lys Leu Gly Thr Gin Val Gin Leu Glu Asn Leu Gin Glu Leu 140 145 150 155

   19 Leu Leu Ser Asn Asn Lys He Gin Ala Leu Lys Ser Glu Glu Leu Asp

   160 165 170

   He Phe Ala Asn Ser Ser Leu Lys Lys Leu Glu Leu Ser Ser Asn Gin 175 180 185

   He Lys Glu Phe Ser Pro Gly Cys Phe His Ala^' He Gly Arg Leu Phe

   190 195 ' 200 Gly Leu Phe Leu Asn' Asn Val Gin Leu Gly Pro Ser Leu Thr Glu Lys

   205 210 215

   Leu Cys Leu Glu Leu Ala Asn Thr Ser He Arg Asn Leu Ser Leu Ser 220 225 230 235

   Asn Ser Gin Leu Ser Thr Thr Ser Asn Thr Thr Phe Leu Gly Leu Lys 240 245 250

   Trp Thr Asn Leu Thr Met Leu Asp Leu Ser Tyr Asn Asn Leu Asn Val 255 260 265

   Val Gly Asn Asp Ser Phe Ala Trp Leu Pro Gin Leu Glu Tyr Phe Phe 270 275 280 Leu Glu Tyr Asn Asn He Gin His Leu Phe Ser His Ser Leu His Gly 285 290 295

   Leu Phe Asn Val Arg Tyr Leu Asn Leu Lys Arg Ser Phe Thr Lys Gin 300 305 310 315

   Ser He Ser Leu Ala Ser Leu Pro Lys He Asp Asp Phe Ser Phe Gin 320 325 330

   Trp Leu Lys Cys Leu Glu His Leu Asn Met Glu Asp Asn Asp He Pro 335 340 345

   Gly He Lys Ser Asn Met Phe Thr Gly Leu He Asn Leu Lys Tyr Leu 350 355 360 Ser Leu Ser Asn Ser Phe Thr Ser Leu Arg Thr Leu Thr Asn Glu Thr 365 370 375

   Phe Val Ser Leu Ala His Ser Pro Leu His He Leu Asn Leu Thr Lys 380 385 390 395

   Asn Lys He Ser Lys He Glu Ser Asp Ala Phe Ser Trp Leu Gly His 400 405 410

   Leu Glu Val Leu Asp Leu Gly Leu Asn Glu He Gly Gin Glu Leu Thr 415 420 425

   Gly Gin Glu^' Trp Arg Gly Leu Glu Asn He Phe Glu He Tyr Leu Ser 430 435 440 Tyr Asn Lys Tyr Leu Gin Leu Thr Arg Asn Ser Phe Ala Leu Val Pro 445 450 455

   Ser Leu Gin Arg Leu Met Leu Arg Arg Val Ala Leu Lys Asn Val Asp

   20 460 465 470 475

   Ser Ser Pro Ser Pro Phe Gin Pro Leu Arg Asn Leu Thr He Leu Asp 480 485 490

   Leu Ser Asn Asn Asn He Ala Asn He Asn Asp. Asp Met Leu Glu Gly 495 500 ^' 505

   Leu Glu Lys Leu Glu He Leu Asp Leu Gin His Asn Asn Leu Ala Arg 510 ^' 515 520

   Leu Trp Lys His Ala Asn Pro Gly Gly Pro He Tyr Phe Leu Lys Gly 525 530 535 Leu Ser His" Leu His He Leu Asn Leu Glu Ser Asn Gly Phe Asp Glu 540 545 550 555

   He Pro Val Glu Val Phe Lys Asp Leu Phe Glu Leu Lys He He Asp 560 565 570

   Leu Gly Leu Asn Asn Leu Asn Thr Leu Pro Ala Ser Val Phe Asn Asn 575 580 585

   Gin Val Ser Leu Lys Ser Leu Asn Leu Gin Lys Asn Leu He Thr Ser 590 595 600

   Val Glu Lys Lys Val Phe Gly Pro Ala Phe Arg Asn Leu Thr Glu Leu 605 610 615

   Asp Met Arg Phe Asn Pro Phe Asp Cys Thr Cys Glu Ser He Ala Trp 620 625 630 635

   Phe Val Asn Trp He Asn Glu Thr His Thr Asn He Pro Glu Leu Ser 640 645 650

   Ser His Tyr Leu Cys Asn Thr Pro Pro His Tyr His Gly Phe Pro Val 655 660 665

   Arg Leu Phe Asp Thr Ser Ser Cys Lys Asp Ser Ala Pro Phe Glu Leu 670 675 680

   Phe Phe Met He Asn Thr Ser He Leu Leu He Phe He Phe He Val 685 690 695 Leu Leu He His Phe Glu Gly Trp Arg He Ser Phe Tyr Trp Asn Val 700 705 710 715

   Ser Val His Arg Val Leu Gly Phe Lys Glu He Asp Arg Gin Thr Glu 720 725 730

   Gin Phe Glu Tyr Ala Ala Tyr He He His Ala Tyr Lys Asp Lys Asp 735 740 745

   Trp Val Trp Glu His Phe Ser Ser Met Glu Lys Glu Asp Gin Ser Leu 750 755 760

   Lys Phe Cys Leu Glu Glu Arg Asp Phe Glu Ala Gly Val Phe Glu Leu 765 770 775

   21 Glu Ala He Val Asn Ser He Lys Arg Ser Arg Lys He He Phe Val

   780 785 790 ^' 795 He Thr His His Leu Leu Lys Asp Pro Leu Cys Lys Arg Phe Lys Val

   800 805 - 810

   His His Ala Val Gin Gin Ala He Glu Gin Asn Leu Asp Ser He He 815 820 825

   Leu Val Phe Leu Glu Glu He Pro Asp Tyr Lys Leu Asn His Ala Leu 830 835 840

   Cys Leu Arg Arg Gly Met Phe Lys Ser His Cys He Leu Asn Trp Pro 845 850 855

   Val Gin Lys Glu Arg He Gly Ala Phe Arg His Lys Leu Gin Val Ala

   860 865 870 875 Leu Gly Ser Lys Asn Ser Val His

   880

   <210> 7 <211> 2400

   <212> DNA

   <213> Unknown

   <220> <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220> <221> CDS <222> (1) .. (2397)

   <400> 7 atg gag ctg aat ttc tac aaa ate ccc gac aac etc ccc ttc tea ace 48

   ■Met Glu Leu Asn Phe Tyr Lys He Pro Asp Asn Leu Pro Phe Ser Thr 1 5 10 15 aag aac ctg gac ctg age ttt aat ccc ctg agg. cat tta ggc age tat 96 Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr 20 ' 25 30 age ttc ttc agt ttc cca gaa ctg cag gtg ctg gat tta tec agg tgt 144 Ser Phe Phe Ser Phe Pro Glu Leu Gin Val Leu Asp Leu Ser Arg Cys 35 40 45 gaa ate cag aca att gaa gat ggg gca tat cag age eta age cac etc 192 Glu He Gin Thr He Glu Asp Gly Ala Tyr Gin Ser Leu Ser His Leu 50 55 60 tct ace tta ata ttg aca gga aac ccc ate cag agt tta gcc ctg gga 240 Ser Thr Leu He Leu Thr Gly Asn Pro He Gin Ser Leu Ala Leu Gly 65 70 75 80 gcc ttt tct gga eta tea agt tta cag aag ctg gtg get gtg gag aca 288

   22 Ala Phe Ser Gly Leu Ser Ser Leu Gin Lys Leu Val Ala Val Glu Thr 85 90 95 aat eta gca tct eta gag aac ttc ccc att gga cat etc aaa act ttg 336 Asn Leu Ala Ser Leu Glu Asn Phe Pro He Gly His Leu Lys Thr Leu 100 105 ;^' 110 aaa gaa ctt aat gtg get cac aat ctt ate caa tct ttc aaa tta cct 384 Lys Glu Leu Asn Val Ala His Asn Leu He Gin Ser Phe Lys Leu Pro 115 ^' 120 125 gag tat ttt tct aat ctg ace aat eta gag cac ttg gac ctt tec age 432

   Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser 130 135 140 aac aag att caa agt att tat tgc aca gac ttg egg gtt eta cat caa 480

   Asn Lys He Gin Ser He Tyr Cys Thr Asp Leu Arg Val Leu His Gin

   145 150 155 160 atg ccc eta etc aat etc tct tta gac ctg tec ctg aac cct atg aac 528 Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn 165 170 175 ttt ate caa cca ggt gca ttt aaa gaa att agg ctt cat aag ctg act 576 Phe He Gin Pro Gly Ala Phe Lys Glu He Arg Leu His Lys Leu Thr 180 185 190 tta aga aat aat ttt gat agt tta aat gta atg aaa act tgt att caa 624 Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys He Gin 195 200 205 ggt ctg get ggt tta gaa gtc cat cgt ttg gtt ctg gga gaa ttt aga 672

   Gly Leu Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg

   210 215 220 aat gaa gga aac ttg gaa aag ttt gac aaa tct get eta gag ggc ctg 720

   Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu

   225 230 235 240 tgc aat ttg ace att gaa gaa ttc cga tta gca tac tta gac tac tac 768 Cys Asn Leu Thr He Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr 245 250 255 etc gat gat att att gac tta ttt aat tgt ttg aca aat gtt tct tea 816 Leu Asp Asp He He Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser 260 265 270 ttt tec ctg gtg agt gtg act att gaa agg gta aaa gac ttt tct tat 864 Phe Ser Leu Val Ser Val Thr He Glu Arg Val Lys Asp Phe Ser Tyr 275 280 285 aat ttc gga tgg caa cat tta gaa tta gtt aac tgt aaa ttt gga cag 912 Asn Phe Gly Trp Gin His Leu Glu Leu Val Asn Cys Lys Phe Gly Gin 290 295 300 ttt ccc aca ttg aaa etc aaa tct etc aaa agg ctt act ttc act tec 960 Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser 305 310 315 320

   23 aac aaa ggt ggg aat get ttt tea gaa gtt gat eta cca age ctt gag 1008

   Asn Lys Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu

   325 330 335 ttt eta gat etc agt aga aat ggc ttg agt ttc. aaa ggt tgc tgt tct 1056

   Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser

   340 345 ' 350 caa agt gat ttt ggg aca ace age eta aag tat tta gat ctg age ttc 1104

   Gin Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe

   355 360 365 aat ggt gtt att ace atg agt tea aac ttc ttg ggc tta gaa caa eta 1152 Asn Gly Val He Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gin Leu

   370 375 380 gaa cat ctg gat ttc cag cat tec aat ttg aaa caa atg agt gag ttt 1200

   Glu His Leu Asp Phe Gin His Ser Asn Leu Lys Gin Met Ser Glu Phe 385 390 395 400 tea gta ttc eta tea etc aga aac etc att tac ctt gac att tct cat 1248

   Ser Val Phe Leu Ser Leu Arg Asn Leu He Tyr Leu Asp He Ser His

   405 410 415 act cac ace aga gtt get ttc aat ggc ate ttc aat ggc ttg tec agt 1296

   Thr His Thr Arg Val Ala Phe Asn Gly He Phe Asn Gly Leu Ser Ser

   420 425 430 etc gaa gtc ttg aaa atg get ggc aat tct ttc cag gaa aac ttc ctt 1344

   Leu Glu Val Leu Lys Met Ala Gly Asn Ser Phe Gin Glu Asn Phe Leu

   435 440 445 cca gat ate ttc aca gag ctg aga aac ttg ace ttc ctg gac etc tct 1392 Pro Asp He Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser

   450 455 460 cag tgt caa ctg gag cag ttg tct cca aca gca ttt aac tea etc tec 1440

   Gin Cys Gin Leu Glu Gin Leu Ser Pro Thr Ala Phe Asn Ser Leu Ser 465 470 475 480 agt ctt cag gta eta aat atg age cac aac aac ttc ttt tea ttg gat 1488

   Ser Leu Gin Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp

   485 490 495 acg ttt cct tat aag tgt ctg aac tec etc cag gtt ctt gat tac agt 1536

   Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gin Val Leu Asp Tyr Ser

   500 505 510 etc aat cac ata atg act tec aaa aaa cag gaa eta cag cat ttt cca 1584

   Leu Asn His He Met Thr Ser Lys Lys Gin Glu Leu Gin His Phe Pro

   515 520 525 agt agt eta get ttc tta aat ctt act cag aat gac ttt get tgt act 1632 Ser Ser Leu Ala Phe Leu Asn Leu Thr Gin Asn Asp Phe Ala Cys Thr

   530 535 540 tgt gaa cac cag agt ttc ctg caa tgg ate aag gac cag agg cag etc 1680

   24 Cys Glu His Gin Ser Phe Leu Gin Trp He Lys Asp Gin Arg Gin Leu 545 550 555 560 ttg gtg gaa gtt gaa cga atg gaa tgt gca aca cct tea gat aag cag 1728 Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gin

   565 570 575 ggc atg cct gtg ctg agt ttg aat ate ace tgt cag atg aat aag ace 1776

   Gly Met Pro Val Leu Ser Leu Asn He Thr Cys Gin Met Asn Lys Thr 580 ' 585 590 ate att ggt gtg teg gtc etc agt gtg ctt gta gta tct gtt gta gca 1824

   He He Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala 595 600 605 gtt ctg gtc tat aag ttc tat ttt cac ctg atg ctt ctt get ggc tgc 1872

   Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Ala Gly Cys

   610 615 620 ata aag tat ggt aga ggt gaa aac ate tat gat gcc ttt gtt ate tac 1920

   He Lys Tyr Gly Arg Gly Glu Asn He Tyr Asp Ala Phe Val He Tyr 625 630 635 640 tea age cag gat gag gac tgg gta agg aat gag eta gta aag aat tta 1968 Ser Ser Gin Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn Leu

   645 650 655 gaa gaa ggg gtg cct cca ttt cag etc tgc ctt cac tac aga gac ttt 2016

   Glu Glu Gly Val Pro Pro Phe Gin Leu Cys Leu His Tyr Arg Asp Phe 660 665 670 att ccc ggt gtg gcc att get gcc aac ate ate cat gaa ggt ttc cat 2064

   He Pro Gly Val Ala He Ala Ala Asn He He His Glu Gly Phe His 675 680 685 aaa age cga aag gtg att gtt gtg gtg tec cag cac ttc ate cag age 2112

   Lys Ser Arg Lys Val He Val Val Val Ser Gin His Phe He Gin Ser

   690 695 700 cgc tgg tgt ate ttt gaa tat gag att get cag ace tgg cag ttt ctg 2160

   Arg Trp Cys He Phe Glu Tyr Glu He Ala Gin Thr Trp Gin Phe Leu 705 710 715 720 age agt cgt get ggt ate ate ttc att gtc ctg cag aag gtg gag aag 2208 Ser Ser Arg Ala Gly He He Phe He Val Leu Gin Lys Val Glu Lys

   725 730 735 ace ctg etc agg cag cag gtg gag ctg tac cgc ctt etc age agg aac 2256

   Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn 740 745 750 act tac ctg gag tgg gag gac agt gtc ctg ggg egg cac ate ttc tgg 2304

   Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His He Phe Trp 755 760 765 aga cga etc aga aaa gcc ctg ctg gat ggt aaa tea tgg aat cca gaa 2352 Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp Asn Pro Glu 770 775 780

   25 gga aca gtg ggt aca gga tgc aat tgg cag gaa gca aca tct ate tga 2400 Gly Thr Val Gly Thr Gly Cys Asn Trp Gin Glu Ala Thr Ser He 785 790 795

   <210> 8

   <211> 799

   <212> PRT <213> Unknown

   <400> 8

   Met' Glu Leu Asn Phe Tyr Lys He Pro Asp Asn Leu Pro Phe Ser Thr 1 5 10 15

   Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu Gly Ser Tyr 20 25 30

   Ser Phe Phe Ser Phe Pro Glu Leu Gin Val Leu Asp Leu Ser Arg Cys 35 40 45

   Glu He Gin Thr He Glu Asp Gly Ala Tyr Gin Ser Leu Ser His Leu

   50 55 60 Ser Thr Leu He Leu Thr Gly Asn Pro He Gin Ser Leu Ala Leu Gly

   65 70 75 80

   Ala Phe Ser Gly Leu Ser Ser Leu Gin Lys Leu Val Ala Val Glu Thr 85 90 95

   Asn Leu Ala Ser Leu Glu Asn Phe Pro He Gly His Leu Lys Thr Leu 100 105 110

   Lys Glu Leu Asn Val Ala His Asn Leu He Gin Ser Phe Lys Leu Pro 115 120 125

   Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp Leu Ser Ser 130 135 140 Asn Lys He Gin Ser He Tyr Cys Thr Asp Leu Arg Val Leu His Gin 145 150 155 160

   Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Asn Pro Met Asn 165 170 175

   Phe He Gin Pro Gly Ala Phe Lys Glu He Arg Leu His Lys Leu Thr 180 185 190

   Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr Cys He Gin 195 200 205

   Gly Leu Ala Gly Leu Glu Val His Arg Leu Val Leu Gly Glu Phe Arg

   210 215 220 Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu Glu Gly Leu

   225 230 235 240

   Cys Asn Leu Thr He Glu Glu Phe Arg Leu Ala Tyr Leu Asp Tyr Tyr

   26 245 250 255

   Leu Asp Asp He He Asp Leu Phe Asn Cys Leu Thr Asn Val Ser Ser 260 265 270

   Phe Ser Leu Val Ser Val Thr He Glu Arg Val /Lys Asp Phe Ser Tyr 275 280 ^'' 285

   Asn Phe Gly Trp Gin His Leu Glu Leu Val Asn Cys Lys Phe Gly Gin 290 ' 295 300

   Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr Phe Thr Ser 305 310 . 315 320 Asn Lys Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro Ser Leu Glu

   325 330 335

   Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly Cys Cys Ser 340 345 350

   Gin Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp Leu Ser Phe 355 360 365

   Asn Gly Val He Thr Met Ser Ser Asn Phe Leu Gly Leu Glu Gin Leu 370 375 380

   Glu His Leu Asp Phe Gin His Ser Asn Leu Lys Gin Met Ser Glu Phe 385 390 395 400 Ser Val Phe Leu Ser Leu Arg Asn Leu He Tyr Leu Asp He Ser His

   405 410 415

   Thr His Thr Arg Val Ala Phe Asn Gly He Phe Asn Gly Leu Ser Ser 420 425 430

   Leu Glu Val Leu Lys Met Ala Gly Asn Ser Phe Gin Glu Asn Phe Leu 435 440 445

   Pro Asp He Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu Asp Leu Ser 450 455 460

   Gin Cys Gin Leu Glu Gin Leu Ser Pro Thr Ala. Phe Asn Ser Leu Ser

   465 470 475 480 Ser Leu Gin Val Leu Asn Met Ser His Asn Asn Phe Phe Ser Leu Asp

   485 490 495

   Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gin Val Leu Asp Tyr Ser 500 505 510

   Leu Asn His He Met Thr Ser Lys Lys Gin Glu Leu Gin His Phe Pro 515 520 ^' 525

   Ser Ser Leu Ala Phe Leu Asn Leu Thr Gin Asn Asp Phe Ala Cys Thr 530 535 ^' 540

   Cys Glu His Gin Ser Phe Leu Gin Trp He Lys Asp Gin Arg Gin Leu

   545 550 ^• 555 560

   27 Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser Asp Lys Gin 565 570 575 Gly Met Pro Val Leu Ser Leu Asn He Thr Cys Gin Met Asn Lys Thr

   580 585 590

   He He Gly Val Ser Val Leu Ser Val Leu Val Val Ser Val Val Ala 595 600- 605

   Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu Ala Gly Cys 610 615 620

   He Lys Tyr Gly Arg Gly Glu Asn He Tyr Asp Ala Phe Val He Tyr 625 630 635 640

   Ser Ser Gin Asp Glu Asp Trp Val Arg Asn Glu Leu Val Lys Asn Leu 645 650 655 Glu Glu Gly Val Pro Pro Phe Gin Leu Cys Leu His Tyr Arg Asp Phe 660 665 670

   He Pro Gly Val Ala He Ala Ala Asn He He His Glu Gly Phe His 675 680 685

   Lys Ser Arg Lys Val He Val Val Val Ser Gin His Phe He Gin Ser 690 695 700

   Arg Trp Cys He Phe Glu Tyr Glu He Ala Gin Thr Trp Gin Phe Leu 705 710 715 720

   Ser Ser Arg Ala Gly He He Phe He Val Leu Gin Lys Val Glu Lys 725 730 735 Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr Arg Leu Leu Ser Arg Asn 740 745 750

   Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His He Phe Trp

   755 760 765

   Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp Asn Pro Glu

   770 775 780

   Gly Thr Val Gly Thr Gly Cys Asn Trp Gin Glu Ala Thr Ser He 785 790 795

   <210> 9

   <211> 1275 <212> DNA

   <213> Unknown

   <220>

   <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220>

   <221> CDS

   28 <222> ( 1 ) . . ( 1095 )

   <400> 9 tgt tgg gat gtt ttt gag gga ctt tct cat ctt caa gtt ctg tat ttg 48 Cys Trp Asp Val Phe Glu Gly Leu Ser His Leu Gin Val Leu Tyr Leu

   1 5 10 15 aat cat aac tat ctt aat tec ctt cca cca gga gta ttt age cat ctg 96

   Asn His Asn Tyr Leu Asn Ser Leu Pro Pro Gly Val Phe Ser His Leu 20 ^' 25 30 act gca tta agg gga eta age etc aac tec aac agg ctg aca gtt ctt 144

   Thr Ala Leu Arg Gly Leu Ser Leu Asn Ser Asn Arg Leu Thr Val Leu

   35 40 45 tct cac aat gat tta cct get aat tta gag ate ctg gac ata tec agg 192

   Ser His Asn Asp Leu Pro Ala Asn Leu Glu He Leu Asp He Ser Arg

   50 55 60 aac cag etc eta get cct aat cct gat gta ttt gta tea ctt agt gtc 240

   Asn Gin Leu Leu Ala Pro Asn Pro Asp Val Phe Val Ser Leu Ser Val

   65 . 70 75 80 ttg gat ata act cat aac aag ttc att tgt gaa tgt gaa ctt age act 288 Leu Asp He Thr His Asn Lys Phe He Cys Glu Cys Glu Leu Ser Thr

   85 90 95 ttt ate aat tgg ctt aat cac ace aat gtc act ata get ggg cct cct 336

   Phe He Asn Trp Leu Asn His Thr Asn Val Thr He Ala Gly Pro Pro 100 105 110 gca gac ata tat tgt gtg tac cct gac teg ttc tct ggg gtt tec etc 384

   Ala Asp He Tyr Cys Val Tyr Pro Asp Ser Phe Ser Gly Val Ser Leu

   115 120 125 ttc tct ctt tec acg gaa ggt tgt gat gaa gag gaa gtc tta aag tec 432

   Phe Ser Leu Ser Thr Glu Gly Cys Asp Glu Glu Glu Val Leu Lys Ser

   130 135 140 eta aag ttc tec ctt ttc att gta tgc act gtc act ctg act ctg ttc 480

   Leu Lys Phe Ser Leu Phe He Val Cys Thr Val Thr Leu Thr Leu Phe

   145 150 155 160 etc atg ace ate etc aca gtc aca aag ttc egg ggc ttc tgt ttt ate 528 Leu Met Thr He Leu Thr Val Thr Lys Phe Arg Gly Phe Cys Phe He

   165 170 175 tgt tat aag aca gcc cag aga ctg gtg ttc aag gac cat ccc cag ggc 576

   Cys Tyr Lys Thr Ala Gin Arg Leu Val Phe Lys Asp His Pro Gin Gly 180 185 190 aca gaa cct gat atg tac aaa tat gat gcc tat ttg tgc ttc age age 624

   Thr Glu Pro Asp Met Tyr Lys Tyr Asp Ala Tyr Leu Cys Phe Ser Ser

   195 200 205 aaa gac ttc aca tgg gtg cag aat get ttg etc aaa cac ctg gac act 672 Lys Asp Phe Thr Trp Val Gin Asn Ala Leu Leu Lys His Leu Asp Thr 210 215 220

   29 caa tac agt gac caa aac aga ttc aac ctg tgc ttt gaa gaa aga gac 720

   Gin Tyr Ser Asp Gin Asn Arg Phe Asn Leu Cys Phe Glu Glu Arg Asp 225 230 235 240 ttt gtc cca gga gaa aac cgc att gcc aat ate _cag gat gcc ate tgg 768

   Phe Val Pro Gly Glu Asn Arg He Ala Asn He ^'Gin Asp Ala He Trp

   245 250 ^• 255 aac agt aga aag ate "gtt tgt ctt gtg age aga cac ttc ctt aga gat 816 Asn Ser Arg Lys He Val Cys Leu Val Ser Arg His Phe Leu Arg Asp 260 265 270 ggc tgg tgc ctt gaa gcc ttc agt tat gcc cag ggc agg tgc tta tct 864 Gly Trp Cys Leu Glu Ala Phe Ser Tyr Ala Gin Gly Arg Cys Leu Ser 275 280 285 gac ctt aac agt get etc ate atg gtg gtg gtt ggg tec ttg tec cag 912 Asp Leu Asn Ser Ala Leu He Met Val Val Val Gly Ser Leu Ser Gin 290 295 300 tac cag ttg atg aaa cat caa tec ate aga ggc ttt gta cag aaa cag 960

   Tyr Gin Leu Met Lys His Gin Ser He Arg Gly Phe Val Gin Lys Gin 305 310 315 320 cag tat ttg agg tgg cct gag gat etc cag gat gtt ggc tgg ttt ctt 1008

   Gin Tyr Leu Arg Trp Pro Glu Asp Leu Gin Asp Val Gly Trp Phe Leu 325 330 335 cat aaa etc tct caa cag ata eta aag aaa gaa aag gaa aag aag aaa 1056 His Lys Leu Ser Gin Gin He Leu Lys Lys Glu Lys Glu Lys Lys Lys 340 345 350 gac aat aac att ccg ttg caa act gta gca ace ate tec taatcaaagg 1105 Asp Asn Asn He Pro Leu Gin Thr Val Ala Thr He Ser 355 360 365 agcaatttee aacttatctc aagceacaaa taactettea ctttgtattt geaccaagtt 1165 atcattttgg ggtcetetct ggaggttttt tttttetttt tgetactatg aaaaeaacat 1225 aaatctctca attttcgtat caaaaaaaaa aaaaaaaaaa tggcggccgc 1275

   <210> 10

   <211> 365

   <212> PRT

   <213> Unknown <400> 10

   Cys Trp Asp Val Phe Glu Gly Leu Ser His Leu Gin Val Leu Tyr Leu 1 5 10 15

   Asn His Asn Tyr Leu Asn Ser Leu Pro Pro Gly Val Phe Ser His Leu 20 25 30

   Thr Ala Leu Arg Gly Leu Ser Leu Asn Ser Asn Arg Leu Thr Val Leu 35 40 45

   30 Ser His Asn Asp Leu Pro Ala Asn Leu Glu He Leu Asp He Ser Arg 50 55 60

   Asn Gin Leu Leu Ala Pro Asn Pro Asp Val Phe Val Ser Leu Ser Val 65 70 75 ' 80

   Leu Asp He Thr His Asn Lys Phe He Cys Glu Cys Glu Leu Ser Thr 85 90 95

   Phe He Asn Trp Leu Asn His Thr Asn Val Thr He Ala Gly Pro Pro 100 105 110

   Ala Asp He Tyr Cys Val Tyr Pro Asp Ser Phe Ser Gly Val Ser Leu 115 120 125

   Phe Ser Leu Ser Thr Glu Gly Cys Asp Glu Glu Glu Val Leu Lys Ser 130 135 140 Leu Lys Phe Ser Leu Phe He Val Cys Thr Val Thr Leu Thr Leu Phe 145 150 155 160

   Leu Met Thr He Leu Thr Val Thr Lys Phe Arg Gly Phe Cys Phe He 165 170 175

   Cys Tyr Lys Thr Ala Gin Arg Leu Val Phe Lys Asp His Pro Gin Gly 180 185 190

   Thr Glu Pro Asp Met Tyr Lys Tyr Asp Ala Tyr Leu Cys Phe Ser Ser 195 200 205

   Lys Asp Phe Thr Trp Val Gin Asn Ala Leu Leu Lys His Leu Asp Thr 210 215 220 Gin Tyr Ser Asp Gin Asn Arg Phe Asn Leu Cys Phe Glu Glu Arg Asp 225 230 235 240

   Phe Val Pro Gly Glu Asn Arg He Ala Asn He Gin Asp Ala He Trp 245 250 255

   Asn Ser Arg Lys He Val Cys Leu Val Ser Arg His Phe Leu Arg Asp 260 265 270

   Gly Trp Cys Leu Glu Ala Phe Ser Tyr Ala Gin Gly Arg Cys Leu Ser 275 280 285

   Asp Leu Asn Ser Ala Leu He Met Val Val Val Gly Ser Leu Ser Gin

   290 295 300 Tyr Gin Leu Met Lys His Gin Ser He Arg Gly Phe Val Gin Lys Gin

   305 310 315 320

   Gin Tyr Leu Arg Trp Pro Glu Asp Leu Gin Asp Val Gly Trp Phe Leu

   325 330 335

   His Lys Leu Ser Gin Gin He Leu Lys Lys Glu Lys Glu Lys Lys Lys

   340 345 350

   31 Asp Asn Asn He Pro Leu Gin Thr Val Ala Thr He Ser 355 360 365

   <210> 11

   <211> 3138 <212> DNA <213> Unknown <220>

   <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220> <221> CDS

   <222> (1) .. (3135) '

   <220>

   <221> mat_peptide <222> ( 67 ) . . (3135 )

   <400> 11 atg tgg aca ctg aag aga eta att ctt ate ctt ttt aac ata ate eta 48

   Met Trp Thr Leu Lys Arg Leu He Leu He Leu Phe Asn He He Leu -20 -15 -10 att tec aaa etc ctt ggg get aga tgg ttt cct aaa act ctg ccc tgt 96

   He Ser Lys Leu Leu Gly Ala Arg Trp Phe Pro Lys Thr Leu Pro Cys

   -5 -1 1 5 10 gat gtc act ctg gat gtt cca aag aac-cat gtg ate gtg gac tgc aca 144

   Asp Val Thr Leu Asp Val Pro Lys Asn His Val He Val Asp Cys Thr 15 20 25 gac aag cat ttg aca gaa att cct gga ggt att ccc acg aac ace acg 192 Asp Lys His Leu Thr Glu He Pro Gly Gly He Pro Thr Asn Thr Thr — 30 35 40 aac etc ace etc ace att aac cac ata cca gac ate tec cca gcg tec 240 Asn Leu Thr Leu Thr He Asn His He Pro Asp He Ser Pro Ala Ser 45 50 55 ttt cac aga ctg gac cat ctg gta gag ate gat ttc aga tgc aac tgt 288 Phe His Arg Leu Asp His Leu Val Glu He Asp Phe Arg Cys Asn Cys 60 65 70 gta cct att cca ctg ggg tea aaa aac aac atg tgc ate aag agg ctg 336

   Val Pro He Pro Leu Gly Ser Lys Asn Asn Met Cys He Lys Arg Leu

   75 80 85 90 cag att aaa ccc aga age ttt agt gga etc act tat tta aaa tec ctt 384

   Gin He Lys Pro Arg Ser Phe Ser Gly Leu Thr Tyr Leu Lys Ser Leu 95 100 105 tac ctg gat gga aac cag eta eta gag ata ccg cag ggc etc ccg cct 432 Tyr Leu Asp Gly Asn Gin Leu Leu Glu He Pro Gin Gly Leu Pro Pro 110 115 120

   32 age tta cag ctt etc age ctt gag gcc aac aac ate ttt tec ate aga 480

   Ser Leu Gin Leu Leu Ser Leu Glu Ala Asn Asn He Phe Ser He Arg

   125 130 135 aaa gag aat eta aca gaa ctg gcc aac ata gaa ata etc tac ctg ggc 528

   Lys Glu Asn Leu Thr Glu Leu Ala Asn He Glu,'Ile Leu Tyr Leu Gly

   140 145 ^' 150 caa aac tgt tat tat cga aat cct tgt tat gtt tea tat tea ata gag 576 Gin Asn Cys Tyr Tyr^" Arg Asn Pro Cys Tyr Val Ser Tyr Ser He Glu

   155 160 165 170 aaa gat gcc ttc eta aac ttg aca aag tta aaa gtg etc tec ctg aaa 624

   Lys Asp Ala Phe Leu Asn Leu Thr Lys Leu Lys Val Leu Ser Leu Lys 175 180 185 gat aac aat gtc aca gcc gtc cct act gtt ttg cca tct act tta aca 672

   Asp Asn Asn Val Thr Ala Val Pro Thr Val Leu Pro Ser Thr Leu Thr

   190 195 200 gaa eta tat etc tac aac aac atg att gca aaa ate caa gaa gat gat 720

   Glu Leu Tyr Leu Tyr Asn Asn Met He Ala Lys He Gin Glu Asp Asp

   205 210 215 ttt aat aac etc aac caa tta caa att ctt gac eta agt gga aat tgc 768

   Phe Asn Asn Leu Asn Gin Leu Gin He Leu Asp Leu Ser Gly Asn Cys

   220 225 230 cct cgt tgt tat aat gcc cca ttt cct tgt gcg ccg tgt aaa aat aat 816 Pro Arg Cys Tyr Asn Ala Pro Phe Pro Cys Ala Pro Cys Lys Asn Asn

   235 240 245 250 tct ccc eta cag ate cct gta aat get ttt gat gcg ctg aca gaa tta 864

   Ser Pro Leu Gin He Pro Val Asn Ala Phe Asp Ala Leu Thr Glu Leu 255 260 265 aaa gtt tta cgt eta cac agt aac tct ctt cag cat gtg ccc cca aga 912

   Lys Val Leu Arg Leu His Ser Asn Ser Leu Gin His Val Pro Pro Arg

   270 275 280 tgg ttt aag aac ate aac aaa etc cag gaa ctg gat ctg tec caa aac 960

   Trp Phe Lys Asn He Asn Lys Leu Gin Glu Leu Asp Leu Ser Gin Asn

   285 290 295 ttc ttg gcc aaa gaa att ggg gat get aaa ttt ctg cat ttt etc ccc 1008

   Phe Leu Ala Lys Glu He Gly Asp Ala Lys Phe Leu His Phe Leu Pro

   300 305 310 age etc ate caa ttg gat ctg tct ttc aat ttt gaa ctt cag gtc tat 1056 Ser Leu He Gin Leu Asp Leu Ser Phe Asn Phe Glu Leu Gin Val Tyr

   315 320 325 330 cgt gca tct atg aat eta tea caa gca ttt tct tea ctg aaa age ctg 1104

   Arg Ala Ser Met Asn Leu Ser Gin Ala Phe Ser Ser Leu Lys Ser Leu 335 340' 345 aaa att ctg egg ate aga gga tat gtc ttt aaa gag ttg aaa age ttt 1152

   Lys He Leu Arg He Arg Gly Tyr Val Phe Lys Glu Leu Lys Ser Phe

   33 350 355 360 aac etc teg cca tta cat aat ctt caa aat ctt gaa gtt ctt gat ctt 1200

   Asn Leu Ser Pro Leu His Asn Leu Gin Asn Leu Glu Val Leu Asp Leu 365 370 375 ggc act aac ttt ata aaa att get aac etc age atg ttt aaa caa ttt 1248

   Gly Thr Asn Phe He Lys He Ala Asn Leu Ser Met Phe Lys Gin Phe 380 385 390 aaa aga ctg aaa gtc ata gat ctt tea gtg aat aaa ata tea cct tea 1296 Lys Arg Leu Lys Val He Asp Leu Ser Val Asn Lys He Ser Pro Ser 395 400 ^• 405 410 gga gat tea agt gaa gtt ggc ttc tgc tea aat gcc aga act tct gta 1344 Gly Asp Ser Ser Glu Val Gly Phe Cys Ser Asn Ala Arg Thr Ser Val 415 420 425 gaa agt tat gaa ccc cag gtc ctg gaa caa tta cat tat ttc aga tat 1392 Glu Ser Tyr Glu Pro Gin Val Leu Glu Gin Leu His Tyr Phe Arg Tyr 430 435 440 gat aag tat gca agg agt tgc aga ttc aaa aac aaa gag get tct ttc 1440

   Asp Lys Tyr Ala Arg Ser Cys Arg Phe Lys Asn Lys Glu Ala Ser Phe 445 450 455 atg tct gtt aat gaa age tgc tac aag tat ggg cag ace ttg gat eta 1488

   Met Ser Val Asn Glu Ser Cys Tyr Lys Tyr Gly Gin Thr Leu Asp Leu 460 465 470 agt aaa aat agt ata ttt ttt gtc aag tec tct gat ttt cag cat ctt 1536

   Ser Lys Asn Ser He Phe Phe Val Lys Ser Ser Asp Phe Gin His Leu

   475 480 485 490 tct ttc etc aaa tgc ctg aat ctg tea gga aat etc att age caa act 1584

   Ser Phe Leu Lys Cys Leu Asn Leu Ser Gly Asn Leu He Ser Gin Thr 495 500 505 ctt aat ggc agt gaa ttc caa cct tta gca gag ctg aga tat ttg gac 1632 Leu Asn Gly Ser Glu Phe Gin Pro Leu Ala Glu Leu Arg Tyr Leu Asp 510 515 520 ttc tec aac aac egg ctt gat tta etc cat tea aca gca ttt gaa gag 1680

   Phe Ser Asn Asn Arg Le^'u Asp Leu Leu His Ser Thr Ala Phe Glu Glu 525 530 535 ctt cac aaa ctg gaa gtt ctg gat ata age agt aat age cat tat ttt 1728

   Leu His Lys Leu Glu Val Leu Asp He Ser Ser Asn Ser His Tyr Phe 540 545 550 caa tea gaa gga att act cat atg eta aac ttt ace aag aac eta aag 1776

   Gin Ser Glu Gly He Thr His Met Leu Asn Phe Thr Lys Asn Leu Lys

   555 560 565 570 gtt ctg cag aaa ctg atg atg aac gac aat gac ate tct tec tec ace 1824

   Val Leu Gin Lys Leu Met Met Asn Asp Asn Asp He Ser Ser Ser Thr 575 580 585

   34 age agg ace atg gag agt gag tct ctt aga act ctg gaa ttc aga gga 1872

   Ser Arg Thr Met Glu Ser Glu Ser Leu Arg Thr Leu Glu Phe Arg Gly

   590 595 600 aat cac tta gat gtt tta tgg aga gaa ggt gat aac aga tac tta caa 1920

   Asn His Leu Asp Val Leu Trp Arg Glu Gly Asp Asn Arg Tyr Leu Gin

   605 610 615 tta ttc aag aat ctg. eta aaa tta gag gaa tta gac ate tct aaa aat 1968 Leu Phe Lys Asn Leu Leu Lys Leu Glu Glu Leu Asp He Ser Lys Asn

   620 625 630 tec eta agt ttc ttg cct tct gga gtt ttt gat ggt atg cct cca aat 2016

   Ser Leu Ser Phe Leu Pro Ser Gly Val Phe Asp Gly Met Pro Pro Asn 635 640 645 650 eta aag aat etc tct ttg gcc aaa aat ggg etc aaa tct ttc agt tgg 2064

   Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys Ser Phe Ser Trp

   655 660 665 aag aaa etc cag tgt eta aag aac ctg gaa act ttg gac etc age cac 2112

   Lys Lys Leu Gin Cys Leu Lys Asn Leu Glu Thr Leu Asp Leu Ser His

   670 675 680 aac caa ctg ace act gtc cct gag aga tta tec aac tgt tec aga age 2160

   Asn Gin Leu Thr Thr Val Pro Glu Arg Leu Ser Asn Cys Ser Arg Ser

   685 690 695 etc aag aat ctg att ctt aag aat aat caa ate agg agt ctg acg aag 2208 Leu Lys Asn Leu He Leu Lys Asn Asn Gin He Arg Ser Leu Thr Lys

   700 705 710 tat ttt eta caa gat gcc ttc cag ttg cga tat ctg gat etc age tea 2256

   Tyr Phe Leu Gin Asp Ala Phe Gin Leu Arg Tyr Leu Asp Leu Ser Ser 715 720 725 730 aat aaa ate cag atg ate caa aag ace age ttc cca gaa aat gtc etc 2304

   Asn Lys He Gin Met He Gin Lys Thr Ser Phe Pro Glu Asn Val Leu

   735 740 745 aac aat ctg aag atg ttg ctt ttg cat cat aat egg ttt ctg tgc ace 2352

   Asn Asn Leu Lys Met Leu Leu Leu His His Asn Arg Phe Leu Cys Thr

   750 755 760 tgt gat get gtg tgg ttt gtc tgg tgg gtt aac cat acg gag gtg act 2400

   Cys Asp Ala Val Trp Phe Val Trp Trp Val Asn His Thr Glu Val Thr

   765 770 775 att cct tac ctg gcc aca gat gtg act tgt gtg ggg cca gga gca cac . 2448 He Pro Tyr Leu Ala Thr Asp Val Thr Cys Val Gly Pro Gly Ala His

   780 785 790 aag ggc caa agt gtg ate tec ctg gat ctg tac ace tgt gag tta gat 2496

   Lys Gly Gin Ser Val He Ser Leu Asp Leu Tyr Thr Cys Glu Leu Asp 795 800 805 810 ctg act aac ctg att ctg ttc tea ctt tec ata tct gta tct etc ttt 2544

   Leu Thr Asn Leu He Leu Phe Ser Leu Ser He Ser Val Ser Leu Phe

   35 815 820 825 etc atg gtg atg atg aca gca agt cac etc tat ttc tgg gat gtg tgg 2592 Leu Met Val Met Met Thr Ala Ser His Leu Tyr Phe Trp Asp Val Trp 830 835 840 tat att tac cat ttc tgt aag gcc aag ata aag ggg tat cag cgt eta 2640

   Tyr He Tyr His Phe Cys Lys Ala Lys He Lys Gly Tyr Gin Arg Leu

   845 850 855 ata tea cca gac tgt tgc tat gat get ttt att gtg tat gac act aaa 2688

   He Ser Pro Asp Cys Cys Tyr Asp Ala Phe He Val Tyr Asp Thr Lys

   860 865 870 gac cca get gtg ace gag tgg gtt ttg get gag ctg gtg gcc aaa ctg 2736 Asp Pro Ala Val Thr Glu Trp Val Leu Ala Glu Leu Val Ala Lys Leu 875 880 885 890 gaa gac cca aga gag aaa cat ttt aat tta tgt etc gag gaa agg gac 2784 Glu Asp Pro Arg Glu Lys His Phe Asn Leu Cys Leu Glu Glu Arg Asp

   895 900 905 tgg tta cca ggg cag cca gtt ctg gaa aac ctt tec cag age ata cag 2832 Trp Leu Pro Gly Gin Pro Val Leu Glu Asn Leu Ser Gin Ser He Gin 910 915 920 ctt age aaa aag aca gtg ttt gtg atg aca gac aag tat gca aag act 2880

   Leu Ser Lys Lys Thr Val Phe Val Met Thr Asp Lys Tyr Ala Lys Thr

   925 930 935 gaa aat ttt aag ata gca ttt tac ttg tec cat cag agg etc atg gat 2928

   Glu Asn Phe Lys He Ala Phe Tyr Leu Ser His Gin Arg Leu Met Asp

   940 945 950 gaa aaa gtt gat gtg att ate ttg ata ttt ctt gag aag ccc ttt cag 2976 Glu Lys Val Asp Val He He Leu He Phe Leu Glu Lys Pro Phe Gin 955 960 965 970 aag tec aag ttc etc cag etc egg aaa agg etc tgt ggg agt tct gtc 3024 Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg Leu Cys Gly Ser Ser Val

   975 980 985 ctt gag tgg cca aca aac ccg caa get cac cca tac ttc tgg cag tgt 3072 Leu Glu Trp Pro Thr Asn Pro Gin Ala His Pro Tyr Phe Trp Gin Cys 990 995 1000 eta aag aac gcc ctg gcc aca gac aat cat gtg gcc tat agt cag gtg 3120 Leu Lys Asn Ala Leu Ala Thr Asp Asn His Val Ala Tyr Ser Gin Val 1005 1010 1015 ttc aag gaa acg gtc tag 313? Phe Lys Glu Thr Val 1020

   <210> 12 <211> 1045 <212> PRT

   36 <213> Unknown

   <400> 12

   Met Trp Thr Leu Lys Arg Leu He Leu He Leu Phe Asn He He Leu -20 -15 -10

   He Ser Lys Leu Leu Giy Ala Arg Trp Phe Pro Lys Thr Leu Pro Cys -5 -1 1 5 10 Asp Val Thr Leu Asp Val Pro Lys Asn His Val He Val Asp Cys Thr

   15 20 25

   Asp Lys His Leu Thr Glu He Pr.o Gly Gly He Pro Thr Asn Thr Thr 30 35 40

   Asn Leu Thr Leu Thr He Asn His He Pro Asp He Ser Pro Ala Ser 45 50 55

   Phe His Arg Leu Asp His Leu Val Glu He Asp Phe Arg Cys Asn Cys 60 65 70

   Val Pro He Pro Leu Gly Ser Lys Asn Asn Met Cys He Lys Arg Leu

   75 80 85 90 Gin He Lys Pro Arg Ser Phe Ser Gly Leu Thr Tyr Leu Lys Ser Leu

   95 100 10~5

   Tyr Leu Asp Gly Asn Gin Leu Leu Glu He Pro Gin Gly Leu Pro Pro 110 115 120

   Ser Leu Gin Leu Leu Ser Leu Glu Ala Asn Asn He Phe Ser He Arg 125 130 135

   Lys Glu Asn Leu Thr Glu Leu Ala Asn He Glu He Leu Tyr Leu Gly 140 145 150

   Gin Asn Cys Tyr Tyr Arg Asn Pro Cys Tyr Val Ser Tyr Ser He Glu 155 160 165 170 Lys Asp Ala Phe Leu Asn Leu Thr Lys Leu Lys Val Leu Ser Leu Lys

   175 180 185

   Asp Asn Asn Val Thr Ala Val Pro Thr Val Leu Pro Ser Thr Leu Thr 190 195 200

   Glu Leu Tyr Leu Tyr Asn Asn Met He Ala Lys He Gin Glu Asp Asp 205 210 215

   Phe Asn Asn Leu Asn Gin Leu Gin He Leu Asp Leu Ser Gly Asn Cys 220 225 230

   Pro Arg Cys Tyr Asn Ala Pro Phe Pro Cys Ala Pro Cys Lys Asn Asn

   235 240 245 250 Ser Pro Leu Gin He Pro Val Asn Ala Phe Asp Ala Leu Thr Glu Leu

   255 260 265

   Lys Val Leu Arg Leu His Ser Asn Ser Leu Gin His Val Pro Pro Arg

   37 270 275 280

   Trp Phe Lys Asn He Asn Lys Leu Gin Glu Leu Asp Leu Ser Gin Asn 285 290 295

   Phe Leu Ala Lys Glu He Gly Asp Ala Lys Phe Leu His Phe Leu Pro 300 305 ^'' 310

   Ser Leu He Gin Leu Asp Leu Ser Phe Asn Phe Glu Leu Gin Val Tyr 315 ' 320 325 330

   Arg Ala Ser Met Asn Leu Ser Gin Ala Phe Ser Ser Leu Lys Ser Leu 335 340 345 Lys He Leu Arg He Arg Gly Tyr Val Phe Lys Glu Leu Lys Ser Phe 350 355 360

   Asn Leu Ser Pro Leu His Asn' Leu Gin Asn Leu Glu Val Leu Asp Leu 365 370 375

   Gly Thr Asn Phe He Lys He Ala Asn Leu Ser Met Phe Lys Gin Phe 380 385 390

   Lys Arg Leu Lys Val He Asp Leu Ser Val Asn Lys He Ser Pro Ser 395 400 405 410

   Gly Asp Ser Ser Glu Val Gly Phe Cys Ser Asn Ala Arg Thr Ser Val

   415 420 425 Glu Ser Tyr Glu Pro Gin Val Leu Glu Gin Leu His Tyr Phe Arg Tyr 430 435 440

   Asp Lys Tyr Ala Arg Ser Cys Arg Phe Lys Asn Lys Glu Ala Ser Phe 445 450 455

   Met Ser Val Asn Glu Ser Cys Tyr Lys Tyr Gly Gin Thr Leu Asp Leu 460 465 470

   Ser Lys Asn Ser He Phe Phe Val Lys Ser Ser Asp Phe Gin His Leu 475 480 485 490

   Ser Phe Leu Lys Cys Leu Asn Leu Ser Gly Asn Leu He Ser Gin Thr

   495 500 505 Leu Asn Gly Ser Glu Phe Gin Pro Leu Ala Glu Leu Arg Tyr Leu Asp 510 515 520

   Phe Ser Asn Asn Arg Leu Asp Leu Leu His Ser Thr Ala Phe Glu Glu 525 530 535

   Leu His Lys Leu Glu Val Leu Asp He Ser Ser Asn Ser His Tyr Phe 540 545 550

   Gin Ser Glu Gly He Thr His Met Leu Asn Phe Thr Lys Asn Leu Lys 555 560 565 570

   Val Leu Gin Lys Leu Met Met Asn Asp Asn Asp He Ser Ser Ser Thr 575 580 585

   38 Ser Arg Thr Met Glu Ser Glu Ser Leu Arg Thr Leu Glu Phe Arg Gly 590 595 600

   Asn His Leu Asp Val Leu Trp Arg Glu Gly Asp Asn Arg Tyr Leu Gin 605 610 615

   Leu Phe Lys Asn Leu Leu Lys Leu Glu Glu Leu Asp He Ser Lys Asn 620 625 630

   Ser Leu Ser Phe Leu Pro Ser Gly Val Phe Asp Gly Met Pro Pro Asn 635 640 645 650

   Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys Ser Phe Ser Trp 655 660 665

   Lys Lys Leu Gin Cys Leu Lys Asn Leu Glu Thr Leu Asp Leu Ser His

   670 675 680 Asn Gin Leu Thr Thr Val Pro Glu Arg Leu Ser Asn Cys Ser Arg Ser 685 690 695

   Leu Lys Asn Leu He Leu Lys Asn Asn Gin He Arg Ser Leu Thr Lys 700 705 710

   Tyr Phe Leu Gin Asp Ala Phe Gin Leu Arg Tyr Leu Asp Leu Ser Ser 715 720 725 730

   Asn Lys He Gin Met He Gin Lys Thr Ser Phe Pro Glu Asn Val Leu 735 740 745

   Asn Asn Leu Lys Met Leu Leu Leu His His Asn Arg Phe Leu Cys Thr 750 755 760 Cys Asp Ala Val Trp Phe Val Trp Trp Val Asn His Thr Glu Val Thr 765 770 775

   He Pro Tyr Leu Ala Thr Asp Val Thr Cys Val Gly Pro Gly Ala His 780 785 790

   Lys Gly Gin Ser Val He Ser Leu Asp Leu Tyr Thr Cys Glu Leu Asp 795 800 805 810

   Leu Thr Asn Leu He Leu Phe Ser Leu Ser He Ser Val Ser Leu Phe 815 820 825

   Leu Met Val Met Met Thr Ala Ser His Leu Tyr Phe Trp Asp Val Trp

   830 835 840 Tyr He Tyr His Phe Cys Lys Ala Lys He Lys Gly Tyr Gin Arg Leu

   845 850 855

   He Ser Pro Asp Cys Cys Tyr Asp Ala Phe He Val Tyr Asp Thr Lys 860 865 870

   Asp Pro Ala Val Thr Glu Trp Val Leu Ala Glu Leu Val Ala Lys Leu

   875 880 885 890

   39 Glu Asp Pro Arg Glu Lys His Phe Asn Leu Cys Leu Glu Glu Arg Asp

   895 900 905

   Trp Leu Pro Gly Gin Pro Val Leu Glu Asn Leu Ser Gin Ser He Gin 910 915 920

   Leu Ser Lys Lys Thr Val Phe Val Met Thr Asp Lys Tyr Ala Lys Thr 925 930 ' 935 Glu Asn Phe Lys He' Ala Phe Tyr Leu Ser His Gin Arg Leu Met Asp 940 945 950

   Glu Lys Val Asp Val He He Leu He Phe ^• Leu Glu Lys Pro Phe Gin 955 960 965 970

   Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg Leu Cys Gly Ser Ser Val 975 980 985

   Leu Glu Trp Pro Thr Asn Pro Gin Ala His Pro Tyr Phe Trp Gin Cys 990 995 1000

   Leu Lys Asn Ala Leu Ala Thr Asp Asn His Val Ala Tyr Ser Gin Val 1005 1010 1015 Phe Lys Glu Thr Val 1020

   <210> 13 <211> 180

   <212> DNA

   <213> Unknown

   <220> <223> Description of Unknown Organism: rodent; surmised Mus musculus

   <220> <221> CDS <222> (1) .. (177)

   <400> 13 ctt gga aaa cct ctt cag aag tct aag ttt ctt cag etc agg aag aga 48

   Leu Gly Lys Pro Leu Gin Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg 1 5 10 15 etc tgc agg age tct gtc ctt gag tgg cct gca aat cca cag get cac 96

   Leu Cys Arg Ser Ser Val Leu Glu Trp Pro Ala Asn Pro Gin Ala His 20 25 30 cca tac ttc tgg cag tgc ctg aaa aat gcc ctg ace aca gac aat cat 144

   Pro Tyr Phe Trp Gin Cys Leu Lys Asn Ala Leu Thr Thr Asp Asn His 35 40 45 gtg get tat agt caa atg ttc aag gaa aca gtc tag 180

   Val Ala Tyr Ser Gin Met Phe Lys Glu Thr Val 50 55

   40 <210> 14 <211> 59 <212> PRT <213> Unknown

   <400> 14

   Leu Gly Lys Pro Leu Gin Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg 1 5 10 15

   Leu Cys Arg Ser Ser Val Leu Glu Trp Pro Ala Asn Pro Gin Ala His 20 25 30

   Pro Tyr Phe Trp Gin Cys Leu Lys Asn Ala Leu Thr Thr Asp Asn His 35 40 45

   Val Ala Tyr Ser Gin Met Phe Lys Glu Thr Val 50 55

   <210> 15 <211> 990 <212> DNA <213> Unknown

   <220>

   <223> Description of Unknown Organism:primate; surmised Homo sapiens <220>

   <221> CDS

   <222> (2) .. (988)

   <400> 15 g aat tec aga ctt ata aac ttg aaa aat etc tat ttg gcc tgg aac tgc 49 Asn Ser Arg Leu He Asn Leu Lys Asn Leu Tyr Leu Ala Trp Asn Cys 1 5 10 15 tat ttt aac aaa gtt tgc gag aaa act aac ata gaa gat gga gta ttt 97 Tyr Phe Asn Lys Val Cys Glu Lys Thr Asn He Glu Asp Gly Val Phe

   20 25 30 gaa acg ctg aca aat ttg gag ttg eta tea eta tct ttc aat tct ctt 145 Glu Thr Leu Thr Asn Leu Glu Leu Leu Ser Leu Ser Phe Asn Ser Leu 35 40 45 tea cat gtg cca ccc aaa ctg cca age tec eta cgc aaa ctt ttt ctg 193

   Ser His Val Pro Pro Lys Leu Pro Ser Ser Leu Arg Lys Leu Phe Leu 50 55 60 age aac ace cag ate aaa tac att agt gaa gaa gat ttc aag gga ttg 241

   Ser Asn Thr Gin He Lys Tyr He Ser Glu Glu Asp Phe Lys Gly Leu 65 70 75 80 ata aat tta aca tta eta gat tta age ggg aac tgt ccg agg tgc ttc 289 He Asn Leu Thr Leu Leu Asp Leu Ser Gly Asn Cys Pro Arg Cys Phe 85 90 95

   41 aat gcc cca ttt cca tgc gtg cct tgt gat ggt ggt get tea att aat 337

   Asn Ala Pro Phe Pro Cys Val Pro Cys Asp Gly Gly Ala Ser He Asn 100 105 110 ata gat cgt ttt get ttt caa aac ttg ace caa ctt cga tac eta aac 385

   He Asp Arg Phe Ala Phe Gin Asn Leu Thr Gin. ^'Leu Arg Tyr Leu Asn

   115 120 ^' 125 etc tct age act tec etc agg aag att aat get gcc tgg ttt aaa aat 433 Leu Ser Ser Thr Ser Leu Arg Lys He Asn Ala Ala Trp Phe Lys Asn 130 135 140 atg cct cat ctg aag gtg ctg gat ctt gaa ttc aac tat tta gtg gga 481

   Met Pro His Leu Lys Val Leu Asp Leu Glu Phe Asn Tyr Leu Val Gly 145 150 155 160 gaa ata gcc tct ggg gca ttt tta acg atg ctg ccc cgc tta gaa ata 529

   Glu He Ala Ser Gly Ala Phe Leu Thr Met Leu Pro Arg Leu Glu He

   165 170 175 ctt gac ttg tct ttt aac tat ata aag ggg agt tat cca cag cat att 577

   Leu Asp Leu Ser Phe Asn Tyr He Lys Gly Ser Tyr Pro Gin His He 180 185 190 aat att tec aga aac ttc tct aaa ctt ttg tct eta egg gca ttg cat 625

   Asn He Ser Arg Asn Phe Ser Lys Leu Leu Ser Leu Arg Ala Leu His

   195 200 205 tta aga ggt tat gtg ttc cag gaa etc aga gaa gat gat ttc cag ccc 673 Leu Arg Gly Tyr Val Phe Gin Glu Leu Arg Glu Asp Asp Phe Gin Pro 210 215 220 ctg atg cag ctt cca aac tta teg act ate aac ttg ggt att aat ttt 721

   Leu Met Gin Leu Pro Asn Leu Ser Thr He Asn Leu Gly He Asn Phe 225 230 235 240 att aag caa ate gat ttc aaa ctt ttc caa aat ttc tec aat ctg gaa 769

   He Lys Gin He Asp Phe Lys Leu Phe Gin Asn Phe Ser Asn Leu Glu

   245 250 255 att att tac ttg tea gaa aac aga ata tea ccg ttg gta aaa gat ace 817

   He He Tyr Leu Ser Glu Asn Arg He Ser Pro Leu Val Lys Asp Thr 260 265 ^' 270 egg cag agt tat gca aat agt tec tct ttt caa cgt cat ate egg aaa 865

   Arg Gin Ser Tyr Ala Asn Ser Ser Ser Phe Gin Arg His He Arg Lys

   275 280 285 cga cgc tea aca gat ttt gag ttt gac cca cat teg aac ttt tat cat 913 Arg Arg Ser Thr Asp Phe Glu Phe Asp Pro His Ser Asn Phe Tyr His „ 290 295 300 ttc ace cgt cct tta ata aag cca caa tgt get get tat gga aaa gcc 961

   Phe Thr Arg Pro Leu He Lys Pro Gin Cys Ala Ala Tyr Gly Lys Ala 305 310 315 320 tta gat tta age etc aac agt att ttc tt 990

   Leu Asp Leu Ser Leu Asn Ser -He Phe

   42 325

   <210> 16 <211> 329 <212> PRT <213> Unknown

   < 400> 16 Asn Ser Arg Leu He Asn Leu Lys Asn Leu Tyr Leu Ala Trp Asn Cys 1 5 10 15

   Tyr Phe Asn Lys Val Cys Glu Lys Thr Asn He Glu Asp Gly Val Phe 20 25 30

   Glu Thr Leu Thr Asn Leu Glu Leu Leu Ser Leu Ser Phe Asn Ser Leu 35 40 45

   Ser His Val Pro Pro Lys Leu Pro Ser Ser Leu Arg Lys Leu Phe Leu 50 55 60

   Ser Asn Thr Gin He Lys Tyr He Ser Glu Glu Asp Phe Lys Gly Leu

   65 70 75 80 He Asn Leu Thr Leu Leu Asp Leu Ser Gly Asn Cys Pro Arg Cys Phe

   85 90 95

   Asn Ala Pro Phe Pro Cys Val Pro Cys Asp Gly Gly Ala Ser He Asn 100 105 110

   He Asp Arg Phe Ala Phe Gin Asn Leu Thr Gin Leu Arg Tyr Leu Asn 115 120 125

   Leu Ser Ser Thr Ser Leu Arg Lys He Asn Ala Ala Trp Phe Lys Asn 130 135 140

   Met Pro His Leu Lys Val Leu Asp Leu Glu Phe Asn Tyr Leu Val Gly

   145 150 155 160 Glu He Ala Ser Gly Ala Phe Leu Thr Met Leu Pro Arg Leu Glu He

   165 170 175

   Leu Asp Leu Ser Phe Asn Tyr He Lys Gly Ser Tyr Pro Gin His He 180 185 190

   Asn He Ser Arg Asn Phe Ser Lys Leu Leu Ser Leu Arg Ala Leu His 195 200 205

   Leu Arg Gly Tyr Val Phe Gin Glu Leu Arg Glu Asp Asp Phe Gin Pro 210 215 220

   Leu Met Gin Leu Pro Asn Leu Ser Thr He Asn Leu Gly He Asn Phe

   225 230 235 240 He Lys Gin He Asp Phe Lys Leu Phe Gin Asn Phe Ser Asn Leu Glu

   245 250 255

   He He Tyr Leu Ser Glu Asn Arg He Ser Pro Leu Val Lys Asp Thr

   43 260 265 270

   Arg Gin Ser Tyr Ala Asn Ser Ser Ser Phe Gin Arg His He Arg Lys 275 280 285

   Arg Arg Ser Thr Asp Phe Glu Phe Asp Pro His. 'Ser Asn Phe Tyr Hfs 290 295 ^{' '} 300

   Phe Thr Arg Pro Leu He Lys Pro Gin Cys Ala Ala Tyr Gly Lys Ala 305 ' 310 315 320

   Leu Asp Leu Ser Leu Asn Ser He Phe 325

   <210> 17

   <211> 1557

   <212> DNA

   <213> Unknown

   <220>

   <223> Description of Unknown Organisπuprimate; surmised Homo sapiens <220>

   <221> CDS

   <222> (1)..(513)

   <220> <221> misc_feature <222> (93) .. (149) <223> Xaa translation depends on genetic code

   <400> 17 cag tct ctt tec aca tec caa act ttc tat gat get tac att tct tat 48

   Gin Ser Leu Ser Thr Ser Gin Thr Phe Tyr Asp Ala Tyr He Ser Tyr

   1 5 10 15 gac ace aaa gat gcc tct gtt act gac tgg gtg ata aat gag ctg cgc 96 Asp Thr Lys Asp Ala Ser Val Thr Asp Trp Val He Asn Glu Leu Arg

   20 25 30 tac cac ctt gaa gag age cga gac aaa aac gtt etc ctt tgt eta gag 144 Tyr His Leu Glu Glu Ser Arg Asp Lys Asn Val Leu Leu Cys Leu Glu 35 40 45 gag agg gat tgg gac ccg gga ttg gcc ate ate gac aac etc atg cag 192

   Glu Arg Asp Trp Asp Pro Gly Leu Ala He He Asp Asn Leu Met Gin

   50 55 60 age ate aac caa age aag aaa aca gta ttt gtt tta ace aaa aaa tat 240

   Ser He Asn Gin Ser Lys Lys Thr Val Phe Val Leu Thr Lys Lys Tyr

   65 70 75 80 gca aaa age tgg aac ttt aaa aca get ttt tac ttg gsc ttg cag agg 288 Ala Lys Ser Trp Asn Phe Lys Thr Ala Phe Tyr Leu Xaa Leu Gin Arg 85 90 95

   44 eta atg ggt gag aac atg gat gtg att ata ttt ate ctg ctg gag cca 336 Leu Met Gly Glu Asn Met Asp Val He He Phe He Leu Leu Glu Pro 100 105 110 gtg tta cag cat tct ccg tat ttg agg eta egg cag egg ate tgt aag 384 Val Leu Gin His Ser Pro Tyr Leu Arg Leu Arg. 'Gin Arg He Cys Lys 115 120 ^'' 125 age tec ate etc cag tgg cct gac aac ccg aag gca gaa agg ttg ttt 432 Ser Ser He Leu Gin^' Trp Pro Asp Asn Pro Lys Ala Glu Arg Leu Phe 130 135 140 tgg caa act ctg wga aat gtg gtc ttg act gaa aat gat tea egg tat 480 Trp Gin Thr Leu Xaa Asn Val Val Leu Thr Glu Asn Asp Ser Arg Tyr 145 150 155 160 aac aat atg tat gtc gat tec att aag caa tac taactgacgt taagtcatga 533 Asn Asn Met Tyr Val Asp Ser He Lys Gin Tyr 165 170 tttcgcgcca taataaagat gcaaaggaat gacat'ttcng tattagttat ctattgctan 593 ggtaacnaaa ttantcccaa aaancttang tnggtttnaa aacaacnaca ttntgctggn 653 cccacagttt ttgagggtca ggagtccagg cccagcataa ctgggtcttc tgcttcaggg 713 tgtctncaga ggctgcaatg taggtgttca ccagagacat aggcatcact ggggtcacac 773 tncatgtggt tgttttctgg attcaattcc tcctgggcta ttggccaaag gctatactca 833 tgtaagccat gcgagcctat cccacaangg cagcttgctt catcagagct agcaaaaaag 893 agaggttgct agcaagatga agtcacaatc ttttgtaatc gaatcaaaaa agtgatatct 953 catcactttg gccatattct atttgttaga agtaaaccac aggtcccacc agctccatgg 1013 gagtgaccac ctcagtccag ggaaaacagc tgaagaccaa gatggtgagc tctgattgct 1073 tcagttggtc atcaactatt ttcccttgac tgctgtcctg ggatggccgg ctatcttgat 1133 ggatagattg tgaatatcag gaggccaggg atcactgtgg accatcttag cagttgacct 1193 aacacatctt cttttcaata tctaagaact tttgccactg tgactaatgg tcctaatatt 1253 aagctgttgt ttatatttat catatatcta tggctacatg gttatattat gctgtggttg 1313 cgttcggttt tatttacagt tgettttaea aatatttgct gtaacatttg acttctaagg 1373 tttagatgcc atttaagaac tgagatggat agcttttaaa gcatctttta cttcttacca 1433 ttttttaaaa gtatgcaget aaattcgaag ettttggtct atattgttaa ttgccattge 1493 tgtaaatett aaaatgaatg aataaaaatg ttteatttta aaaaaaaaaa aaaaaaaaaa 1553 aaaa 1557

   <210> 18

   45 <211> 171 <212> PRT <213> Unknown < 400> 18

   Gin Ser Leu Ser Thr Ser Gin Thr Phe Tyr Asp Ala Tyr He Ser Tyr 1 5 10 15

   Asp Thr Lys Asp Ala Ser Val Thr Asp Trp Val He Asn Glu Leu Arg 20 ' 25 30

   Tyr His Leu Glu Glu Ser Arg Asp Lys Asn Val Leu Leu Cys Leu Glu 35 40 45 Glu Arg Asp Trp Asp Pro Gly Leu Ala He He Asp Asn Leu Met Gin 50 55 60

   Ser He Asn Gin Ser Lys Lys Thr Val Phe Val Leu Thr Lys Lys Tyr 65 70 75 80

   Ala Lys Ser Trp Asn Phe Lys Thr Ala Phe Tyr Leu Xaa Leu Gin Arg 85 90 95

   Leu Met Gly Glu Asn Met Asp Val He He Phe He Leu Leu Glu Pro 100 105 110

   Val Leu Gin His Ser Pro Tyr Leu Arg Leu Arg Gin Arg He Cys Lys 115 120 125 Ser Ser He Leu Gin Trp Pro Asp Asn Pro Lys Ala Glu Arg Leu Phe 130 135 140

   Trp Gin Thr Leu Xaa Asn Val Val Leu Thr Glu Asn Asp Ser Arg Tyr 145 150 155 ^' 160

   Asn Asn Met Tyr Val Asp Ser He Lys Gin Tyr 165 170

   <210> 19

   <211> 629

   <212> DNA

   <213> Unknown <220>

   <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220> <221> CDS

   <222> (1)..(486)

   <220>

   <221> misc_feature <222> (48).. (75)

   <223> Xaa translation depends on genetic code

   <400> 19

   46 aat gaa ttg ate ccc aat eta gag aag gaa gat ggt tct ate ttg att 48

   Asn Glu Leu He Pro Asn Leu Glu Lys Glu Asp Gly Ser He Leu He

   1 5 10 15 tgc ctt tat gaa age tac ttt gac cct ggc aaa age att agt gaa aat 96

   Cys Leu Tyr Glu Ser Tyr Phe Asp Pro Gly Lys. 'Ser He Ser Glu Asn

   20 25 ^'" 30 att gta age ttc att gag aaa age tat aag tec ate ttt gtt ttg tcy 144 He Val Ser Phe He' Glu Lys Ser Tyr Lys Ser He Phe Val Leu Xaa

   35 40 45 ccc aac ttt gtc cag aat gag tgg tgc cat tat gaa ttc tac ttt gcc 192

   Pro Asn Phe Val Gin Asn Glu Trp Cys His Tyr Glu Phe Tyr Phe Ala 50 55 60 cac cac aat etc ttc cat gaa aat tct gat cay ata att ctt ate tta 240

   His His Asn Leu Phe His Glu Asn Ser Asp Xaa He He Leu He Leu

   65 70 75 80 ctg gaa ccc att cca ttc tat tgc att ccc ace agg tat cat aaa ctg 288

   Leu Glu Pro He Pro Phe Tyr Cys He Pro Thr Arg Tyr His Lys Leu

   85 90 95 gaa get etc ctg gaa aaa aaa gca tac ttg gaa tgg ccc aag gat agg 336

   Glu Ala Leu Leu Glu Lys Lys Ala Tyr Leu Glu Trp Pro Lys Asp Arg

   100 105 110 cgt aaa tgt ggg ctt ttc tgg gca aac ctt cga get get gtt aat gtt 384 Arg Lys Cys Gly Leu Phe Trp Ala Asn Leu Arg Ala Ala Val Asn Val

   115 120 125 aat gta tta gcc ace aga gaa atg tat gaa ctg cag aca ttc aca gag 432

   Asn Val Leu Ala Thr Arg Glu Met Tyr Glu Leu Gin Thr Phe Thr Glu 130 135 140 tta aat gaa gag tct cga ggt tct aca ate tct ctg atg aga aca gac 480

   Leu Asn Glu Glu Ser Arg Gly Ser Thr He Ser Leu Met Arg Thr Asp

   145 150 155 160 tgt eta taaaatccca cagtccttgg gaagttgggg accaeataca ctgttgggat 536 Cys Leu gtacattgat aeaaccttta tgatggeaat ttgaeaatat ttattaaaat aaaaaatggt 596 tattccettc aaaaaaaaaa aaaaaaaaaa aaa 629

   <210> 20 <211> 162

   <212> PRT

   <213> Unknown

   <400> 20 Asn Glu Leu He Pro Asn Leu Glu Lys Glu Asp Gly Ser He Leu He 1 5 10 15

   Cys Leu Tyr Glu Ser Tyr Phe Asp Pro Gly Lys Ser He Ser Glu Asn

   47 20 25 30

   He Val Ser Phe He Glu Lys Ser Tyr Lys Ser He Phe Val Leu Xaa 35 40 45

   Pro Asn Phe Val Gin Asn Glu Trp Cys His Tyr -Glu Phe Tyr Phe Ala 50 55 ^'" 60

   His His Asn Leu Phe His Glu Asn Ser Asp Xaa He He Leu He Leu 65 ' 70 75 80

   Leu Glu Pro He Pro Phe Tyr Cys He Pro Thr Arg Tyr His Lys Leu 85 90 95 Glu Ala Leu Leu Glu Lys Lys Ala Tyr Leu Glu Trp Pro Lys Asp Arg 100 105 110

   Arg Lys Cys Gly Leu Phe Trp Ala Asn Leu Arg Ala Ala Val Asn Val 115 120 125

   Asn Val Leu Ala Thr Arg Glu Met Tyr Glu Leu Gin Thr Phe Thr Glu 130 135 140

   Leu Asn Glu Glu Ser Arg Gly Ser Thr He Ser Leu Met Arg Thr Asp 145 150 155 160

   Cys Leu

   <210> 21 <211> 427 <212> DNA <213> Unknown

   <220>

   <223> Description of Unknown Organism-.primate; surmised Homo sapiens <220>

   <221> CDS

   <222> (1) .. (426)

   <400> 21 aag aac tec aaa gaa aac etc cag ttt cat get ttt att tea tat agt 48

   Lys Asn Ser Lys Glu Asn Leu Gin Phe His Ala Phe He Ser Tyr Ser 1 5 10 15 gaa cat gat tct gcc tgg gtg aaa agt gaa ttg gta cct tac eta gaa 96 Glu His Asp Ser Ala Trp Val Lys Ser Glu Leu Val Pro Tyr Leu Glu

   20 25 30 aaa gaa gat ata cag att tgt ctt cat gag aga aac ttt gtc cct ggc 144 Lys Glu Asp He Gin He Cys Leu His Glu Arg Asn Phe Val Pro Gly 35 40 45 aag age att gtg gaa aat ate ate aac tgc att gag aag agt tac aag 192 Lys Ser He Val Glu Asn He He Asn Cys He Glu Lys Ser Tyr Lys

   48 50 55 60 tec ate ttt gtt ttg tct ccc aac ttt gtc cag agt gag tgg tgc cat 240

   Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Ser Glu Trp Cys His 65 70 75 80 tac gaa etc tat ttt gcc cat cac ^'aat etc ttt^' cat gaa gga tct aat 288

   Tyr Glu Leu Tyr Phe Ala His His Asn Leu Phe His Glu Gly Ser Asn

   85 90 95 aac tta ate etc ate tta ctg gaa ccc att cca cag aac age att ccc 336

   Asn Leu He Leu He Leu Leu Glu Pro He Pro Gin Asn Ser He Pro

   100 105 110 aac aag tac cac aag ctg aag get etc atg acg cag egg act tat ttg 384

   Asn Lys Tyr His Lys Leu Lys Ala Leu Met Thr Gin Arg Thr Tyr Leu

   115 120 125 cag tgg ccc aag gag aaa age aaa cgt ggg etc ttt tgg get a 427 Gin Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe Trp Ala

   130 135 140

   <210> 22 <211> 142

   <212> PRT

   <213> Unknown

   <400> 22 Lys Asn Ser Lys Glu Asn Leu Gin Phe His Ala Phe He Ser Tyr Ser 1 5 10 15

   Glu His Asp Ser Ala Trp Val Lys Ser Glu Leu Val Pro Tyr Leu Glu 20 25 30

   Lys Glu Asp He Gin He Cys Leu His Glu Arg Asn Phe Val Pro Gly 35 40 45

   Lys Ser He Val Glu Asn He He Asn Cys He Glu Lys Ser Tyr Lys 50 55 60

   Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Ser Glu Trp Cys His

   65 70 75 80 Tyr Glu Leu Tyr Phe Ala His His Asn Leu Phe His Glu Gly Ser Asn

   85 90 95

   Asn Leu He Leu He Leu Leu Glu Pro He Pro Gin Asn Ser He Pro 100 105 110

   Asn Lys Tyr His Lys Leu Lys Ala Leu Met Thr Gin Arg Thr Tyr Leu 115 120 125

   Gin Trp Pro Lys Glu Lys Ser Lys Arg Gly Leu Phe Trp Ala 130 135 140

   <210> 23

   49 <211> 662 <212> DNA <213> Unknown <220>

   <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220> <221> CDS

   <222> (1)..(627)

   <220>

   <221> misc_feature <222> (18).. (136)

   <223> Xaa translation depends on genetic code

   <400> 23 get tec ace tgt gcc tgg cct ggc ttc cct ggc ggg ggc ggc aaa gtg 48 Ala Ser Thr Cys Ala Trp Pro Gly Phe Pro Gly Gly Gly Gly Lys Val 1 5 10 15 ggc gar atg agg atg ccc tgc cct acg atg cct teg tgg tct teg aca 96 Gly Xaa Met Arg Met Pro Cys Pro Thr Met Pro Ser Trp Ser Ser Thr 20 25 30 aaa cgc rga gcg cag tgg cag act ggg tgt aca acg age ttc ggg ggc 144

   Lys Arg Xaa Ala Gin Trp Gin Thr Gly Cys Thr Thr Ser Phe Gly Gly

   35 40 45 age tgg agg agt gcc gtg ggc get ggg cac tec gcc tgt gcc tgg agg 192

   Ser Trp Arg Ser Ala Val Gly Ala Gly His Ser Ala Cys Ala Trp Arg 50 55 60 aac gcg act ggc tgc ctg gca aaa ccc tct ttg aga ace tgt ggg cct 240 Asn Ala Thr Gly Cys Leu Ala Lys Pro Ser Leu Arg Thr Cys Gly Pro •—^• 65 70 75 80 egg tct atg gca gcc gca aga cgc tgt ttg tgc tgg ccc aca egg ace 288 Arg Ser Met Ala Ala Ala Arg Arg Cys Leu Cys Trp Pro Thr Arg Thr

   85 90 95 ggg tea gtg gtc tct tgc gcg cca ktt ntc ctg ctg gcc cag cag cgc 336 Gly Ser Val Val Ser Cys Ala Pro Xaa Xaa Leu Leu Ala Gin Gin Arg 100 105 110 ctg ctg gar gac cgc aag gac gtc gtg gtg ctg gtg ate eta ang cct 384

   Leu Leu Xaa Asp Arg Lys Asp Val Val Val Leu Val He Leu Xaa Pro

   115 120 125 gac ggc caa gcc tec cga eta cnn gat gcg ctg ace age gcc tct gcc 432

   Asp Gly Gin Ala Ser Arg Leu Xaa Asp Ala Leu Thr Ser Ala Ser Ala

   130 135 140 gcc aga gtg tec tec tct ggc ccc ace age cca gtg gtc gcg cag ctt 480 Ala Arg Val Ser Ser Ser Gly Pro Thr Ser Pro Val Val Ala Gin Leu 145 150 155 160

   50 ctg agg cca gca tgc atg gcc ctg ac agg gac aac cac cac ttc tat 528

   Leu Arg Pro Ala Cys Met Ala Leu Thr Arg Asp Asn His His Phe Tyr

   165 170 175 aac egg aac ttc tgc cag gga ace cac ggc cga ata gcc gtg age egg 576

   Asn Arg Asn Phe Cys Gin Gly Thr His Gly Arg<-Ile Ala Val Ser Arg

   180 185 ^'' 190 aat cct gca egg tgc cac etc cac aca cac eta aca tat gcc tgc ctg 624 Asn Pro Ala Arg Cys His Leu His Thr His Leu Thr Tyr Ala Cys Leu

   195 200 205 ate tgaccaacac atgctcgcca ccctcaccac acacc 662

   He

   <210> 24

   <211> 209

   <212> PRT <213> Unknown

   <400> 24

   Ala Ser Thr Cys Ala Trp Pro Gly Phe Pro Gly Gly Gly Gly Lys Val 1 5 10 15

   Gly Xaa Met Arg Met Pro Cys Pro Thr Met Pro Ser Trp Ser Ser Thr 20 25 30

   Lys Arg Xaa Ala Gin Trp Gin Thr Gly Cys Thr Thr Ser Phe Gly Gly 35 40 45

   Ser Trp Arg Ser Ala Val Gly Ala Gly His Ser Ala Cys Ala Trp Arg 50 55 60 Asn Ala Thr Gly Cys Leu Ala Lys Pro Ser Leu Arg Thr Cys Gly Pro 65 70 75 80

   Arg Ser Met Ala Ala Ala Arg Arg Cys Leu Cys Trp Pro Thr Arg Thr 85 90 95

   Gly Ser Val Val Ser Cys Ala Pro Xaa Xaa Leu Leu Ala Gin Gin Arg 100 105 110

   Leu Leu Xaa Asp Arg Lys Asp Val Val Val Leu Val He Leu Xaa Pro 115 120 125

   Asp Gly Gin Ala Ser Arg Leu Xaa Asp Ala Leu Thr Ser Ala Ser Ala 130 135 140 Ala Arg Val Ser Ser Ser Gly Pro Thr Ser Pro Val Val Ala Gin Leu 145 150 155 160

   Leu Arg Pro Ala Cys Met Ala Leu Thr Arg Asp Asn His His Phe Tyr

   165 170 175

   Asn Arg Asn Phe Cys Gin Gly Thr His Gly Arg He Ala Val Ser Arg

   180 185 190

   51 Asn Pro Ala Arg Cys His Leu His Thr His Leu Thr Tyr Ala Cys Leu 195 200 205

   He

   <210> 25

   < 211> 4865

   < 212> DNA

   <213> Unknown

   <220>

   <223> Description of Unknown Organisrr primate; surmised Homo sapiens

   <220> <221> CDS

   <222> ( 107 ) . . ( 2617 )

   <220>

   <221> mat_peptide

   <222> ( 173 ) . . ( 2617 ) <220>

   <221> misc_feature

   <222> ( 189)

   <223> Xaa translation depends on genetic code <400> 25 aaaataetce ettgccteaa aaaetgctcg gtcaaaeggt gatagcaaae cacgcattca 60 cagggccact gctgctcaca naascagtga ggatgatgcc aggatg atg tct gcc 115

   Met Ser Ala -20 teg cgc ctg get ggg act ctg ate cca gcc atg gcc ttc etc tec tgc 163

   Ser Arg Leu Ala Gly Thr Leu He Pro Ala Met Ala Phe Leu Ser Cys -15 -10 -5 gtg aga cca gaa age tgg gag ccc tgc gtg gag gtt cct aat att act 211

   Val Arg Pro Glu Ser Trp Glu Pro Cys Val Glu Val Pro Asn He Thr

   -1 1 . 5 10 tat caa tgc atg gag ctg aat ttc tac aaa ate ccc gac aac etc ccc 259 Tyr Gin Cys Met Glu Leu Asn Phe Tyr Lys He Pro Asp Asn Leu Pro 15 20 25 ttc tea ace aag aac ctg gac ctg age ttt aat ccc ctg agg cat tta 307 Phe Ser Thr Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu Arg His Leu 30 35 40 45 ggc age tat age ttc ttc agt ttc cca gaa ctg cag gtg ctg gat tta 355 Gly Ser Tyr Ser Phe Phe Ser Phe Pro Glu Leu Gin Val Leu Asp Leu 50 55 60 tec agg tgt gaa ate cag aca att gaa gat ggg gca tat cag age eta 403 Ser Arg Cys Glu He Gin Thr He Glu Asp Gly Ala Tyr Gin Ser Leu

   52 65 70 75 age cac etc tct ace tta ata ttg aca gga aac ccc ate cag agt tta 451

   Ser His Leu Ser Thr Leu He Leu Thr Gly Asn Pro He Gin Ser Leu 80 85 90 gcc ctg gga gcc ttt tct gga eta tea agt tta cag aag ctg gtg get 499

   Ala Leu Gly Ala Phe Ser Gly Leu Ser Ser Leu Gin Lys Leu Val Ala 95 100 105 gtg gag aca aat eta gca tct eta gag aac ttc ccc att gga cat etc 547

   Val Glu Thr Asn Leu Ala Ser Leu Glu Asn Phe Pro He Gly His Leu 110 115 120 125 aaa act ttg aaa gaa ctt aat gtg get cac aat ctt ate caa tct ttc 595

   Lys Thr Leu Lys Glu Leu Asn Val Ala His Asn Leu He Gin Ser Phe

   130 135 140 aaa tta cct gag tat ttt tct aat ctg ace aat eta gag cac ttg gac 643 Lys Leu Pro Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu His Leu Asp 145 150 155 ctt tec age aac aag att caa agt att tat tgc aca gac ttg egg gtt 691

   Leu Ser Ser Asn Lys He Gin Ser He Tyr Cys Thr Asp Leu Arg Val 160 165 170 eta cat caa atg ccc eta etc aat etc tct tta gac ctg tec ctg aay 739

   Leu His Gin Met Pro Leu Leu Asn Leu Ser Leu Asp Leu Ser Leu Xaa 175 180 185 cct atg aac ttt ate caa cca ggt gca ttt aaa gaa att agg ctt cat 787

   Pro Met Asn Phe He Gin Pro Gly Ala Phe Lys Glu He Arg Leu His 190 195 200 205 aag ctg act tta aga aat aat ttt gat agt tta aat gta atg aaa act 835

   Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu Asn Val Met Lys Thr

   210 215 220 tgt att caa ggt ctg get ggt tta gaa gtc cat cgt ttg gtt ctg gga 883 Cys He Gin Gly Leu Ala Gly Leu Glu Val His Arg Leu Val Leu Gly 225 230 235 gaa ttt aga aat gaa gga aac ttg gaa aag ttt gac aaa tct get eta 931

   Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys Ser Ala Leu 240 245 250 gag ggc ctg tgc aat ttg ace att gaa gaa ttc cga tta gca tac tta 979

   Glu Gly Leu Cys Asn Leu Thr He Glu Glu Phe Arg Leu Ala Tyr Leu 255 260 265 gac tac tac etc gat gat att att gac tta ttt aat tgt ttg aca aat 1027

   Asp Tyr Tyr Leu Asp Asp He He Asp Leu Phe Asn Cys Leu Thr Asn 270 275 280 285 gtt tct tea ttt tec ctg gtg agt gtg act att gaa agg gta aaa gac 1075

   Val Ser Ser Phe Ser Leu Val Ser Val Thr He Glu Arg Val Lys Asp

   290 295 300

   53 ttt tct tat aat ttc gga tgg caa cat tta gaa tta gtt aac tgt aaa 1123 Phe Ser Tyr Asn Phe Gly Trp Gin His Leu Glu Leu Val Asn Cys Lys 305 310 315 ttt gga cag ttt ccc aca ttg aaa etc aaa tct etc aaa agg ctt act 1171 Phe Gly Gin Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys Arg Leu Thr 320 325' ^'' 330 ttc act tec aac aaa ggt ggg aat get ttt tea gaa gtt gat eta cca 1219 Phe Thr Ser Asn Lys' Gly Gly Asn Ala Phe Ser Glu Val Asp Leu Pro 335 340 345 age ctt gag ttt eta gat etc agt aga aat ggc ttg agt ttc aaa ggt 1267 Ser Leu Glu Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser Phe Lys Gly 350 355 360 365 tgc tgt tct caa agt gat ttt ggg aca ace age eta aag tat tta gat 1315

   Cys Cys Ser Gin Ser Asp Phe Gly Thr Thr Ser Leu Lys Tyr Leu Asp

   370 375 380 ctg age ttc aat ggt gtt att ace atg agt tea aac ttc ttg ggc tta 1363

   Leu Ser Phe Asn Gly Val He Thr Met Ser Ser Asn Phe Leu Gly Leu

   385^' 390 395 gaa caa eta gaa cat ctg gat ttc cag cat tec aat ttg aaa caa atg 1411

   Glu Gin Leu Glu His Leu Asp Phe Gin His Ser Asn Leu Lys Gin Met 400 405 410 agt gag ttt tea gta ttc eta tea etc aga aac etc att tac ctt gac 1459 Ser Glu Phe Ser Val Phe Leu Ser Leu Arg Asn Leu He Tyr Leu Asp

   415 420 425 att tct cat act cac ace aga gtt get ttc aat ggc ate ttc aat ggc 1507 He Ser His Thr His Thr Arg Val Ala Phe Asn Gly He Phe Asn Gly 430 435 440 445 ttg tec agt etc gaa gtc ttg aaa atg get ggc aat tct ttc cag gaa 1555

   Leu Ser Ser Leu Glu Val Leu Lys Met Ala Gly Asn Ser Phe Gin Glu

   450 455 460 aac ttc ctt cca gat ate ttc aca gag ctg aga aac ttg ace ttc ctg 1603

   Asn Phe Leu Pro Asp He Phe Thr Glu Leu Arg Asn Leu Thr Phe Leu

   465 470 475 gac etc tct cag tgt caa ctg gag cag ttg tct cca aca gca ttt aac 1651 Asp Leu Ser Gin Cys Gin Leu Glu Gin Leu Ser Pro Thr Ala Phe Asn 480 485 490 tea etc tec agt ctt cag gta eta aat atg age cac aac aac ttc ttt 1699 Ser Leu Ser Ser Leu Gin Val Leu Asn Met Ser His Asn Asn Phe Phe 495 500 505 tea ttg gat acg ttt cct tat aag tgt ctg aac tec etc cag gtt ctt 1747 Ser Leu Asp Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu Gin Val Leu 510 515 520 525 gat tac agt etc aat cac ata atg act tec aaa aaa cag gaa eta cag 1795 Asp Tyr Ser Leu Asn His He Met Thr Ser Lys Lys Gin Glu Leu Gin

   54 530 535 540 cat ttt cca agt agt eta get ttc tta aat ctt act cag aat gac ttt 1843

   His Phe Pro Ser Ser Leu Ala Phe Leu Asn Leu Thr Gin Asn Asp Phe 545 550 555 get tgt act tgt gaa cac cag agt ttc ctg caa tgg ate aag gac cag 1891

   Ala Cys Thr Cys Glu His Gin Ser Phe Leu Gin Trp He Lys Asp Gin

   560 565 570 agg cag etc ttg gtg gaa gtt gaa cga atg gaa tgt gca aca cct tea 1939

   Arg Gin Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala Thr Pro Ser 575 580 585 gat aag cag ggc atg cct gtg ctg agt ttg aat ate ace tgt cag atg 1987

   Asp Lys Gin Gly Met Pro Val Leu Ser Leu Asn He Thr Cys Gin Met 590 595 600 605 aat aag ace ate att ggt gtg teg gtc etc agt gtg ctt gta gta tct 2035 Asn Lys Thr He He Gly Val Ser Val Leu Ser Val Leu Val Val Ser

   610 615 620 gtt gta gca gtt ctg gtc tat aag ttc tat ttt cac ctg atg ctt ctt 2083

   Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu Met Leu Leu 625 630 635 get ggc tgc ata aag tat ggt aga ggt gaa aac ate tat gat gcc ttt 2131

   Ala Gly Cys He Lys Tyr Gly Arg Gly Glu Asn He Tyr Asp Ala Phe

   640 645 650 gtt ate tac tea age cag gat gag gac tgg gta agg aat gag eta gta 2179

   Val He Tyr Ser Ser Gin Asp Glu Asp Trp Val Arg Asn Glu Leu Val 655 660 665 aag aat tta gaa gaa ggg gtg cct cca ttt cag etc tgc ctt cac tac 2227

   Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gin Leu Cys Leu His Tyr -«. 670 675 680 685 aga gac ttt att ccc ggt gtg gcc att get gcc aac ate ate cat gaa 2275 Arg Asp Phe He Pro Gly Val Ala He Ala Ala Asn He He His Glu

   690 695 700 ggt ttc cat aaa age cga aag gtg att gtt gtg gtg tec cag cac ttc 2323

   Gly Phe His Lys Ser Arg Lys Val He Val Val Val Ser Gin His Phe 705 710 715 ate cag age cgc tgg tgt ate ttt gaa tat gag att get cag ace tgg 2371

   He Gin Ser Arg Trp Cys He Phe Glu Tyr Glu He Ala Gin Thr Trp

   720 725 730 cag ttt ctg age agt cgt get ggt ate ate ttc att gtc ctg cag aag 2419

   Gin Phe Leu Ser Ser Arg Ala Gly He He Phe He Val Leu Gin Lys 735 740 745 gtg gag aag ace ctg etc agg cag cag gtg gag ctg tac cgc ctt etc 2467

   Val Glu Lys Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr Arg Leu Leu 750 755 760 765

   55 age agg aac act tac ctg gag tgg gag gac agt gtc ctg ggg egg cac 2515

   Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu Gly Arg His

   770 775 780 ate ttc tgg aga cga etc aga aaa gcc ctg ctg gat ggt aaa tea tgg 2563

   He Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly Lys Ser Trp

   785 790 ^' 795 aat cca gaa gga aca gtg ggt aca gga tgc aat tgg cag gaa gca aca 2611 Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gin Glu Ala Thr

   800 805 810 tct ate tgaagaggaa aaataaaaac ctcctgaggc atttcttgcc cagctgggtc 2667

   Ser He 815 caacacttgt tcagttaata agtattaaat gctgccacat gtcaggcctt atgctaaggg 2727 tgagtaattc eatggtgcac tagatatgca gggctgctaa teteaaggag cttccagtgc 2787 agagggaata aatgctagac taaaatacag agtcttccag gtgggcattt caaccaactc 2847 agtcaaggaa cccatgacaa agaaagtcat ttcaactctt acctcatcaa gttgaataaa 2907 gacagagaaa acagaaagag acattgttct tttcctgagt cttttgaatg gaaattgtat 2967 tatgttatag ccatcataaa accattttgg tagttttgac tgaactgggt gttcactttt 3027 tcctttttga ttgaatacaa tttaaattct acttgatgac tgcagtcgtc aaggggctcc 3087 tgatgcaaga tgccccttcc attttaagtc tgtctcctta cagakgttaa agtctantgg 3147 ctaattccta aggaaacctg attaacacat gctcacaacc atcctggtca ttctcganca 3207 tgttctattt tttaactaat cacccctgat atatttttat ttttatatat ccagttttca 3267 tttttttacg tcttgcctat aagctaatat cataaataag gttgtttaag acgtgcttca 3327 aatatccata ttaaccacta tttttcaagg aagtatggaa aagtacactc tgtcactttg 3387 tcactcgatg tcattccaaa gttattgcct actaagtaat gactgtcatg aaagcagcat 3447 tgaaataatt tgtttaaagg gggcactctt ttaaacggga agaaaatttc cgcttcctgg 3507 tcttatcatg gacaatttgg gctakaggca kgaaggaagt gggatkacct caggangtca 3567 ccttttcttg attccagaaa catatgggct gataaacccg gggtgacctc atgaaatgag 3627 ttgcagcaga wgtttatttt tttcagaaca agtgatgttt gatggacctm tgaatctmtt 3687 tagggagaca cagatggctg ggatccctcc cctgtaccct tctcactgmc aggagaacta 3747 cgtgtgaagg tattcaaggc agggagtata cattgctgtt tcctgttggg caatgctcct 3807 tgaccaeatt ttgggaagag tggatgttat cattgagaaa acaatgtgtc tggaattaat 3867 ggggttetta taaagaaggt teccagaaaa gaatgttcat tecagettct tcaggaaaca 3927

   56 ggaacattca aggaaaagga caatcaggat gtcatcaggg aaatgaaaat aaaaaccaca 3987 atgagatate acettatace aggtagatgg ctactataaa aaaatgaagt gtcatcaagg 4047 atatagagaa attggaaece ttettcactg etggagggaa tggaaaatgg tgtagecgtt 4107 atgaaaaaca gtacggaggt ttctcaaaaa ttaaaaatag ^' aactgctata tgatceagca 4167 atctcacttc tgtatatata cccaaaataa ttgaaatcag aatttcaaga aaatatttac 4227 actcccatgt tcattgtggc actcttcaca atcactgttt ccaaagttat ggaaacaacc 4287 caaatttcca ttggaaaata aatggacaaa ggaaatgtgc atataacgta caatggggat 4347 attattcagc ctaaaaaaag gggggatcct gttatttatg acaacatgaa taaacccgga 4407 ggccattatg ctatgtaaaa tgagcaagta acagaaagac aaatactgcc tgatttcatt 4467 tatatgaggt tctaaaatag tcaaactcat agaagcagag aatagaacag tggttcctag 4527 ggaaaaggag gaagggagaa atgaggaaat agggagttgt ctaattggta taaaattata 4587 gtatgcaaga tgaattagct ctaaagatca gctgtatagc agagttcgta taatgaacaa 4647 tactgtatta tgcacttaac attttgttaa gagggtacct ctcatgttaa gtgttcttac 4707 catatacata tacacaagga agcttttgga ggtgatggat atatttatta ccttgattgt 4767 ggtgatggtt tgacaggtat gtgactatgt ctaaactcat caaattgtat acattaaata 4827 tatgcagttt tataatatca aaaaaaaaaa aaaaaaaa 4865

   <210> 26 <211> 837

   <212> PRT

   <213> Unknown

   <400> 26 Met Ser Ala Ser Arg Leu Ala Gly Thr Leu He Pro Ala Met Ala Phe -20 -15 -10

   Leu Ser Cys Val Arg Pro Glu Ser Trp Glu Pro Cys Val Glu Val Pro -5 -1 1 5 10

   Asn He Thr Tyr Gin Cys Met Glu Leu Asn Phe Tyr Lys He Pro Asp 15 20 25

   Asn Leu Pro Phe Ser Thr Lys Asn Leu Asp Leu Ser Phe Asn Pro Leu 30 35 40

   Arg His Leu Gly Ser Tyr Ser Phe Phe Ser Phe Pro Glu Leu Gin Val

   45 50 55 Leu Asp Leu Ser Arg Cys Glu He Gin Thr He Glu Asp Gly Ala Tyr

   60 65 70

   Gin Ser Leu Ser His Leu Ser Thr Leu He Leu Thr Gly Asn Pro He

   57 75 80 85 90

   Gin Ser Leu Ala Leu Gly Ala Phe Ser Gly Leu Ser Ser Leu Gin Lys 95 100 105

   Leu Val Ala Val Glu Thr Asn Leu Ala Ser Leu_/'Glu Asn Phe Pro He 110 115 ^'' 120

   Gly His Leu Lys Thr Leu Lys Glu Leu Asn Val Ala His Asn Leu He 125 ' 130 135

   Gin Ser Phe Lys Leu Pro Glu Tyr Phe Ser Asn Leu Thr Asn Leu Glu 140 145 150 His Leu Asp Leu Ser Ser Asn Lys He Gin Ser He Tyr Cys Thr Asp 155 160 165 170

   Leu Arg Val Leu His Gin Met Pro Leu Leu Asn Leu Ser Leu Asp Leu 175 180 185

   Ser Leu Xaa Pro Met Asn Phe He Gin Pro Gly Ala Phe Lys Glu He 190 195 200

   Arg Leu His Lys Leu Thr Leu Arg Asn Asn Phe Asp Ser Leu Asn Val 205 210 215

   Met Lys Thr Cys He Gin Gly Leu Ala Gly Leu Glu Val His Arg Leu 220 225 230 Val Leu Gly Glu Phe Arg Asn Glu Gly Asn Leu Glu Lys Phe Asp Lys 235 240 245 250

   Ser Ala Leu Glu Gly Leu Cys Asn Leu Thr He Glu Glu Phe Arg Leu 255 260 265

   Ala Tyr Leu Asp Tyr Tyr Leu Asp Asp He He Asp Leu Phe Asn Cys 270 275 280

   Leu Thr Asn Val Ser Ser Phe Ser Leu Val Ser Val Thr He Glu Arg 285 290 295

   Val Lys Asp Phe Ser Tyr Asn Phe Gly Trp Gin His Leu Glu Leu Val 300 305 310 Asn Cys Lys Phe Gly Gin Phe Pro Thr Leu Lys Leu Lys Ser Leu Lys 315 320 325 330

   Arg Leu Thr Phe Thr Ser Asn Lys Gly Gly Asn Ala Phe Ser Glu Val 335 340 345

   Asp Leu Pro Ser Leu Glu Phe Leu Asp Leu Ser Arg Asn Gly Leu Ser 350 355 360 ^'

   Phe Lys Gly Cys Cys Ser Gin Ser Asp Phe Gly Thr Thr Ser Leu Lys 365 370 375

   Tyr Leu Asp Leu Ser Phe Asn Gly Val He Thr Met Ser Ser Asn Phe 380 385 390

   58 Leu Gly Leu Glu Gin Leu Glu His Leu Asp Phe Gin His Ser Asn Leu 395 400 405 410

   Lys Gin Met Ser Glu Phe Ser Val Phe Leu Ser Leu Arg Asn Leu He 415 420 - 425

   Tyr Leu Asp He Ser His Thr His Thr Arg Val Ala Phe Asn Gly He 430 435 440

   Phe Asn Gly Leu Ser Ser Leu Glu Val Leu Lys Met Ala Gly Asn Ser 445 450 455

   Phe Gin Glu Asn Phe Leu Pro Asp He Phe Thr Glu Leu Arg Asn Leu 460 465 470

   Thr Phe Leu Asp Leu Ser Gin Cys Gin Leu Glu Gin Leu Ser Pro Thr 475 480 485 490 Ala Phe Asn Ser Leu Ser Ser Leu Gin Val Leu Asn Met Ser His Asn

   495 500 505

   Asn Phe Phe Ser Leu Asp Thr Phe Pro Tyr Lys Cys Leu Asn Ser Leu 510 515 520

   Gin Val Leu Asp Tyr Ser Leu Asn His He Met Thr Ser Lys Lys Gin 525 530 535

   Glu Leu Gin His Phe Pro Ser Ser Leu Ala Phe Leu Asn Leu Thr Gin 540 545 550

   Asn Asp Phe Ala Cys Thr Cys Glu His Gin Ser Phe Leu Gin Trp He 555 560 565 570 Lys Asp Gin Arg Gin Leu Leu Val Glu Val Glu Arg Met Glu Cys Ala

   575 580 585

   Thr Pro Ser Asp Lys Gin Gly Met Pro Val Leu Ser Leu Asn He Thr 590 595 600

   Cys Gin Met Asn Lys Thr He He Gly Val Ser Val Leu Ser Val Leu 605 610 615

   Val Val Ser Val Val Ala Val Leu Val Tyr Lys Phe Tyr Phe His Leu 620 625 630

   Met Leu Leu Ala Gly Cys He Lys Tyr Gly Arg Gly Glu Asn He Tyr 635 640 645 650 Asp Ala Phe Val He Tyr Ser Ser Gin Asp Glu Asp Trp Val Arg Asn

   655 660 665

   Glu Leu Val Lys Asn Leu Glu Glu Gly Val Pro Pro Phe Gin Leu Cys 670 675 680

   Leu His Tyr Arg Asp Phe He Pro Gly Val Ala He Ala Ala Asn He 685 690 695

   59 He His Glu Gly Phe His Lys Ser Arg Lys Val He Val Val Val Ser

   700 705 710

   Gin His Phe He Gin Ser Arg Trp Cys He Phe Glu Tyr Glu He Ala 715 720 725 730

   Gin Thr Trp Gin Phe Leu Ser Ser Arg Ala Gly^' He He Phe He Val

   735 740 ^• 745 Leu Gin Lys Val Glu' Lys Thr Leu Leu Arg Gin Gin Val Glu Leu Tyr 750 755 760

   Arg Leu Leu Ser Arg Asn Thr Tyr Leu Glu Trp Glu Asp Ser Val Leu 765 770 775

   Gly Arg His He Phe Trp Arg Arg Leu Arg Lys Ala Leu Leu Asp Gly 780 785 790

   Lys Ser Trp Asn Pro Glu Gly Thr Val Gly Thr Gly Cys Asn Trp Gin 795 800 805 810

   Glu Ala Thr Ser He 815

   <210> 27

   <211> 300

   <212> DNA

   <213> Unknown

   <220>

   <223> Description of Unknown Organism: rodent; surmised Mus musculus <220>

   <221> CDS —

   <222> (1) .. (300)

   <220> <221> misc_feature

   <222> (62).. (100)

   <223> Xaa translation depends on genetic code

   <400> 27 tec tat tct atg gaa aaa gat get ttc eta ttt atg aga aat ttg aag 48 Ser Tyr Ser Met Glu Lys Asp Ala Phe Leu Phe Met Arg Asn Leu Lys 1 5 10 15 gtt etc tea eta aaa gat aac aat gtc aca get gtc ccc ace act ttg 96 Val Leu Ser Leu Lys Asp Asn Asn Val Thr Ala Val Pro Thr Thr Leu -

   20 25 30 cca cct aat tta eta gag etc tat ctt tat aac aat ate att aag aaa 144 Pro Pro Asn Leu Leu Glu Leu Tyr Leu Tyr Asn Asn He He Lys Lys 35 40 45 ate caa gaa aat gat ttc aat aac etc aat gag ttg caa gtn ctt gac 192 He Gin Glu Asn Asp Phe Asn -Asn Leu Asn Glu Leu Gin Xaa Leu Asp

   60 50 55 60 eta ngt gga aat tgc cct cga tgt nat aat gtc cca tat ccg tgt aca 240

   Leu Xaa Gly Asn Cys Pro Arg Cys Xaa Asn Val Pro Tyr Pro Cys Thr 65 70 75 80 ccg tgt gaa aat aat tec ccc tta cag ate cat gan aat get ttc aat 288

   Pro Cys Glu Asn Asn Ser Pro Leu Gin He His Xaa Asn Ala Phe Asn 85 90 95 tea teg aca gan 300

   Ser Ser Thr Xaa

   100

   <210> 28

   <211> 100

   <212> PRT

   <213> Unknown

   <400> 28

   Ser Tyr Ser Met Glu Lys Asp Ala Phe Leu Phe Met Arg Asn Leu Lys 1 5 10 15 Val Leu Ser Leu Lys Asp Asn Asn Val Thr Ala Val Pro Thr Thr Leu

   20 25 30

   Pro Pro Asn Leu Leu Glu Leu Tyr Leu Tyr Asn Asn He He Lys Lys 35 40 45

   He Gin Glu Asn Asp Phe Asn Asn Leu Asn Glu Leu Gin Xaa Leu Asp 50 55 60

   Leu Xaa Gly Asn Cys Pro Arg Cys Xaa Asn Val Pro Tyr Pro Cys Thr 65 70 75 80

   Pro Cys Glu Asn Asn Ser Pro Leu Gin He His Xaa Asn Ala Phe Asn

   85 90 95 Ser Ser Thr Xaa 100

   <210> 29 <211> 1756

   <212> DNA

   <213> Unknown

   <220> <223> Description of Unknown Organism: rodent; surmised Mus musculus

   <220> <221> CDS <222> (1)..(1182)

   <400> 29 tct cca gaa att ccc tgg aat tec ttg cct cct gag gtt ttt gag ggt 48

   61 Ser Pro Glu He Pro Trp Asn Ser Leu Pro Pro Glu Val Phe Glu Gly 1 5 10 15 atg ccg cca aat eta aag aat etc tec ttg gcc aaa aat ggg etc aaa 96 Met Pro Pro Asn Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys 20 25 30 tct ttc ttt tgg gac aga etc cag tta ctg aag cat ttg gaa att ttg 144 Ser Phe Phe Trp Asp Arg Leu Gin Leu Leu Lys His Leu Glu He Leu 35 ^' 40 45 gac etc age cat aac cag ctg aca aaa gta cct gag aga ttg gcc aac 192

   Asp Leu Ser His Asn Gin Leu Thr Lys Val Pro Glu Arg Leu Ala Asn

   50 55 60 tgt tec aaa agt etc aca aca ctg att ctt aag cat aat caa ate agg 240

   Cys Ser Lys Ser Leu Thr Thr Leu He Leu Lys His Asn Gin He Arg

   65 70 75 80 caa ttg aca aaa tat ttt eta gaa gat get ttg caa ttg cgc tat eta 288 Gin Leu Thr Lys Tyr Phe Leu Glu Asp Ala Leu Gin Leu Arg Tyr Leu 85 90 95 gac ate agt tea aat aaa ate cag gtc att cag aag act age ttc cca 336 Asp He Ser Ser Asn Lys He Gin Val He Gin Lys Thr Ser Phe Pro 100 105 110 gaa aat gtc etc aac aat ctg gag atg ttg gtt tta cat cac aat cgc 384 Glu Asn Val Leu Asn Asn Leu Glu Met Leu Val Leu His His Asn Arg 115 120 125 ttt ctt tgc aac tgt gat get gtg tgg ttt gtc tgg tgg gtt aac cat 432

   Phe Leu Cys Asn Cys Asp Ala Val Trp Phe Val Trp Trp Val Asn His

   130 135 140 aca gat gtt act att cca tac ctg gcc act gat gtg act tgt gta ggt 480

   Thr Asp Val Thr He Pro Tyr Leu Ala Thr Asp Val Thr Cys Val Gly 145 150 155 160 cca gga gca cac aaa ggt caa agt gtc ata tec ctt gat ctg tat acg 528 Pro Gly Ala His Lys Gly Gin Ser Val He Ser Leu Asp Leu Tyr Thr 165 170 175 tgt gag tta gat etc aca aac ctg att ctg ttc tea gtt tec ata tea 576 Cys Glu Leu Asp Leu Thr Asn Leu He Leu Phe Ser Val Ser He Ser 180 185 190 tea gtc etc ttt ctt atg gta gtt atg aca aca agt cac etc ttt ttc 624 Ser Val Leu Phe Leu Met Val Val Met Thr Thr Ser His Leu Phe Phe 195 200 205 tgg gat atg tgg tac att tat tat ttt tgg aaa gca aag ata aag ggg 672 Trp Asp Met Trp Tyr He Tyr Tyr Phe Trp Lys Ala Lys He Lys Gly 210 215 220 tat cca gca tct gca ate cca tgg agt cct tgt tat gat get ttt att 720 Tyr Pro Ala Ser Ala He Pro Trp Ser Pro Cys Tyr Asp Ala Phe He 225 230 235 240

   62 gtg tat gac act aaa aac tea get gtg aca gaa tgg gtt ttg cag gag 768

   Val Tyr Asp Thr Lys Asn Ser Ala Val Thr Glu Trp Val Leu Gin Glu

   245 250 255 ctg gtg gca aaa ttg gaa gat cca aga gaa aaa cac tc aat ttg tgt 816

   Leu Val Ala Lys Leu Glu Asp Pro Arg Glu Lys ^'His Phe Asn Leu Cys

   260 265 ^■ 270 eta gaa gaa aga gac 'tgg eta cca gga cag cca gtt eta gaa aac ctt 864 Leu Glu Glu Arg Asp Trp Leu Pro Gly Gin Pro Val Leu Glu Asn Leu 275 280 285 tec cag age ata cag etc age aaa aag aca gtg ttt gtg atg aca cag 912 Ser Gin Ser He Gin Leu Ser Lys Lys Thr Val Phe Val Met Thr Gin 290 295 300 aaa tat get aag act gag agt ttt aag atg gca ttt tat ttg tct cat 960 Lys Tyr Ala Lys Thr Glu Ser Phe Lys Met Ala Phe Tyr Leu Ser His 305 310 315 320 cag agg etc ctg gat gaa aaa gtg gat gtg att ate ttg ata ttc ttg 1008

   Gin Arg Leu Leu Asp Glu Lys Val Asp Val He He Leu He Phe Leu

   325 330 335 gaa aga cct ctt cag aag tct aag ttt ctt cag etc agg aag aga etc 1056

   Glu Arg Pro Leu Gin Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg Leu

   340 345 350 tgc agg age tct gtc ctt gag tgg cct gca aat cca cag get cac cca 1104 Cys Arg Ser Ser Val Leu Glu Trp Pro Ala Asn Pro Gin Ala His Pro 355 360 365 tac ttc tgg cag tgc ctg aaa aat gcc ctg ace aca gac aat cat gtg 1152 Tyr Phe Trp Gin Cys Leu Lys Asn Ala Leu Thr Thr Asp Asn His Val 370 375 380 get tat agt caa atg ttc aag gaa aca gtc tagctctctg aagaatgtca 1202 Ala Tyr Ser Gin Met Phe Lys Glu Thr Val 385 390 ccacctagga catgccttgg tacctgaagt tttcataaag gtttccataa atgaaggtct 1262 gaatttttcc taacagttgt catggctcag attggtggga aatcatcaat atatggctaa 1322 gaaattaaga aggggagact gatagaagat aatttctttc ttcatgtgcc atgctcagtt 1382 aaatatttcc cctagctcaa atctgaaaaa ctgtgcctag gagacaacac aaggctttga 1442 tttatctgca tacaattgat aagagccaca catctgccct gaagaagtac tagtagtttt 1502 agtagtaggg taaaaattae acaagctttc tctctetetg atactgaaet gtaccagagt 1562 tcaatgaaat aaaagcccag agaacttctc agtaaatggt ttcattatca tgtagtatcc 1622 aceatgcaat atgccacaaa rccgctactg gtacaggaea gntggtagct gcttcaakgc 1682 ctettatcat tttcttgggg cccatggagg ggttctytgg gaaadaggga agkttttttt 1742

   63 tggccatcca tgaa 1756

   <210> 30 <211> 394 <212> PRT <213> Unknown <400> 30

   Ser Pro Glu He Pro Trp Asn Ser Leu Pro Pro Glu Val Phe Glu Gly 1 5 10 15

   Met Pro Pro Asn Leu Lys Asn Leu Ser Leu Ala Lys Asn Gly Leu Lys 20 25 30

   Ser Phe Phe Trp Asp Arg Leu Gin Leu Leu Lys His Leu Glu He Leu 35 40 45 Asp Leu Ser His Asn Gin Leu Thr Lys Val Pro Glu Arg Leu Ala Asn 50 55 60

   Cys Ser Lys Ser Leu Thr Thr Leu He Leu Lys His Asn Gin He Arg 65 70 75 80

   Gin Leu Thr Lys Tyr Phe Leu Glu Asp Ala Leu Gin Leu Arg Tyr Leu 85 90 95

   Asp He Ser Ser Asn Lys He Gin Val He Gin Lys Thr Ser Phe Pro 100 105 110

   Glu Asn Val Leu Asn Asn Leu Glu Met Leu Val Leu His His Asn Arg 115 120 125 Phe Leu Cys Asn Cys Asp Ala Val Trp Phe Val Trp Trp Val Asn His 130 135 140

   Thr Asp Val Thr He Pro Tyr Leu Ala Thr Asp Val Thr Cys Val Gly 145 150 155 160

   Pro Gly Ala His Lys Gly Gin Ser Val He Ser Leu Asp Leu Tyr Thr 165 170 175

   Cys Glu Leu Asp Leu Thr Asn Leu He Leu Phe Ser Val Ser He Ser 180 185 190

   Ser Val Leu Phe Leu Met Val Val Met Thr Thr Ser His Leu Phe Phe

   195 200 205 Trp Asp Met Trp Tyr He Tyr Tyr Phe Trp Lys Ala Lys He Lys Gly 210 215 220

   Tyr Pro Ala Ser Ala He Pro Trp Ser Pro Cys Tyr Asp Ala Phe He

   225 230 235 240

   Val Tyr Asp Thr Lys Asn Ser Ala Val Thr Glu Trp Val Leu Gin Glu

   245 250 255

   64 Leu Val Ala Lys Leu Glu Asp Pro Arg Glu Lys His Phe Asn Leu Cys

   260 265 270

   Leu Glu Glu Arg Asp Trp Leu Pro Gly Gin Pro Val Leu Glu Asn Leu 275 280 285

   Ser Gin Ser He Gin Leu Ser Lys Lys Thr Val ^'Phe Val Met Thr Gin

   290 295 ' 300 Lys Tyr Ala Lys Thr Glu Ser Phe Lys Met Ala Phe Tyr Leu Ser His

   305 310 315 320

   Gin Arg Leu Leu Asp Glu Lys Val Asp Val He He Leu He Phe Leu 325 330 335

   Glu Arg Pro Leu Gin Lys Ser Lys Phe Leu Gin Leu Arg Lys Arg Leu 340 345 350

   Cys Arg Ser Ser Val Leu Glu Trp Pro Ala Asn Pro Gin Ala His Pro 355 360 365

   Tyr Phe Trp Gin Cys Leu Lys Asn Ala Leu Thr Thr Asp Asn His Val 370 375 380 Ala Tyr Ser Gin Met Phe Lys Glu Thr Val 385 390

   <210> 31 <211> 999

   <212> DNA

   <213> Unknown

   <220> <223> Description of Unknown Organism:primate; surmised

   Homo sapiens ""^"

   <220> <221> CDS <222> (2).. (847)

   <220>

   <221> misc_feature <222> (1) .. (282) <223> Xaa translation depends on genetic code

   <400> 31 c ten gat gcc aag att egg cac nag gca tat tea gag gtc atg atg gtt 49

   Xaa Asp Ala Lys He Arg His Xaa Ala Tyr Ser Glu Val Met Met Val 1 5 10 15 - gga tgg tea gat tea tac ace tgt gaa tac cct tta aac eta agg gga 97

   Gly Trp Ser Asp Ser Tyr Thr Cys Glu Tyr Pro Leu Asn Leu Arg Gly

   20 25 30 act agg tta aaa gac gtt cat etc cac gaa tta tct tgc aac aca get 145

   Thr Arg Leu Lys Asp Val His Leu His Glu Leu Ser Cys Asn Thr Ala

   35 '40 45

   65 ctg ttg att gtc ace att gtg gtt att atg eta gtt ctg ggg ttg get 193

   Leu Leu He Val Thr He Val Val He Met Leu Val Leu Gly Leu Ala

   50 55 60 gtg gcc ttc tgc tgt etc cac ttt gat ctg ccc tgg tat etc agg atg 241

   Val Ala Phe Cys Cys Leu His Phe Asp Leu Pro^' Trp Tyr Leu Arg Met 65 70 75 80 eta ggt caa tgc aca' caa aca tgg cac agg gtt agg aaa aca ace caa 289

   Leu Gly Gin Cys Thr Gin Thr Trp His Arg Val Arg Lys Thr Thr Gin 85 90 95 gaa caa etc aag aga aat gtc cga ttc cac gca ttt att tea tac agt 337 Glu Gin Leu Lys Arg Asn Val Arg Phe His Ala Phe He Ser Tyr Ser 100 105 110 gaa cat gat tct ctg tgg gtg aag aat gaa ttg ate ccc aat eta gag 385

   Glu His Asp Ser Leu Trp Val Lys Asn Glu Leu He Pro Asn Leu Glu 115 120 125 aag gaa gat ggt tct ate ttg att tgc ctt tat gaa age tac ttt gac 433

   Lys Glu Asp Gly Ser He Leu He Cys Leu Tyr Glu Ser Tyr Phe Asp

   130 135 140 cct ggc aaa age att agt gaa aat att gta age ttc att gag aaa age 481

   Pro Gly Lys Ser He Ser Glu Asn He Val Ser Phe He Glu Lys Ser 145 150 155 160 tat aag tec ate ttt gtt ttg tct ccc aac ttt gtc cag aat gag tgg 529

   Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Asn Glu Trp 165 170 175 tgc cat tat gaa ttc tac ttt gcc cac cac aat etc ttc cat gaa aat 577 Cys His Tyr Glu Phe Tyr Phe Ala His His Asn Leu Phe His Glu Asn 180 185 190 tct gat cac ata att ctt ate tta ctg gaa ccc att cca ttc tat tgc 625

   Ser Asp His He He Leu He Leu Leu Glu Pro He Pro Phe Tyr Cys 195 200 205 att ccc ace agg tat cat aaa ctg raa get etc ctg gaa aaa aaa gca 673

   He Pro Thr Arg Tyr His Lys Leu Xaa Ala Leu Leu Glu Lys Lys Ala

   210 215 220 tac ttg gaa tgg ccc aag gat agg cgt aaa tgt ggg ctt tty tgg gca 721

   Tyr Leu Glu Trp Pro Lys Asp Arg Arg Lys Cys Gly Leu Xaa Trp Ala 225 230 235 240 aac ctt cga get get gtt aat gtt aat gta tta gcc ace aga gaa atg 769

   Asn Leu Arg Ala Ala Val Asn Val Asn Val Leu Ala Thr Arg Glu Met 245 250 255 tat gaa ctg cag aca ttc aca gag tta aat gaa gag tct cga ggt tct 817 Tyr Glu Leu Gin Thr Phe Thr Glu Leu Asn Glu Glu Ser Arg Gly Ser 260 265 270 aca ate tyt ctg atg aga aca gac tgt yta taaaatccca cagtccttgg 867

   66 Thr He Xaa Leu Met Arg Thr Asp Cys Xaa 275 280 gaagttgggg accaeataca ctgttgggat gtacattgat aeaaccttta tgatggeaat 927 ttgaeaatat ttattaaaat aaaaaatggt tattccettc aaaaaaaaaa aaaaaaaaaa 987 aaaaaaaaaa aa ^• 999

   <210> 32 <211> 282 <212> PRT <213> Unknown

   <400> 32

   ^• Xaa Asp Ala Lys He Arg His Xaa Ala Tyr Ser Glu Val Met Met Val 1 5 10 15 Gly Trp Ser Asp Ser Tyr Thr Cys Glu Tyr Pro Leu Asn Leu Arg Gly

   20 25 30

   Thr Arg Leu Lys Asp Val His Leu His Glu Leu Ser Cys Asn Thr Ala 35 40 45

   Leu Leu He Val Thr He Val Val He Met Leu Val Leu Gly Leu Ala 50 55 60

   Val Ala Phe Cys Cys Leu His Phe Asp Leu Pro Trp Tyr Leu Arg Met 65 70 75 80

   Leu Gly Gin Cys Thr Gin Thr Trp His Arg Val Arg Lys Thr Thr Gin

   85 90 95 Glu Gin Leu Lys Arg Asn Val Arg Phe His Ala Phe He Ser Tyr Ser 100 105 110

   Glu His Asp Ser Leu Trp Val Lys Asn Glu Leu He Pro Asn Leu Glu 115 120 125

   Lys Glu Asp Gly Ser He Leu He Cys Leu Tyr Glu Ser Tyr Phe Asp 130 135 140

   Pro Gly Lys Ser He Ser Glu Asn He Val Ser Phe He Glu Lys Ser 145 150 155 160

   Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Asn Glu Trp 165 170 175 Cys His Tyr Glu Phe Tyr Phe Ala His His Asn Leu Phe His Glu Asn 180 185 190

   Ser Asp His He He Leu He Leu Leu Glu Pro He Pro Phe Tyr Cys 195 200 205

   He Pro Thr Arg Tyr His Lys Leu Xaa Ala Leu Leu Glu Lys Lys Ala 210 215 220

   67 Tyr Leu Glu Trp Pro Lys Asp Arg Arg Lys Cys Gly Leu Xaa Trp Ala 225 230 235 240

   Asn Leu Arg Ala Ala Val Asn Val Asn Val Leu Ala Thr Arg Glu Met 245 250 255

   Tyr Glu Leu Gin Thr Phe Thr Glu Leu Asn Glu Glu Ser Arg Gly Ser 260 265 ^' 270 Thr He Xaa Leu Met Arg Thr Asp Cys Xaa 275 280

   <210> 33 <211> 1173 <212> DNA

   <213> Unknown

   <220> <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220> <221> CDS <222> (1)..(1008)

   <220>

   <221> misc_feature <222> (285) <223> Xaa translation depends on genetic code

   <400> 33 ctg cct get ggc ace egg etc egg agg ctg gat gtc age tgc aac. age 48

   Leu Pro Ala Gly Thr Arg Leu Arg Arg Leu Asp Val Ser Cys Asn Ser 1 5 10 ^' 15 ate age ttc gtg gcc ccc ggc ttc ttt tec aag gcc aag gag ctg cga 96

   He Ser Phe Val Ala Pro Gly Phe Phe Ser Lys Ala Lys Glu Leu Arg

   20 25 30 gag etc aac ctt age gcc aac gcc etc aag aca gtg gac cac tec tgg 144

   Glu Leu Asn Leu Ser Ala Asn Ala Leu Lys Thr Val Asp His Ser Trp

   35 40 45 ttt ggg ccc ctg gcg agt gcc ctg caa ata eta gat gta age gcc aac 192 Phe Gly Pro Leu Ala Ser Ala Leu Gin He Leu Asp Val Ser Ala Asn 50 55 60 cct ctg cac tgc gcc tgt ggg gcg gcc ttt atg gac ttc ctg ctg gag 240 Pro Leu His Cys Ala Cys Gly Ala Ala Phe Met Asp Phe Leu Leu Glu 65 70 75 80 gtg cag get gcc gtg ccc ggt ctg ccc age egg gtg aag tgt ggc agt 288 Val Gin Ala Ala Val Pro Gly Leu Pro Ser Arg Val Lys Cys Gly Ser 85 90 95 ccg ggc cag etc cag ggc etc age ate ttt gca cag gac ctg cgc etc 336 Pro Gly Gin Leu Gin Gly Leu Ser He Phe Ala Gin Asp Leu Arg Leu

   68 100 105 110 tgc ctg gat gag gcc etc tec tgg gac tgt ttc gcc etc teg ctg ctg 384

   Cys Leu Asp Glu Ala Leu Ser Trp Asp Cys Phe Ala Leu Ser Leu Leu 115 -120 125 get gtg get ctg ggc ctg ggt gtg ccc atg ctg cat cac etc tgt ggc 432

   Ala Val Ala Leu Gly Leu Gly Val Pro Met Leu' His His Leu Cys Gly

   130 ^' 135 140 tgg gac etc tgg tac tgc ttc cac ctg tgc ctg gcc tgg ctt ccc tgg 480

   Trp Asp Leu Trp Tyr Cys Phe His Leu Cys Leu Ala Trp Leu Pro Trp 145 150 155 160 egg ggg egg caa agt ggg cga gat gag gat gcc ctg ccc tac gat gcc 528

   Arg Gly Arg Gin Ser Gly Arg Asp Glu Asp Ala Leu Pro Tyr Asp Ala 165 170 175 ttc gtg gtc ttc gac aaa acg cag age gca gtg gca gac tgg gtg tac 576 Phe Val Val Phe. Asp Lys Thr Gin Ser Ala Val Ala Asp Trp Val Tyr

   180 185 190 aac gag ctt egg ggg cag ctg gag gag tgc cgt ggg cgc tgg gca etc 624

   Asn Glu Leu Arg Gly Gin Leu Glu Glu Cys Arg Gly Arg Trp Ala Leu 195 200 205 cgc ctg tgc ctg gag gaa cgc gac tgg ctg cct ggc aaa ace etc ttt 672

   Arg Leu Cys Leu Glu Glu Arg Asp Trp Leu Pro Gly Lys Thr Leu Phe 210 215 220 gag aac ctg tgg gcc teg gtc tat ggc age cgc aag acg ctg ttt gtg 720 Glu Asn Leu Trp Ala Ser Val Tyr Gly Ser Arg Lys Thr Leu Phe Val 225 230 235 .240 ctg gcc cac acg gac egg gtc agt ggt etc ttg cgc gcc age ttc ctg 768

   Leu Ala His Thr Asp Arg Val Ser Gly Leu Leu Arg Ala Ser Phe Leu 245 250 255 ctg gcc cag cag cgc ctg ctg gag gac cgc aag gac gtc gtg gtg ctg 816 Leu Ala Gin Gin Arg Leu Leu Glu Asp Arg Lys Asp Val Val Val Leu

   260 265 270 gtg ate ctg age cct gac ggc cgc cgc tec cgc tac gkg egg ctg cgc 864

   Val He Leu Ser Pro Asp Gly Arg Arg Ser Arg Tyr Xaa Arg Leu Arg 275 280 285 cag cgc etc tgc cgc cag agt gtc etc etc tgg ccc cac cag ccc agt 912

   Gin Arg Leu Cys Arg Gin Ser Val Leu Leu Trp Pro His Gin Pro Ser 290 295 300 ggt cag cgc age ttc tgg gcc cag ctg ggc atg gcc ctg ace agg gac 960

   Gly Gin Arg Ser Phe Trp Ala Gin Leu Gly Met Ala Leu Thr Arg Asp 305 310 315 320 aac cac cac ttc tat aac egg aac ttc tgc cag gga ccc acg gcc gaa 1008

   Asn His His Phe Tyr Asn Arg Asn Phe Cys Gin Gly Pro Thr Ala Glu 325 330 335

   69 tagcegtgag ccggaatcct gcaeggtgce aectccacac teaccteacc tetgcctgec 1068 tggtctgaec eteccetget egcctccctc accccacaec tgacacagag caggcaetca 1128 ataaatgcta ccgaaggcta aaaaaaaaaa aaaaaaaaaa aanna 1173

   <210> 34 <211> 336 <212> PRT

   <213> Unknown

   <400> 34

   Leu Pro Ala Gly Thr Arg Leu Arg Arg Leu Asp Val Ser Cys Asn Ser 1 5 10 15

   He Ser Phe Val Ala Pro Gly Phe Phe Ser Lys Ala Lys Glu Leu Arg 20 25 30 Glu Leu Asn Leu Ser Ala Asn Ala Leu Lys Thr Val Asp His Ser Trp 35 40 45

   Phe Gly Pro Leu Ala Ser Ala Leu Gin He Leu Asp Val Ser Ala Asn 50 55 60

   Pro Leu His Cys Ala Cys Gly Ala Ala Phe Met Asp Phe Leu Leu Glu 65 70 75 80

   Val Gin Ala Ala Val Pro Gly Leu Pro Ser Arg Val Lys Cys Gly Ser 85 ^' 90 95

   Pro Gly Gin Leu Gin Gly Leu Ser He Phe Ala Gin Asp Leu Arg Leύ

   100 105 110 Cys Leu Asp Glu Ala Leu Ser Trp Asp Cys Phe Ala Leu Ser Leu Leu

   115 ^' 120 125

   Ala Val Ala Leu Gly Leu Gly Val Pro Met Leu His His Leu Cys Gly 130 135 140

   Trp Asp Leu Trp Tyr Cys Phe His Leu Cys Leu Ala Trp Leu Pro Trp 145 150 155 160

   Arg Gly Arg Gin Ser Gly Arg Asp Glu Asp Ala Leu Pro Tyr Asp Ala 165 170 175

   Phe Val Val Phe Asp Lys Thr Gin Ser Ala Val Ala Asp Trp Val Tyr 180 185 190 Asn Glu Leu Arg Gly Gin Leu Glu Glu Cys Arg Gly Arg Trp Ala Leu 195 200 205

   Arg Leu Cys Leu Glu Glu Arg Asp Trp Leu Pro Gly Lys Thr Leu Phe 210 215 220

   Glu Asn Leu Trp Ala Ser Val Tyr Gly Ser Arg Lys Thr Leu Phe Val 225 230 235 240

   70 Leu Ala His Thr Asp Arg Val Ser Gly Leu Leu Arg Ala Ser Phe Leu 245 250 255

   Leu Ala Gin Gin Arg Leu Leu Glu Asp Arg Lys Asp Val Val Val Leu 260 265 270

   Val He Leu Ser Pro Asp Gly Arg Arg Ser Arg Tyr Xaa Arg Leu Arg 275 280 ' 285 Gin Arg Leu Cys Arg 'Gin Ser Val Leu Leu Trp Pro His Gin Pro Ser • 290 295 300

   Gly Gin Arg Ser Phe Trp Ala Gin Leu Gly Met Ala Leu Thr Arg Asp 305 310 315 320

   Asn His His Phe Tyr Asn Arg Asn Phe Cys Gin Gly Pro Thr Ala Glu 325 330 335

   <210> 35

   <211> 497

   <212> DNA

   <213> Unknown <220>

   <223> Description of Unknown Organism: rodent; surmised Mus musculus

   <400> 35 tggcccacac ggaccgcgtc agtggcctcc tgcgcaccag cttcctgctg gctcagcagc 60 gcctgttgga agacegcaag gacgtggtgg tgttggtgat cctgegteeg gatgccccac 120 cgtcccgcta tgtgcgactg cgccagcgtc tctgccgcca gagtgtgctc ttctggcccc 180 agcgacccaa cgggcagggg ggcttctggg cccagctgag tacagccctg actagggaca 240 accgccaett ctataaccag aacttetgcc ggggaectae agcagaatag etcagagcaa 300 cagctggaaa cagctgcatc ttcatgtctg gttcccgagt tgctctgcct gccttgctct 360 gtcttactac accgctattt ggcaagtgcg caatatatgc taccaagcca ccaggcccac 420 ggageaaagg ttggetgtaa agggtagttt tctteeeatg eatctttcag gagagtgaag 480 atagacacca aacccac 497

   <210> 36 <211> 3099

   <212> DNA

   <213> Unknown

   <220> <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220>

   71 <221> CDS

   <222> (1)..(3096)

   <220> <221> mat_peptide <222> (52).. (3096)

   <220>

   <221> misc_feature <222> (725)

   <223> Xaa translation depends on genetic code

   <400> 36 atg ctg ace tgc att ttc ctg eta ata tct ggt tec tgt gag tta tgc 48 Met Leu Thr Cys He Phe Leu Leu He Ser Gly Ser Cys Glu Leu Cys -15 -10 -5 gcc gaa gaa aat ttt tct aga age tat cct tgt gat gag aaa aag caa 96 Ala Glu Glu Asn Phe Ser Arg Ser Tyr Pro Cys Asp Glu Lys Lys Gin -1 1 5 10 15 aat gac tea gtt att gca gag tgc age aat cgt cga eta cag gaa gtt 144

   Asn Asp Ser Val He Ala Glu Cys Ser Asn Arg Arg Leu Gin Glu Val 20 25 30 ccc caa acg gtg ggc aaa tat gtg aca gaa eta gac ctg tct gat aat 192

   Pro Gin Thr Val Gly Lys Tyr Val Thr Glu Leu Asp Leu Ser Asp Asn 35 40 45 ttc ate aca cac ata acg aat gaa tea ttt caa ggg ctg caa aat etc 240 Phe He Thr His He Thr Asn Glu Ser Phe Gin Gly Leu Gin Asn Leu 50 55 60 act aaa ata aat eta aac cac aac ccc aat gta cag cac cag aac gga 288 Thr Lys He Asn Leu Asn His Asn Pro Asn Val Gin His Gin Asn Gly 65 70 75 aat ccc ggt ata caa tea aat ggc ttg aat ate aca gac ggg gca ttc 336 Asn Pro Gly He Gin Ser Asn Gly Leu Asn He Thr Asp Gly Ala Phe 80 85 90 95 etc aac eta aaa aac eta agg gag tta ctg ctt gaa gac aac cag tta 384 Leu Asn Leu Lys Asn Leu Arg Glu Leu Leu Leu Glu Asp Asn Gin Leu 100 105 110 ccc caa ata ccc tct ggt ttg cca gag tct ttg aca gaa ctt agt eta 432 Pro Gin He Pro Ser Gly Leu Pro Glu Ser Leu Thr Glu Leu Ser Leu 115 120 125 att caa aac aat ata tac aac ata act aaa gag ggc att tea aga ctt 480 He G n Asn Asn He Tyr Asn He Thr Lys Glu Gly He Ser Arg Leu 130 135 140 ata aac ttg aaa aat etc tat ttg gcc tgg aac tgc tat ttt aac aaa 528 He Asn Leu Lys Asn Leu Tyr Leu Ala Trp Asn Cys Tyr Phe Asn Lys 145 150 155 gtt tgc gag aaa act aac ata gaa gat gga gta ttt gaa acg ctg aca 576

   72 Val Cys Glu Lys Thr Asn He Glu Asp Gly Val Phe Glu Thr Leu Thr

   160 165 170 175 aat ttg gag ttg eta tea eta tct ttc aat tct ctt tea cat gtg cca 624 Asn Leu Glu Leu Leu Ser Leu Ser Phe Asn Ser Leu Ser His Val Pro

   180 185 , 190 ccc aaa ctg cca age tec eta cgc aaa ctt ttt ctg age aac ace cag 672

   Pro Lys Leu Pro Ser Ser Leu Arg Lys Leu Phe Leu Ser Asn Thr Gin 195 ^' 200 205 ate aaa tac att agt gaa gaa gat ttc aag gga ttg ata aat tta aca 720

   He Lys Tyr He Ser Glu Glu Asp Phe Lys Gly Leu He Asn Leu Thr 210 215 220 tta eta gat tta age ggg aac tgt ccg agg tgc ttc aat gcc cca ttt 768

   Leu Leu Asp Leu Ser Gly Asn Cys Pro Arg Cys Phe Asn Ala Pro Phe

   225 230 235 cca tgc gtg cct tgt gat ggt ggt get tea att aat ata gat cgt ttt 816

   Pro Cys Val Pro Cys Asp Gly Gly Ala Ser He Asn He Asp Arg Phe

   240 245 250 255 get ttt caa aac ttg ace caa ctt cga tac eta aac etc tct age act 864 Ala Phe Gin Asn Leu Thr Gin Leu Arg Tyr Leu Asn Leu Ser Ser Thr

   260 265 270 tec etc agg aag att aat get gcc tgg ttt aaa aat atg cct cat ctg 912

   Ser Leu Arg Lys He Asn Ala Ala Trp Phe Lys Asn Met Pro His Leu 275 280 285 aag gtg ctg gat ctt gaa ttc aac tat tta gtg gga gaa ata gcc tct 960

   Lys Val Leu Asp Leu Glu Phe Asn Tyr Leu Val Gly Glu He Ala Ser 290 295 300 ggg gca ttt tta acg atg ctg ccc cgc tta gaa ata ctt gac ttg tct —^■ 1008

   Gly Ala Phe Leu Thr Met Leu Pro Arg Leu Glu He Leu Asp Leu Ser

   305 310 315 ttt aac tat ata aag ggg agt tat cca cag cat att aat att tec aga 1056

   Phe Asn Tyr He Lys Gly Ser Tyr Pro Gin His He Asn He Ser Arg

   320 325 330 335 aac ttc tct aaa ctt ttg tct eta egg gca ttg cat tta aga ggt tat 1104^" Asn Phe Ser Lys Leu Leu Ser Leu Arg Ala Leu His Leu Arg Gly Tyr

   340 345 350 gtg ttc cag gaa etc aga gaa gat gat ttc cag ccc ctg atg cag ctt 1152

   Val Phe Gin Glu Leu Arg Glu Asp Asp Phe Gin Pro Leu Met Gin Leu 355 360 365 cca aac tta teg act ate aac ttg ggt att aat ttt att aag caa ate 1200

   Pro Asn Leu Ser Thr He Asn Leu Gly He Asn Phe He Lys Gin He 370 375 380 gat ttc aaa ctt ttc caa aat ttc tec aat ctg gaa att att tac ttg 1248 Asp Phe Lys Leu Phe Gin Asn Phe Ser Asn Leu Glu He He Tyr Leu 385 390- 395

   73 tea gaa aac aga ata -tea ccg ttg gta aaa gat ace egg cag agt tat 1296

   Ser Glu Asn Arg He Ser Pro Leu Val Lys Asp Thr Arg Gin Ser Tyr 400 405 410 415 gca aat agt tec tct ttt caa cgt cat ate cgg^'aaa cga cgc tea aca 1344

   Ala Asn Ser Ser Ser Phe Gin Arg^' His He Arg Lys Arg Arg Ser Thr

   420 425 ' 430 gat ttt gag ttt gac cca cat teg aac ttt tat cat ttc ace cgt cct 1392

   Asp Phe Glu Phe Asp Pro His Ser Asn Phe Tyr His Phe Thr Arg Pro

   435 440 445 tta ata aag cca caa tgt get get tat gga aaa gcc tta gat tta age 1440 Leu He Lys Pro Gin Cys Ala Ala Tyr Gly Lys Ala Leu Asp Leu Ser

   450 455 ^' 460 etc aac agt att ttc ttc att ggg cca aac caa ttt gaa aat ctt cct 1488

   Leu Asn Ser He Phe Phe He Gly Pro Asn Gin Phe Glu Asn Leu Pro 465 470 475 gac att gcc tgt. tta aat ctg tct gca aat age aat get caa gtg tta 1536

   Asp He Ala Cys Leu Asn Leu Ser Ala Asn Ser Asn Ala Gin Val Leu 480 485 490 495 agt gga act gaa ttt tea gcc att cct cat gtc aaa tat ttg gat ttg 1584

   Ser Gly Thr Glu Phe Ser Ala He Pre His Val Lys Tyr Leu Asp Leu

   500 505 510 aca aac aat aga eta gac ttt gat aat get agt get ctt act gaa ttg 1632

   Thr Asn Asn Arg Leu Asp Phe Asp Asn Ala Ser Ala Leu Thr Glu Leu

   515 520 525 tec gac ttg gaa gtt eta gat etc age tat aat tea cac tat ttc aga 1680 Ser Asp Leu Glu Val Leu Asp Leu Ser Tyr Asn Ser His Tyr Phe Arg

   530 535 540 ata gca ggc gta aca cat cat eta gaa ttt att caa aat ttc aca aat 1728

   He Ala Gly Val Thr His His Leu Glu Phe He Gin Asn Phe Thr Asn 545 550 555 eta aaa gtt tta aac ttg age cac aac aac att tat act tta aca gat 1776

   Leu Lys Val Leu Asn Leu Ser His Asn Asn He Tyr Thr Leu Thr Asp 560 565 570 575 aag tat aac ctg gaa age aag tec ctg gta gaa tta gtt ttc agt ggc 1824

   Lys Tyr Asn Leu Glu Ser Lys Ser Leu Val Glu Leu Val Phe Ser Gly

   580 585 590 aat cgc ctt gac att ttg tgg aat gat gat gac aac agg tat ate tec 1872

   Asn Arg Leu Asp He Leu Trp Asn Asp Asp Asp Asn Arg Tyr He Ser

   595 600 605 att ttc aaa ggt etc aag aat ctg aca cgt ctg gat tta tec ctt aat 1920 He Phe Lys Gly Leu Lys Asn Leu Thr Arg Leu Asp Leu Ser Leu Asn

   610 615 620 agg etc aag cac ate cca aat gaa gca ttc ctt aat ttg cca gcg agt 19.68

   74 Arg Leu Lys His He Pro Asn Glu Ala Phe Leu Asn Leu Pro Ala Ser 625 630 635 etc act gaa eta cat ata aat gat aat atg tta aag ttt ttt aac tgg 2016 Leu Thr Glu Leu His He Asn Asp Asn Met Leu Lys Phe Phe Asn Trp 640 645 650;^' 655 aca tta etc cag cag ttt cct cgt etc gag ttg ctt gac tta cgt gga 2064

   Thr Leu Leu Gin Gin Phe Pro Arg Leu Glu Leu Leu Asp Leu Arg Gly 660 665 670 aac aaa eta etc ttt tta act gat age eta tct gac ttt aca tct tec 2112

   Asn Lys Leu Leu Phe Leu Thr Asp Ser Leu Ser Asp Phe Thr Ser Ser 675 680 685 ctt egg aca ctg ctg ctg agt cat aac agg att tec cac eta ccc tct 2160

   Leu Arg Thr Leu Leu Leu Ser His Asn Arg He Ser His Leu Pro Ser 690 695 700 ggc ttt ctt tct gaa gtc agt agt ctg aag cac etc gat tta agt tec 2208

   Gly Phe Leu Ser Glu Val Ser Ser Leu Lys His Leu Asp Leu Ser Ser 705 710 715 aat ctg eta aaa aca atm aac aaa tec gca ctt gaa act aag ace ace 2256 Asn Leu Leu Lys Thr Xaa Asn Lys Ser Ala Leu Glu Thr Lys Thr Thr 720 725 730 735 ace aaa tta tct atg ttg gaa eta cac gga aac ccc ttt gaa tgc ace 2304

   Thr Lys Leu Ser Met Leu Glu Leu His Gly Asn Pro Phe Glu Cys Thr 740 745 750 tgt gac att gga gat ttc cga aga tgg atg gat gaa cat ctg aat gtc 2352

   Cys Asp He Gly Asp Phe Arg Arg Trp Met Asp Glu His Leu Asn Val 755 760 765 aaa att ccc aga ctg gta gat gtc att tgt gcc agt cct ggg gat caa 2400

   Lys He Pro Arg Leu Val Asp Val He Cys Ala Ser Pro Gly Asp Gin 770 775 780 aga ggg aag agt att gtg agt ctg gag eta aca act tgt gtt tea gat 2448

   Arg Gly Lys Ser He Val Ser Leu Glu Leu Thr Thr Cys Val Ser Asp 785 790 795 gtc act gca gtg ata tta ttt ttc ttc acg ttc ttt ate ace ace atg 2496 Val Thr Ala Val He Leu Phe Phe Phe Thr Phe Phe He Thr Thr Met 800 805 810 815 gtt atg ttg get gcc ctg get' cac cat ttg ttt tac tgg gat gtt tgg 2544

   Val Met Leu Ala Ala Leu Ala His His Leu Phe Tyr Trp Asp Val Trp 820 825 830 ttt ata tat aat gtg tgt tta get aag tta aaa ggc tac agg tct ctt 2592

   Phe He Tyr Asn Val Cys Leu Ala Lys Leu Lys Gly Tyr Arg Ser Leu 835 840 • 845 tec aca tec caa act ttc tat gat get tac att tct tat gac ace aaa 2640 Ser Thr Ser Gin Thr Phe Tyr Asp Ala Tyr He Ser Tyr Asp Thr Lys 850 855 860

   75 gat gcc tct gtt act gac tgg gtg ata aat gag ctg cgc tac cac ctt 2688

   Asp Ala Ser Val Thr Asp Trp Val He Asn Glu Leu Arg Tyr His Leu

   865 870 875 gaa gag age cga gac aaa aac gtt etc ctt tgt. ^'eta gag gag agg gat 2736

   Glu Glu Ser Arg Asp Lys Asn Val Leu Leu Cys Leu Glu Glu Arg Asp 880 885 890 895 tgg gac ccg gga ttg gcc ate ate gac aac etc atg cag age ate aac 2784

   Trp Asp Pro Gly Leu Ala He He Asp Asn Leu Met Gin Ser He Asn 900 905 910 caa age aag aaa aca gta ttt gtt tta ace aaa aaa tat gca aaa age 2832 Gin Ser Lys Lys Thr Val Phe Val Leu Thr Lys Lys Tyr Ala Lys Ser 915 920 925 tgg aac ttt aaa aca get ttt tac ttg gcc ttg cag agg eta atg ggt 2880

   Trp Asn Phe Lys Thr Ala Phe Tyr Leu Ala Leu Gin Arg Leu Met Gly 930 935 940 gag aac atg gat gtg att ata ttt ate ctg ctg gag cca gtg tta cag 2928

   Glu Asn Met Asp Val He He Phe He Leu Leu Glu Pro Val Leu Gin

   945 950 955 cat tct ccg tat ttg agg eta egg cag egg ate tgt aag age tec ate 2976

   His Ser Pro Tyr Leu Arg Leu Arg Gin Arg He Cys Lys Ser Ser He 960 965 970 975 etc cag tgg cct gac aac ccg aag gca gaa ggc ttg ttt tgg caa act 3024

   Leu Gin Trp Pro Asp Asn Pro Lys Ala Glu Gly Leu Phe Trp Gin Thr 980 985 990 ctg aga aat gtg gtc ttg act gaa aat gat tea egg tat aac aat atg 3072 Leu Arg Asn Val Val Leu Thr Glu Asn Asp Ser Arg Tyr Asn Asn Met 995 1000 1005 tat gtc gat tec att aag caa tac taa 3099

   Tyr Val Asp Ser He Lys Gin Tyr 1010 1015

   <210> 37 <211> 1032 <212> PRT

   <213> Unknown

   <400> 37

   Met Leu Thr Cys He Phe Leu Leu He Ser Gly Ser Cys Glu Leu Cys -15 -10 -5

   Ala Glu Glu Asn Phe Ser Arg Ser Tyr Pro Cys Asp Glu Lys Lys Gin -1 1 5 10 15 Asn Asp Ser Val He Ala Glu Cys Ser Asn. Arg Arg Leu Gin Glu Val

   20 25 30

   Pro Gin Thr Val Gly Lys Tyr Val Thr Glu Leu Asp Leu Ser Asp Asn

   76 35 40 45

   Phe He Thr His He Thr Asn Glu Ser Phe Gin Gly Leu Gin Asn Leu 50 55 60

   Thr Lys He Asn Leu Asn His Asn Pro Asn Val'^' Gin His Gin Asn Gly 65 70 ^'' 75

   Asn Pro Gly He Gin Ser Asn Gly Leu Asn He Thr Asp Gly Ala Phe 80 ^' 85 90 95

   Leu Asn Leu Lys Asn Leu Arg Glu Leu Leu Leu Glu Asp Asn Gin Leu 100 105 110 Pro Gin He Pro Ser Gly Leu Pro Glu Ser Leu Thr Glu Leu Ser Leu 115 120 125

   He Gin Asn Asn He Tyr Asn He Thr Lys Glu Gly He Ser Arg Leu 130 135 140

   He Asn Leu Lys Asn Leu Tyr Leu Ala Trp Asn Cys Tyr Phe Asn Lys 145 150 155

   Val Cys Glu Lys Thr Asn He Glu Asp Gly Val Phe Glu Thr Leu Thr 160 165 170 175

   Asn Leu Glu Leu Leu Ser Leu Ser Phe Asn Ser Leu Ser His Val Pro

   180 185 190 Pro Lys Leu Pro Ser Ser Leu Arg Lys Leu Phe Leu Ser Asn Thr Gin 195 200 205

   He Lys Tyr He Ser Glu Glu Asp Phe Lys Gly Leu He Asn Leu Thr 210 215 220

   Leu Leu Asp Leu Ser Gly Asn Cys Pro Arg Cys Phe Asn Ala Pro Phe 225 230 235

   Pro Cys Val Pro Cys Asp Gly Gly Ala Ser He Asn He Asp Arg Phe 240 245 250 255

   Ala Phe Gin Asn Leu Thr Gin Leu Arg Tyr Leu Asn Leu Ser Ser Thr

   260 265 . 270 Ser Leu Arg Lys He Asn Ala Ala Trp Phe Lys Asn Met Pro His Leu 275 280 285

   Lys Val Leu Asp Leu Glu Phe Asn Tyr Leu Val Gly Glu He Ala Ser 290 295 300

   Gly Ala Phe Leu Thr Met Leu Pro Arg Leu Glu He Leu Asp Leu Ser 305 310 315

   Phe Asn Tyr He Lys Gly Ser Tyr Pro Gin His He Asn He Ser Arg 320 325 330 335

   Asn Phe Ser Lys Leu Leu Ser Leu Arg Ala Leu His Leu Arg Gly Tyr

   340 345 350

   77 Val Phe Gin Glu Leu Arg Glu Asp Asp Phe Gin Pro Leu Met Gin Leu 355 360 365

   Pro Asn Leu Ser Thr He Asn Leu Gly He Asn Phe He Lys Gin He 370 375 . 380

   Asp Phe Lys Leu Phe Gin Asn Phe Ser Asn Leu Glu He He Tyr Leu 385 390 395

   Ser Glu Asn Arg He Ser Pro Leu Val Lys Asp Thr Arg Gin Ser Tyr 400 405 410 415

   Ala Asn Ser Ser Ser Phe Gin Arg His He Arg Lys Arg Arg Ser Thr 420 425 430

   Asp Phe Glu Phe Asp Pro His Ser Asn Phe Tyr His Phe Thr Arg Pro

   435 440 445 Leu He Lys Pro Gin Cys Ala Ala Tyr Gly Lys Ala Leu Asp Leu Ser 450 455 460

   Leu Asn Ser He Phe Phe He Gly Pro Asn Gin Phe Glu Asn Leu Pro 465 470 475

   Asp He Ala Cys Leu Asn Leu Ser Ala Asn Ser Asn Ala Gin Val Leu 480 485 490 495

   Ser Gly Thr Glu Phe Ser Ala He Pro His Val Lys Tyr Leu Asp Leu 500 505 510

   Thr Asn Asn Arg Leu Asp Phe Asp Asn Ala Ser Ala Leu Thr Glu Leu 515 520 525 Ser Asp Leu Glu Val Leu Asp Leu Ser Tyr Asn Ser His Tyr Phe Arg 530 535 540

   He Ala Gly Val Thr His His Leu Glu Phe He Gin Asn Phe Thr Asn 545 550 555

   Leu Lys Val Leu Asn Leu Ser His Asn Asn He Tyr Thr Leu Thr Asp 560 565 570. 575

   Lys Tyr Asn Leu Glu Ser Lys Ser Leu Val Glu Leu Val Phe Ser Gly 580 585 590

   Asn Arg Leu Asp He Leu Trp Asn Asp Asp Asp Asn Arg Tyr He Ser 595 600 605 He Phe Lys Gly Leu Lys Asn Leu Thr Arg Leu Asp Leu Ser Leu Asn. 610 615 620

   Arg Leu Lys His He Pro Asn Glu Ala Phe Leu Asn Leu Pro Ala Ser 625 630 635

   Leu Thr Glu Leu His He Asn Asp Asn Met Leu Lys Phe Phe Asn Trp

   640 645 650 655

   78 Thr Leu Leu Gin Gin Phe Pro Arg Leu Glu Leu Leu Asp Leu Arg Gly

   660 ^' 665 670

   Asn Lys Leu Leu Phe Leu Thr Asp Ser Leu Ser Asp Phe Thr Ser Ser 675 680 685

   Leu Arg Thr Leu Leu Leu Ser His Asn Arg lie Ser His Leu Pro Ser

   690 695 ' 700 Gly Phe Leu Ser Glu Val Ser Ser Leu Lys His Leu Asp Leu Ser Ser

   705 710 715

   Asn Leu Leu Lys Thr Xaa Asn Lys Ser Ala Leu Glu Thr Lys Thr Thr 720 725 730 735

   Thr Lys Leu Ser Met Leu Glu Leu His Gly Asn Pro Phe Glu Cys Thr 740 745 750

   Cys Asp He Gly Asp Phe Arg Arg Trp Met Asp Glu His Leu Asn Val 755 760 765

   Lys He Pro Arg Leu Val Asp Val He Cys Ala Ser Pro Gly Asp Gin 770 775 780 Arg Gly Lys Ser He Val Ser Leu Glu Leu Thr Thr Cys Val Ser Asp 785 790 795

   Val Thr Ala Val He Leu Phe Phe Phe Thr Phe Phe He Thr Thr Met 800 805 810 815

   Val Met Leu Ala Ala Leu Ala His His Leu Phe Tyr Trp Asp Val Trp 820 825 830

   Phe He Tyr Asn Val Cys Leu Ala Lys Leu Lys Gly Tyr Arg Ser Leu 835 840 845

   Ser Thr Ser Gin Thr Phe Tyr Asp Ala Tyr He Ser Tyr Asp Thr Lys 850 855 860 Asp Ala Ser Val Thr Asp Trp Val He Asn Glu Leu Arg Tyr His Leu 865 870 875

   Glu Glu Ser Arg Asp Lys Asn Val Leu Leu Cys Leu Glu Glu Arg Asp 880 885 890 895

   Trp Asp Pro Gly Leu Ala He He Asp Asn Leu Met Gin Ser He Asn 900 905 910

   Gin Ser Lys Lys Thr Val Phe Val Leu Thr Lys Lys Tyr Ala Lys Ser 915 920 925

   Trp Asn Phe Lys Thr Ala Phe Tyr Leu Ala Leu Gin Arg Leu Met Gly

   930 935 940 Glu Asn Met Asp Val He He Phe He Leu Leu Glu Pro Val Leu Gin

   945 950 955

   His Ser Pro Tyr Leu Arg Leu Arg Gin Arg He Cys Lys Ser Ser He

   79 960 965 970 975

   Leu Gin Trp Pro Asp Asn Pro Lys Ala Glu Gly Leu Phe Trp Gin Thr 980 985 990

   Leu Arg Asn Val Val Leu Thr Glu Asn Asp Ser ^'Arg Tyr Asn Asn Met 995 1000 ^'' 1005

   Tyr Val Asp Ser He Lys Gin Tyr 1010 ^' 1015

   <210> 38

   <211> 3046 <212> DNA

   <213> Unknown

   <220>

   <223> Description of Unknown Organism: primate; surmised Homo sapiens

   <220>

   <221> CDS

   <222> (111) .. (2543)

   <220>

   <221> mat_peptide

   <222> (168) .. (2543) <400> 38 gaatcateca egcaectgca gctctgetga gagagtgeaa gcegtggggg ttttgagctc 60 atcttcatca ttcatatgag gaaataagtg gtaaaatcct tggaaataca atg aga 116

   Met Arg etc ate aga aac att tac ata ttt tgt agt att gtt atg aca gca gag 164

   Leu He Arg Asn He Tyr He Phe Cys Ser He Val Met Thr Ala Glu

   -15 -10 -5 ggt gat get cca gag ctg cca gaa gaa agg gaa ctg atg ace aac tgc 212

   Gly Asp Ala Pro Glu Leu Pro Glu Glu Arg Glu Leu Met Thr Asn Cys

   -1 1 5 10 15 tec aac atg tct eta aga aag gtt ccc gca gac ttg ace cca gcc aca 260 Ser Asn Met Ser Leu Arg Lys Val Pro Ala Asp Leu Thr Pro Ala Thr

   20 25 30 acg aca ctg gat tta tec tat aac etc ctt ttt caa etc cag agt tea 308

   Thr Thr Leu Asp Leu Ser Tyr Asn Leu Leu Phe Gin Leu Gin Ser Ser 35 40 45 gat ttt cat tct gtc tec aaa ctg aga gtt ttg att eta tgc cat aac 356

   Asp Phe His Ser Val Ser Lys Leu Arg Val Leu He Leu Cys His Asn

   50 55 60 aga att caa cag ctg gat etc aaa ace ttt gaa ttc aac aag gag tta 404 Arg He Gin Gin Leu Asp Leu Lys Thr Phe Glu Phe Asn Lys Glu Leu 65 70 75

   80 aga tat tta gat ttg tct aat aac aga ctg aag agt gta act tgg tat 452

   Arg Tyr Leu Asp Leu Ser Asn Asn Arg Leu Lys Ser Val Thr Trp Tyr 80 85 90 95 tta ctg gca ggt etc agg tat tta gat ctt tct ttt aat gac ttt gac 500

   Leu Leu Ala Gly Leu Arg Tyr Leu Asp Leu Ser Phe Asn Asp Phe Asp

   100 105 ' 110 ace atg cct ate tgt gag gaa get ggc aac atg tea cac ctg gaa ate 548

   Thr Met Pro He Cys Glu Glu Ala Gly Asn Met Ser His Leu Glu He

   115 120 125 eta ggt ttg agt ggg gca aaa ata caa aaa tea gat ttc cag aaa att 596 Leu Gly Leu Ser Gly Ala Lys He Gin Lys Ser Asp Phe Gin Lys He 130 135 140 get cat ctg cat eta aat act gtc ttc tta gga ttc aga act ctt cct 644

   Ala His Leu His Leu Asn Thr Val Phe Leu Gly Phe Arg Thr Leu Pro 145 150 155 cat tat gaa gaa ggt age ctg ccc ate tta aac aca aca aaa ctg cac 692

   His Tyr Glu Glu Gly Ser Leu Pro He Leu Asn Thr Thr Lys Leu His

   160 165 170 175 att gtt tta cca atg gac aca aat ttc tgg gtt ctt ttg cgt gat gga 740

   He Val Leu Pro Met Asp Thr Asn Phe Trp Val Leu Leu Arg Asp Gly

   180 185 190 ate aag act tea aaa ata tta gaa atg aca aat ata gat ggc aaa age 788

   He Lys Thr Ser Lys He Leu Glu Met Thr Asn He Asp Gly Lys Ser

   195 200 205 caa ttt gta agt tat gaa atg caa cga aat ctt agt tta gaa aat get 836 Gin Phe Val Ser Tyr Glu Met Gin Arg Asn Leu Ser Leu Glu Asn Ala

   210 215 220 aag aca teg gtt eta ttg ctt aat aaa gtt gat tta etc tgg gac gac 884

   Lys Thr Ser Val Leu Leu Leu Asn Lys Val Asp Leu Leu Trp Asp Asp 225 230 235 ctt ttc ctt ate tta caa ttt gtt tgg cat aca tea gtg gaa cac ttt 932

   Leu Phe Leu He Leu Gin Phe Val Trp His Thr Ser Val Glu His Phe

   240 245 250 255 cag ate cga aat gtg act ttt ggt ggt aag get tat ctt gac cac aat 980

   Gin He Arg Asn Val Thr Phe Gly Gly Lys Ala Tyr Leu Asp His Asn

   260 265 270 tea ttt gac tac tea aat act gta atg aga act ata aaa ttg gag cat 1028

   Ser Phe Asp Tyr Ser Asn Thr Val Met Arg Thr He Lys Leu Glu His

   275 280 285 gta cat ttc aga gtg ttt tac att caa cag gat aaa ate tat ttg ctt 1076 Val His Phe Arg Val Phe Tyr He Gin Gin Asp Lys He Tyr Leu Leu

   290 295 300 ttg ace aaa atg gac ata gaa aac ctg aca ata tea aat gca caa atg 1124

   81 Leu Thr Lys Met Asp He Glu Asn Leu Thr He Ser Asn Ala Gin Met 305 310 315 cca cac atg ctt ttc ccg aat tat cct acg aaa ttc caa tat tta aat 1172 Pro His Met Leu Phe Pro Asn Tyr Pro Thr Lys Phe Gin Tyr Leu Asn 320 325 330:^' 335 ttt gcc aat aat ate tta aca gac gag ttg ttt aaa aga act ate caa 1220 Phe Ala Asn Asn He Leu Thr Asp Glu Leu Phe Lys Arg Thr He Gin 34θ^" 345 350 ctg cct cac ttg aaa act etc att ttg aat ggc aat aaa ctg gag aca 1268

   Leu Pro His Leu Lys Thr Leu He Leu Asn Gly Asn Lys Leu Glu Thr

   355 360 365 ctt tct tta gta agt tgc ttt get aac aac aca ccc ttg gaa cac ttg 1316

   Leu Ser Leu Val Ser Cys Phe Ala Asn Asn Thr Pro Leu Glu His Leu 370 375 380 gat ctg agt caa aat eta tta caa cat aaa aat gat gaa aat tgc tea 1364 Asp Leu Ser Gin Asn Leu Leu Gin His Lys Asn Asp Glu Asn Cys Ser 385 390 395 tgg cca gaa act gtg gtc aat atg aat ctg tea tac aat aaa ttg tct 1412 Trp Pro Glu Thr Val Val Asn Met Asn Leu Ser Tyr Asn Lys Leu Ser 400 405 410 415 gat tct gtc ttc agg tgc ttg ccc aaa agt att caa ata ctt gac eta 1460 Asp Ser Val Phe Arg Cys Leu Pro Lys Ser He Gin He Leu Asp Leu 420. 425 430 aat aat aac caa ate caa act gta cct aaa gag act att cat ctg atg 1508

   Asn Asn Asn Gin He Gin Thr Val Pro Lys Glu Thr He His Leu Met 435 440 445 gcc tta cga gaa eta aat att gca ttt aat ttt eta act gat etc cct 1556

   Ala Leu Arg Glu Leu Asn He Ala Phe Asn Phe Leu Thr Asp Leu Pro 450 455 460 gga tgc agt cat ttc agt aga ctt tea gtt ctg aac att gaa atg aac 1604 Gly Cys Ser His Phe Ser Arg Leu Ser Val Leu Asn He Glu Met Asn 465 470 475 ttc att etc age cca tct ctg gat ttt gtt cag age tgc cag gaa gtt 1652 Phe He Leu Ser Pro Ser Leu Asp Phe Val Gin Ser Cys Gin Glu Val 480 485 490 495 aaa act eta aat gcg gga aga aat cca ttc egg tgt ace tgt gaa tta 1700 Lys Thr Leu Asn Ala Gly Arg Asn Pro Phe Arg Cys Thr Cys Glu Leu 500 505 510 aaa aat ttc att cag ctt gaa aca tat tea gag gtc atg atg gtt gga 1748 Lys Asn Phe He Gin Leu Glu Thr Tyr Ser Glu Val Met Met Val Gly 515 520 525 tgg tea gat tea tac ace tgt gaa tac cct tta aac eta agg gga act 1796 Trp Ser Asp Ser Tyr Thr Cys Glu Tyr Pro Leu Asn Leu Arg Gly Thr 530 535 540

   82 agg tta aaa gac gtt cat etc cac gaa tta tct tgc aac aca get ctg 1844

   Arg Leu Lys Asp Val His Leu His Glu Leu Ser Cys Asn Thr Ala Leu 545 550 555 ttg att gtc ace att gtg gtt att atg eta gtt_/'ctg ggg ttg get gtg 1892

   Leu He Val Thr He Val Val He Met Leu Vaϊ Leu Gly Leu Ala Val

   560 565 570 575 gcc ttc tgc tgt etc cac ttt gat ctg ccc tgg tat etc agg atg eta 1940

   Ala Phe Cys Cys Leu His Phe Asp Leu Pro Trp Tyr Leu Arg Met Leu 580 585 590 ggt caa tgc aca caa aca tgg cac agg gtt agg aaa aca ace caa gaa 1988 Gly Gin Cys Thr Gin Thr Trp His Arg Val Arg Lys Thr Thr Gin Glu 595 600 605 caa etc aag aga aat gtc cga ttc cac gca ttt att tea tac agt gaa 2036

   Gin Leu Lys Arg Asn Val Arg Phe His Ala Phe He Ser Tyr Ser Glu 610 615 620 cat gat tct ctg tgg gtg aag aat gaa ttg ate ccc aat eta gag aag 2084 His Asp Ser Leu Trp Val Lys Asn Glu Leu He Pro Asn Leu Glu Lys gaa gat ggt tct ate ttg att tgc ctt tat gaa age tac ttt gac cct 2132

   Glu Asp Gly Ser He Leu He Cys Leu Tyr Glu Ser Tyr Phe Asp Pro

   640 645 650 655 ggc aaa age att agt gaa aat att gta age ttc att gag aaa age tat 2180

   Gly Lys Ser He Ser Glu Asn He Val- Ser Phe He Glu Lys Ser Tyr

   660 665 670 aag tec ate ttt gtt ttg tct ccc aac ttt gtc cag aat gag tgg tgc 2228 Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Asn Glu Trp Cys

   675 680 685 — cat tat gaa ttc tac ttt gcc cac cac aat etc ttc cat gaa aat tct 2276

   His Tyr Glu Phe Tyr Phe Ala His His Asn Leu Phe His Glu Asn Ser 690 695 700 gat cat ata att ctt ate tta ctg gaa ccc att cca ttc tat tgc att 2324

   Asp His He He Leu He Leu Leu Glu Pro He Pro Phe Tyr Cys He

   705 ^' 710 715 ccc ace agg tat cat aaa ctg aaa get etc ctg gaa aaa aaa gca tac 2372

   Pro Thr Arg Tyr His Lys Leu Lys Ala Leu Leu Glu Lys Lys Ala Tyr

   720 725 730 735 ttg gaa tgg ccc aag gat agg cgt aaa tgt ggg ctt ttc tgg gca aac - 2420

   Leu Glu Trp Pro Lys Asp Arg Arg Lys Cys Gly Leu Phe Trp Ala Asn

   740 745 750 ctt cga get get att aat gtt aat gta tta gcc ace aga gaa atg tat 2468 Leu Arg Ala Ala He Asn Val Asn Val Leu Ala Thr Arg Glu Met Tyr

   755 760 765 gaa ctg cag aca ttc aca gag ^'tta aat gaa' gag tct cga ggt tct aca 2516

   83 Glu Leu Gin Thr Phe Thr Glu Leu Asn Glu Glu Ser Arg Gly Ser Thr 770 775 780 ate tct ctg atg aga aca gat tgt eta taaaatccca cagtccttgg 2563 He Ser Leu Met Arg Thr Asp Cys Leu 785 790 gaagttgggg accaeataca ctgttgggat gtacattgat aeaaccttta tgatggeaat 2623 ttgaeaatat ttattaaa'at aaaaaatggt tattccettc atatcagttt etagaaggat 2683 ttctaagaat gtatcetata gaaacacett cacaagttta taagggctta tggaaaaagg 2743 tgttcatccc aggattgttt ataatcatga aaaatgtggc caggtgcagt ggctcactct 2803 tgtaatecca geaetatggg aggecaaggt gggtgaccea cgaggtcaag agatggagac 2863 catcctggcc aacatggtga aaccctgtct ctactaaaaa tacaaaaatt agctgggcgt 2923 gatggtgcac gcctgtagtc ccagctactt gggaggctga ggcaggagaa tcgcttgaac 2983. ccgggaggtg gcagttgcag tgagctgaga tcgagccact gcactccagc ctggtgacag 3043 age 3046

   <210> 39

   <211> 811

   <212> PRT <213> Unknown

   <400> 39

   Met Arg Leu He Arg Asn He Tyr He Phe Cys Ser He Val Met Thr -15 -10 -5

   Ala Glu Gly Asp Ala Pro Glu Leu Pro Glu Glu Arg Glu Leu Met Thr -1 1 5 10

   Asn Cys Ser Asn Met Ser Leu Arg Lys Val Pro Ala Asp Leu Thr Pro 15 20 25

   Ala Thr Thr Thr Leu Asp Leu Ser Tyr Asn Leu Leu Phe Gin Leu Gin 30 35 40 45 Ser Ser Asp Phe His Ser Val Ser Lys Leu Arg Val Leu He Leu Cys

   50 55 60

   His Asn Arg He Gin Gin Leu Asp Leu Lys Thr Phe Glu Phe Asn Lys

   65 70 75

   Glu Leu Arg Tyr Leu Asp Leu Ser Asn Asn Arg Leu Lys Ser Val Thr 80 85 90

   Trp Tyr Leu Leu Ala Gly Leu Arg Tyr Leu Asp Leu Ser Phe Asn Asp 95 100 105

   Phe Asp Thr Met Pro He Cys Glu Glu Ala Gly Asn Met Ser His Leu

   HO 115 120 125

   84 Glu He Leu Gly Leu Ser Gly Ala Lys He Gin Lys Ser Asp Phe Gin 130 135 140 Lys He Ala His Leu His Leu Asn Thr Val Phe Leu Gly Phe Arg Thr 145 150 155

   Leu Pro His Tyr Glu Glu Gly Ser Leu Pro He Leu Asn Thr Thr Lys 160 165 170

   Leu His He Val Leu Pro Met Asp Thr Asn Phe Trp Val Leu Leu Arg 175 180 185

   Asp Gly He Lys Thr Ser Lys He Leu Glu Met Thr Asn He Asp Gly 190 195 200 205

   Lys Ser Gin Phe Val Ser Tyr Glu Met Gin Arg Asn Leu Ser Leu Glu 210 215 220 Asn Ala Lys Thr Ser Val Leu Leu Leu Asn Lys Val Asp Leu Leu Trp 225 230 235

   Asp Asp Leu Phe Leu He Leu Gin Phe Val Trp His Thr Ser Val Glu 240 245 250

   His Phe Gin He Arg Asn Val Thr Phe Gly Gly Lys Ala Tyr Leu Asp 255 260 265

   His Asn Ser Phe Asp Tyr Ser Asn Thr Val Met Arg Thr He Lys Leu 270 275 280 285

   Glu His Val His Phe Arg Val Phe Tyr He Gin Gin Asp Lys He Tyr 290 295 300 Leu Leu Leu Thr Lys Met Asp He Glu Asn Leu Thr He Ser Asn Ala 305 310 315

   Gin Met Pro His Met Leu Phe Pro Asn Tyr Pro Thr Lys Phe Gin Tyr 320 325 330

   Leu Asn Phe Ala Asn Asn He Leu Thr Asp Glu Leu Phe Lys Arg Thr 335 340 345

   He Gin Leu Pro His Leu Lys Thr Leu He Leu Asn Gly Asn Lys Leu 350 355 360 365

   Glu Thr Leu Ser Leu Val Ser Cys Phe Ala Asn Asn Thr Pro Leu Glu 370 375 380 His Leu Asp Leu Ser Gin Asn Leu Leu Gin His Lys Asn Asp Glu Asn

   385 390 395

   Cys Ser Trp Pro Glu Thr Val Val Asn Met Asn Leu Ser Tyr Asn Lys 400 405 410

   Leu Ser Asp Ser Val Phe Arg Cys Leu Pro Lys Ser He Gin He Leu 415 420 425

   85 Asp Leu Asn Asn Asn Gin He Gin Thr Val Pro Lys Glu Thr He His

   430 435 440 445

   Leu Met Ala Leu Arg Glu Leu Asn He Ala Phe Asn Phe Leu Thr Asp 450 455 460

   Leu Pro Gly Cys Ser His Phe Ser Arg Leu Ser Val Leu Asn He Glu 465 470 ' 475 Met Asn Phe He Leu' Ser Pro Ser Leu Asp Phe Val Gin Ser Cys Gin 480 485 490

   Glu Val Lys Thr Leu Asn Ala Gly Arg Asn Pro Phe Arg Cys Thr Cys 495 500 505

   Glu Leu Lys Asn Phe He Gin Leu Glu Thr Tyr Ser Glu Val Met Met 510 515 520 525

   Val Gly Trp Ser Asp Ser Tyr Thr Cys Glu Tyr Pro Leu Asn Leu Arg 530 535 540

   Gly Thr Arg Leu Lys Asp Val His Leu His Glu Leu Ser Cys Asn Thr 545 550 555 Ala Leu Leu He Val Thr He Val Val He Met Leu Val Leu Gly Leu 560 565 570

   Ala Val Ala Phe Cys Cys Leu His Phe Asp Leu Pro Trp Tyr Leu Arg 575 580 585

   Met Leu Gly Gin Cys Thr Gin Thr Trp His Arg Val Arg Lys Thr Thr 590 595 600 605

   Gin Glu Gin Leu Lys Arg Asn Val Arg Phe His Ala Phe He Ser Tyr 610 615 620

   Ser Glu His Asp Ser Leu Trp Val Lys Asn Glu Leu He Pro Asn Leu

   625 630 635 Glu Lys Glu Asp Gly Ser He Leu He Cys Leu Tyr Glu Ser Tyr Phe 640 645 650

   Asp Pro Gly Lys Ser He Ser Glu Asn He Val Ser Phe He Glu Lys 655 660 665

   Ser Tyr Lys Ser He Phe Val Leu Ser Pro Asn Phe Val Gin Asn Glu

   670 675 680 685

   Trp Cys His Tyr Glu Phe Tyr Phe Ala His His Asn Leu Phe His Glu 690 695 700

   Asn Ser Asp His He He Leu He Leu Leu Glu Pro He Pro Phe Tyr

   705 710 715 Cys He Pro Thr Arg Tyr His Lys Leu Lys Ala Leu Leu Glu Lys Lys

   720 725 730

   Ala Tyr Leu Glu Trp Pro Lys Asp Arg Arg Lys Cys Gly Leu Phe Trp

   86 735 740 745

   Ala Asn Leu Arg Ala Ala He Asn Val Asn Val Leu Ala Thr Arg Glu

   750 755 760 765

   Met Tyr Glu Leu Gin Thr Phe Thr Glu Leu Asn Glu Glu Ser Arg Gly

   770 775 780

   Ser Thr He Ser Leu Met Arg Thr Asp Cys Leu 785 ^' 790

   <210> 40 <211> 2760 <212> DNA

   <213> Unknown

   <220>

   <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220> <221> CDS <222> (68).. (2455)

   <220>

   <221> mat_peptide

   <222> ( 161 ) . . ( 2455 ) <220>

   <221> misc_feature

   <222> (2529)

   <223> n may be a, c, g, or t <400> 40 aagaatttgg actcatatca agatgetctg aagaagaaca acectttagg atagecactg 60 caacatc atg ace aaa gac aaa gaa cct att gtt aaa age ttc cat ttt 109 Met Thr Lys Asp Lys Glu Pro He Val Lys Ser Phe His Phe -30 -25 -20 gtt tgc ctt atg ate ata ata gtt gga ace aga ate cag ttc tec gac 157

   Val Cys Leu Met He He He Val Gly Thr Arg He Gin Phe Ser Asp

   -15 -10 -5 gga aat gaa ttt gca gta gac aag tea aaa aga ggt ctt att cat gtt 205

   Gly Asn Glu Phe Ala Val Asp Lys Ser Lys Arg Gly Leu He His Val

   -1 1 5 10 15 cca aaa gac eta ccg ctg aaa ace aaa gtc tta gat atg tct cag aac 253 Pro Lys Asp Leu Pro Leu Lys Thr Lys Val Leu Asp Met Ser Gin Asn 20 25 30 tac ate get gag ctt cag gtc tct gac atg age ttt eta tea gag ttg 301 Tyr He Ala Glu Leu Gin Val Ser Asp Met Ser Phe Leu Ser Glu Leu

   35 40 45 aca gtt ttg aga ctt tec cat aac aga ate cag eta ctt gat tta agt 349

   87 Thr Val Leu Arg Leu Ser His Asn Arg He Gin Leu Leu Asp Leu Ser 50 55 ■ 60 gtt ttc aag ttc aac cag gat tta gaa tat ttg gat tta tct cat aat 397 Val Phe Lys Phe Asn Gin Asp Leu Glu Tyr Leu Asp Leu Ser His Asn 65 70 . 75 cag ttg caa aag ata tec tgc cat cct att gtg agt ttc agg cat tta 445

   Gin Leu Gin Lys He Ser Cys His Pro He Val Ser Phe Arg His Leu 80 ^* 85 90 95 gat etc tea ttc aat gat ttc aag gcc ctg ccc ate tgt aag gaa ttt 493

   Asp Leu Ser Phe Asn Asp Phe Lys Ala Leu Pro He Cys Lys Glu Phe

   100 105 110 ggc aac tta tea caa ctg aat ttc ttg gga ttg agt get atg aag ctg 541

   Gly Asn Leu Ser Gin Leu Asn Phe Leu Gly Leu Ser Ala Met Lys Leu

   115 120 125 caa aaa tta gat ttg ctg cca att get cac ttg cat eta agt tat ate 589

   Gin Lys Leu Asp Leu Leu Pro He Ala His Leu His Leu Ser Tyr He 130 135 140 ctt ctg gat tta aga aat tat tat ata aaa gaa aat gag aca gaa agt 637 Leu Leu Asp Leu Arg Asn Tyr Tyr He Lys Glu Asn Glu Thr Glu Ser 145 150 155 eta caa att ctg aat gca aaa ace ctt cac ctt gtt ttt cac cca act 685

   Leu Gin He Leu Asn Ala Lys Thr Leu His Leu Val Phe His Pro Thr 160 165 170 175 agt tta ttc get ate caa gtg aac ata tea gtt aat act tta ggg tgc 733

   Ser Leu Phe Ala He Gin Val Asn He Ser Val Asn Thr Leu Gly Cys

   180 185 190 tta caa ctg act aat att aaa ttg aat gat gac aac tgt caa gtt ttc J81

   Leu Gin Leu Thr Asn He Lys Leu Asn Asp Asp Asn Cys Gin Val Phe

   195 200 205 att aaa ttt tta tea gaa etc ace aga ggt cca ace tta ctg aat ttt 829

   He Lys Phe Leu Ser Glu Leu Thr Arg Gly Pro Thr Leu Leu Asn Phe 210 215 220 ace etc aac cac ata gaa acg act tgg aaa tgc ctg gtc aga gtc ttt 877 Thr Leu Asn His He Glu Thr Thr Trp Lys Cys Leu Val Arg Val Phe 225 230 235 caa ttt ctt tgg ccc aaa cct gtg gaa tat etc aat att tac aat tta 925

   Gin Phe Leu Trp Pro Lys Pro Val Glu Tyr Leu Asn He Tyr Asn Leu 240 245 250 255 _ aca ata att gaa age att cgt gaa gaa gat ttt act tat tct aaa acg 973

   Thr He He Glu Ser He Arg Glu Glu Asp Phe Thr Tyr Ser Lys Thr

   260 265 270 aca ttg aaa gca ttg aca ata gaa cat ate acg aac caa gtt ttt ctg 1021 Thr Leu Lys Ala Leu Thr He Glu His He Thr Asn Gin Val Phe Leu 275 ^• 280 285

   88 ttt tea cag aca get ttg tac ace gtg ttt tct gag atg aac att atg 1069

   Phe Ser Gin Thr Ala Leu Tyr Thr Val Phe Ser Glu Met Asn He Met

   290 295 300 atg tta ace att tea gat aca cct ttt ata cac_/ ^'atg ctg tgt cct cat 1117

   Met Leu Thr He Ser Asp Thr Pro Phe He His^' Met Leu Cys Pro His

   305 310 ' 315 gca cca age aca ttc^' aag ttt ttg aac ttt ace cag aac gtt ttc aca 1165

   Ala Pro Ser Thr Phe Lys Phe Leu Asn Phe Thr Gin Asn Val Phe Thr

   320 325 330 335 gat agt att ttt gaa aaa tgt tec acg tta gtt aaa ttg gag aca ctt 1213 Asp Ser He Phe Glu Lys Cys Ser Thr Leu Val Lys Leu Glu Thr Leu

   340 345 350 ate tta caa aag aat gga tta aaa gac ctt ttc aaa gta ggt etc atg 1261

   He Leu Gin Lys Asn Gly Leu Lys Asp Leu Phe Lys Val Gly Leu Met 355 360 365 acg aag gat atg cct tct ttg gaa ata ctg gat gtt age tgg aat tct 1309

   Thr Lys Asp Met Pro Ser Leu Glu He Leu Asp Val Ser Trp Asn Ser

   370 375 380 ttg gaa tct ggt aga cat aaa gaa aac tgc act tgg gtt gag agt ata 1357

   Leu Glu Ser Gly Arg His Lys Glu Asn Cys Thr Trp Val Glu Ser He

   385 390 395 gtg gtg tta aat ttg tct tea aat atg ctt act gac tct gtt ttc aga 1405

   Val Val Leu Asn Leu Ser Ser Asn Met Leu Thr Asp Ser Val Phe Arg

   400 405 410 415 tgt tta cct ccc agg ate aag gta ctt gat ctt cac age aat aaa ata 1453 Cys Leu Pro Pro Arg He Lys Val Leu Asp Leu His Ser Asn Lys He

   420 425 430 aag age gtt cct aaa caa gtc gta aaa ctg gaa get ttg caa gaa etc 1501

   Lys Ser Val Pro Lys Gin Val Val Lys Leu Glu Ala Leu Gin Glu Leu 435 440 445 aat. gtt get ttc aat tct tta act gac ctt cct gga tgt ggc age ttt 1549

   Asn Val Ala Phe Asn Ser Leu Thr Asp Leu Pro Gly Cys Gly Ser Phe

   450 455 460 age age ctt tct gta ttg ate att gat cac aat tea gtt tec cac cca 1597

   Ser Ser Leu Ser Val Leu He He Asp His Asn Ser Val Ser His Pro

   465 470 475 teg get gat ttc ttc cag age tgc cag aag atg agg tea ata aaa gca 1645

   Ser Ala Asp Phe Phe Gin Ser Cys Gin Lys Met Arg Ser He Lys Ala

   480 485 490 495 ggg gac aat cca ttc caa tgt ace tgt gag eta aga gaa ttt gtc aaa 1693 Gly Asp Asn Pro Phe Gin Cys Thr Cys Glu Leu Arg Glu Phe Val Lys

   500 505 510 aat ata gac caa gta tea agt gaa gtg tta gag ggc tgg cct gat tct 1741

   89 DX0724XK

   Asn He Asp Gin Val Ser Ser Glu Val Leu Glu Gly Trp Pro Asp Ser 515 520 525 tat aag tgt gac tac cca gaa agt tat aga gga age cca eta aag gac 1789 Tyr Lys Cys Asp Tyr Pro Glu Ser Tyr Arg Gly Ser Pro Leu Lys Asp 530 535 .' 540 ttt cac atg tct gaa tta tec tgc aac ata act ctg ctg ate gtc ace 1837 Phe His Met Ser Glu Leu Ser Cys Asn He Thr Leu Leu He Val Thr 545 ' 550 555 ate ggt gcc ace atg ctg gtg ttg get. gtg act gtg ace tec etc tgc 1885

   He Gly Ala Thr Met Leu Val Leu Ala Val Thr Val Thr Ser Leu Cys 560 565 570 575 ate tac ttg gat ctg ccc tgg tat etc agg atg gtg tgc cag tgg ace 1933

   He Tyr Leu Asp Leu Pro Trp Tyr Leu Arg Met Val Cys Gin Trp Thr 580 585 590 cag act egg cgc agg gcc agg aac ata ccc tta gaa gaa etc caa aga 1981 Gin Thr Arg Arg Arg Ala Arg Asn He Pro Leu Glu Glu Leu Gin Arg 595 600 605 aac etc cag ttt cat get ttt att tea tat agt gaa cat gat tct gcc 2029 Asn Leu Gin Phe His Ala Phe He Ser Tyr Ser Glu His Asp Ser Ala 610 615 620 tgg gtg aaa agt gaa ttg gta cct tac eta gaa aaa gaa gat ata cag 2077 Trp Val Lys Ser Glu Leu Val Pro Tyr Leu Glu Lys Glu Asp He Gin 625 630 635 att tgt ctt cat gag agg aac ttt gtc cct ggc aag age att gtg gaa 2125

   He Cys Leu His Glu Arg Asn Phe Val Pro Gly Lys Ser He Val Glu

   640 645 650 655 aat ate ate aac tgc att gag aag agt tac aag tec ate ttt gtt ttg 2173

   Asn He He Asn Cys He Glu Lys Ser Tyr Lys Ser He Phe Val Leu

   660 665 670 tct ccc aac ttt gtc cag agt gag tgg tgc cat tac gaa etc tat ttt 2221 Ser Pro Asn Phe Val Gin Ser Glu Trp Cys His Tyr Glu Leu Tyr Phe 675 680 685 gcc cat cac aat etc ttt cat gaa gga tct aat aac tta ate etc ate 2269 Ala His His Asn Leu Phe His Glu Gly Ser Asn Asn Leu He Leu He 690 695 700 tta ctg gaa ccc att cca cag aac age att ccc aac aag tac cac aag 2317 Leu Leu Glu Pro He Pro Gin Asn Ser He Pro Asn Lys Tyr His Lys 705 710 715 ctg aag get etc atg acg cag egg act tat ttg cag tgg ccc aag gag 2365 Leu Lys Ala Leu Met Thr Gin Arg Thr Tyr Leu Gin Trp Pro Lys Glu 720 725 730 735 aaa age aaa cgt ggg etc ttt tgg get aac att aga gcc get ttt aat 2413 Lys Ser Lys Arg Gly Leu Phe Trp Ala Asn He Arg Ala Ala Phe Asn 740 745 750

   90 DX0724XK

   atg aaa tta aca eta gtc act gaa aac aat gat gtg aaa tct 2455

   Met Lys Leu Thr Leu Val Thr Glu Asn Asn Asp Val Lys Ser 755 760 765 taaaaaaatt taggaaattc aacttaagaa aceattattt . acttggatga tggtgaatag 2515 taeagtcgta agtnactgte tggaggtgce tccattatce teatgcettc aggaaagact 2575 taacaaaaac aatgtttcat ctggggaact gagctaggcg gtgaggttag cctgccagtt 2635 agagacagec cagtetcttc tggtttaate attatgtttc aaattgaaac agtctctttt 2695 gagtaaatgc tcagtttttc agetcctctc cactctgctt teccaaatgg attctgttgg 2755 tgaag 2760

   <210> 41 <211> 796 <212> PRT <213> Unknown

   <400> 41 Met Thr Lys Asp Lys Glu Pro He Val Lys Ser Phe His Phe Val Cys -30 -25 -20

   Leu Met He He He Val Gly Thr Arg He Gin Phe Ser Asp Gly Asn -15 -10 -5 -1 1

   Glu Phe Ala Val Asp Lys Ser Lys Arg Gly Leu He His Val Pro Lys 5 10 15

   Asp Leu Pro Leu Lys Thr Lys Val Leu Asp Met Ser Gin Asn Tyr He 20 25 30

   Ala Glu Leu Gin Val Ser Asp Met Ser Phe Leu Ser Glu Leu Thr Val

   35 40 45 Leu Arg Leu Ser His Asn Arg He Gin Leu Leu Asp Leu Ser Val Phe

   50 55 60 65

   Lys Phe Asn Gin Asp Leu Glu Tyr Leu Asp Leu Ser His Asn Gin Leu 70 75 80

   Gin Lys He Ser Cys His Pro He Val Ser Phe Arg His Leu Asp Leu 85 90 95

   Ser Phe Asn Asp Phe Lys Ala Leu Pro He Cys Lys Glu Phe Gly Asn 100 105 110

   Leu Ser Gin Leu Asn Phe Leu Gly Leu Ser Ala Met Lys Leu Gin Lys

   115 120 125 Leu Asp Leu Leu Pro He Ala His Leu His Leu Ser Tyr He Leu Leu

   91 150 155 160

   He Leu Asn Ala Lys Thr Leu His Leu Val Phe His Pro Thr Ser Leu 165 170 175

   Phe Ala He Gin Val Asn He Ser Val Asn Thr 'Leu Gly Cys Leu Gin 180 185 ^'' 190

   Leu Thr Asn He Lys Leu Asn Asp Asp Asn Cys Gin Val Phe He Lys 195 ' 200 205

   Phe Leu Ser Glu Leu Thr Arg Gly Pro Thr Leu Leu Asn Phe Thr Leu 210^' 215 220 225 Asn His He Glu Thr Thr Trp Lys Cys Leu Val Arg Val Phe Gin Phe

   230 235 240

   Leu Trp Pro Lys Pro Val Glu Tyr Leu Asn He Tyr Asn Leu Thr He 245 250 255

   He Glu Ser He Arg Glu Glu Asp Phe Thr Tyr Ser Lys Thr Thr Leu 260 265 270

   Lys Ala Leu Thr He Glu His He Thr Asn Gin Val Phe Leu Phe Ser 275 280 285

   Gin Thr Ala Leu Tyr Thr Val Phe Ser Glu Met Asn He Met Met Leu

   290 295 300 305 Thr He Ser Asp Thr Pro Phe He His Met Leu Cys Pro His Ala Pro

   310 315 320

   Ser Thr Phe Lys Phe Leu Asn Phe Thr Gin Asn Val Phe Thr Asp Ser 325 330 335

   He Phe Glu Lys Cys Ser Thr Leu Val Lys Leu Glu Thr Leu He Leu 340 345 350

   Gin Lys Asn Gly Leu Lys Asp Leu Phe Lys Val Gly Leu Met Thr Lys 355 360 365

   Asp Met Pro Ser Leu Glu He Leu Asp Val Ser Trp Asn Ser Leu Glu 370 375 380 385 Ser Gly Arg His Lys Glu Asn Cys Thr Trp Val Glu Ser He Val Val

   390 395 400

   Leu Asn Leu Ser Ser Asn Met Leu Thr Asp Ser Val Phe Arg Cys Leu 405 410 415

   Pro Pro Arg He Lys Val Leu Asp Leu His Ser Asn Lys He Lys Ser 420 425 430

   Val Pro Lys Gin Val Val Lys Leu Glu Ala Leu Gin Glu Leu Asn Val 435 440 445

   Ala Phe Asn Ser Leu Thr Asp Leu Pro Gly Cys Gly Ser Phe Ser Ser

   450 455 460 465

   92 Leu Ser Val Leu He He Asp His Asn Ser Val Ser His Pro Ser Ala 470 475 480 Asp Phe Phe Gin Ser Cys Gin Lys Met Arg Ser He Lys Ala Gly Asp 485 490 495

   Asn Pro Phe Gin Cys Thr Cys Glu Leu Arg Glu Phe Val Lys Asn He 500 505 510

   Asp Gin Val Ser Ser Glu Val Leu Glu Gly Trp Pro Asp Ser Tyr Lys 515 520 525

   Cys Asp Tyr Pro Glu Ser Tyr Arg Gly Ser Pro Leu Lys Asp Phe His 530 535 540 545

   Met Ser Glu Leu Ser Cys Asn He Thr Leu Leu He Val Thr He Gly

   550 555 560 Ala Thr Met Leu Val Leu Ala Val Thr Val Thr Ser Leu Cys He Tyr 565 570 575

   Leu Asp Leu Pro Trp Tyr Leu Arg Met Val Cys Gin Trp Thr Gin Thr 580 585 590

   Arg Arg Arg Ala Arg Asn He Pro Leu Glu Glu Leu Gin Arg Asrr Leu 595 600 605

   Gin Phe His Ala Phe He Ser Tyr Ser Glu His Asp Ser Ala Trp Val 610 615 620 625

   Lys Ser Glu Leu Val Pro Tyr Leu Glu Lys Glu Asp He Gin He Cys 630 635 640 Leu His Glu Arg Asn Phe Val Pro Gly Lys Ser He Val Glu Asn He 645 650 655

   He Asn Cys He Glu Lys Ser Tyr Lys Ser He Phe Val Leu Ser Pro 660 665 670

   Asn Phe Val Gin Ser Glu Trp Cys His Tyr Glu Leu Tyr Phe Ala His 675 680 685

   His Asn Leu Phe His Glu Gly Ser Asn Asn Leu He Leu He Leu Leu 690 695 700 705

   Glu Pro He Pro Gin Asn Ser He Pro Asn Lys Tyr His Lys Leu Lys

   710 715 720 Ala Leu Met Thr Gin Arg Thr Tyr Leu Gin Trp Pro Lys Glu Lys Ser 725 730 735

   Lys Arg Gly Leu Phe Trp Ala Asn He Arg Ala Ala Phe Asn Met Lys 740 745 750

   Leu Thr Leu Val Thr Glu Asn Asn Asp Val Lys Ser 755 760 765

   93 <210> 42 <211> 3168 <212> DNA <213> Unknown

   <220>

   <223> Description of Unknown Organism:primate; surmised Homo sapiens

   <220>

   <221> CDS

   <222> (1) .. (3165) <220>

   <221> mat_ρeptide <222> (144) .. (3165)

   <400> 42 atg ccc atg aag tgg agt ggg tgg agg tgg age tgg ggg ccg gcc act 48

   Met Pro Met Lys Trp Ser Gly Trp Arg Trp Ser Trp Gly Pro Ala Thr -45 -40 -35 cac aca gcc etc cca ccc cca cag ggt ttc tgc cgc age gcc ctg cac 96 His Thr Ala Leu Pro Pro Pro Gin Gly Phe Cys Arg Ser Ala Leu His -30 -25 -20 ccg ctg tct etc ctg gtg cag gcc ate atg ctg gcc atg ace ctg gcc 144 Pro Leu Ser Leu Leu Val Gin Ala He Met Leu Ala Met Thr Leu Ala -15 -10 -5 -1 ctg ggt ace ttg cct gcc ttc eta ccc tgt gag etc cag ccc cac ggc 192

   Leu Gly Thr Leu Pro Ala Phe Leu Pro Cys Glu Leu Gin Pro His Gly

   1 5 10 15 ctg gtg aac tgc aac tgg ctg ttc ctg aag tct gtg ccc cac ttc tec ,,240

   Leu Val Asn Cys Asn Trp Leu Phe Leu Lys Ser Val Pro His Phe Ser

   20 25 30 atg gca gca ccc cgt ggc aat gtc ace age ctt tec ttg tec tec aac 288 Met Ala Ala Pro Arg Gly Asn Val Thr Ser Leu Ser Leu Ser Ser Asn 35 40 45 cgc ate cac cac etc cat gat tct gac ttt gcc cac ctg ccc age ctg 336 Arg He His His Leu His Asp Ser Asp Phe Ala His Leu Pro Ser Leu 50 55 60 egg cat etc aac etc aag tgg aac tgc ccg ccg gtt ggc etc age ccc 384 Arg His Leu Asn Leu Lys Trp Asn Cys Pro Pro Val Gly Leu Ser Pro 65 70 75 80 _^ atg cac ttc ccc tgc cac atg ace ate gag ccc age ace ttc ttg get 432 Met His Phe Pro Cys His Met Thr He Glu Pro Ser Thr Phe Leu Ala 85 90 95 gtg ccc ace ctg gaa gag eta aac ctg age tac aac aac ate atg act 480 Val Pro Thr Leu Glu Glu Leu Asn Leu Ser Tyr Asn Asn He Met Thr 100 • 105 110

   94 gtg cct gcg ctg ccc aaa tec etc ata tec ctg tec etc age cat ace 528

   Val Pro Ala Leu Pro Lys Ser Leu He Ser Leu Ser Leu Ser His Thr

   115 120 125 aac ate ctg atg eta gac tct gcc age etc gcc. ggc ctg cat gcc ctg 576

   Asn He Leu Met Leu Asp Ser Ala^' Ser Leu Ala^' Gly Leu His Ala Leu

   130 135 ' 140 cgc ttc eta ttc atg' gac ggc aac tgt tat tac aag aac ccc tgc agg 624 Arg Phe Leu Phe Met Asp Gly Asn Cys Tyr Tyr Lys Asn Pro Cys Arg 145 150 155 160 cag gca ctg gag gtg gcc ccg ggt gcc etc ctt ggc ctg ggc aac etc 672 Gin Ala Leu Glu Val Ala Pro Gly Ala Leu Leu Gly Leu Gly Asn Leu

   165 170 175 ace cac ctg tea etc aag tac aac aac etc act gtg gtg ccc cgc aac 720 Thr His Leu Ser Leu Lys Tyr Asn Asn Leu Thr Val Val Pro Arg Asn 180 185 190 ctg cct tec age ctg gag tat ctg ctg ttg tec tac aac cgc ate gtc 768

   Leu Pro Ser Ser Leu Glu Tyr Leu Leu Leu Ser Tyr Asn Arg He Val

   195 200 205 aaa ctg gcg cct gag gac ctg gcc aat ctg ace gcc ctg cgt gtg etc 816

   Lys Leu Ala Pro Glu Asp Leu Ala Asr> Leu Thr Ala Leu Arg Val Leu 210 215 220 gat gtg ggc gga aat tgc cgc cgc tgc gac cac get ccc aac ccc tgc 864 Asp Val Gly Gly Asn Cys Arg Arg Cys Asp His Ala Pro Asn Pro Cys 225 230 235 240 atg gag tgc cct cgt cac ttc ccc cag eta cat ccc gat ace ttc age 912 Met Glu Cys Pro Arg His Phe Pro Gin Leu His Pro Asp Thr Phe Ser

   245 250 255 cac ctg age cgt ctt gaa ggc ctg gtg ttg aag gac agt tct etc tec 960 His Leu Ser Arg Leu Glu Gly Leu Val Leu Lys Asp Ser Ser Leu Ser 260 265 270 tgg ctg aat gcc agt tgg ttc cgt ggg ctg gga aac etc cga gtg ctg 1008

   Trp Leu Asn Ala Ser Trp Phe Arg Gly Leu Gly Asn Leu Arg Val Leu

   275 ^• 280 285 gac ctg agt gag aac ttc etc tac aaa tgc ate act aaa ace aag gcc 1056

   Asp Leu Ser Glu Asn Phe Leu Tyr Lys Cys He Thr Lys Thr Lys Ala

   290 295 300 ttc cag ggc eta aca cag ctg cgc aag ctt aac ctg tec ttc aat tac 1104 Phe Gin Gly Leu Thr Gin Leu Arg Lys Leu Asn Leu Ser Phe Asn Tyr 305 310 315 320 caa aag agg gtg tec ttt gcc cac ctg tct ctg gcc cct tec ttc ggg 1152 Gin Lys Arg Val Ser Phe Ala His Leu Ser Leu Ala Pro Ser Phe Gly

   325 330 335 age ctg gtc gcc ctg aag gag ctg gac atg cac ggc ate ttc ttc cgc 1200

   95 Ser Leu Val Ala Leu Lys Glu Leu Asp Met His Gly He Phe Phe Arg 340 345 350 tea etc gat gag ace acg etc egg cca ctg gcc cgc ctg ccc atg etc 1248 Ser Leu Asp Glu Thr Thr Leu Arg Pro Leu Ala Arg Leu Pro Met Leu 355 360 . 365 cag act ctg cgt ctg cag atg aac ttc ate aac cag gcc cag etc ggc 1296 Gin Thr Leu Arg Leu Gin Met Asn Phe He Asn Gin Ala Gin Leu Gly 370 ' 375 380 ate ttc agg gcc ttc cct ggc ctg cgc tac gtg gac ctg teg gac aac 1344

   He Phe Arg Ala Phe Pro Gly Leu Arg Tyr Val Asp Leu Ser Asp Asn

   385 390 395 400 cgc ate age gga get teg gag ctg aca gcc ace atg ggg gag gca gat 1392

   Arg He Ser Gly Ala Ser Glu Leu Thr Ala Thr Met Gly Glu Ala Asp

   405 410 415 gga ggg gag aag gtc tgg ctg cag cct ggg gac ctt get ccg gcc cca 1440 Gly Gly Glu Lys Val Trp Leu Gin Pro Gly Asp Leu Ala Pro Ala Pro 420 425 430 gtg gac act ccc age tct gaa gac ttc agg ccc aac tgc age ace etc 1488 Val Asp Thr Pro Ser Ser Glu Asp Phe Arg Pro Asn Cys Ser Thr Leu 435 440 445 aac ttc ace ttg gat ctg tea egg aac aac ctg gtg ace gtg cag ccg 1536 Asn Phe Thr Leu Asp Leu Ser Arg Asn Asn Leu Val Thr Val Gin Pro 450 455 460 gag atg ttt gcc cag etc teg cac ctg cag tgc ctg cgc ctg age cac 1584

   Glu Met Phe Ala Gin Leu Ser His Leu Gin Cys Leu Arg Leu Ser His

   465 470 475 480 aac tgc ate teg cag gca gtc aat ggc tec cag ttc ctg ccg ctg ace 1632

   Asn Cys He Ser Gin Ala Val Asn Gly Ser Gin Phe Leu Pro Leu Thr 485 490 495 ggt ctg cag gtg eta gac ctg tec cac aat aag ctg gac etc tac cac 1680 Gly Leu Gin Val Leu Asp Leu Ser His Asn Lys Leu Asp Leu Tyr His 500 505 510 gag cac tea ttc acg gag eta cca cga ctg gag gcc ctg gac etc age 1728 Glu His Ser Phe Thr Glu Leu Pro Arg Leu Glu Ala Leu Asp Leu Ser 515 520 525 tac aac age cag ccc ttt ggc atg cag ggc gtg ggc cac aac ttc age 1776 Tyr Asn Ser Gin Pro Phe Gly Met Gin Gly Val Gly His Asn Phe Ser 530 535 540 ttc gtg get cac ctg cgc ace ctg cgc cac etc age ctg gcc cac aac 1824 Phe Val Ala His Leu Arg Thr Leu Arg His Leu Ser Leu Ala His Asn 545 550 555 560 aac ate cac age caa gtg tec cag cag etc tgc agt acg teg ctg egg 1872 Asn He His Ser Gin Val Ser Gin Gin Leu Cys Ser Thr Ser Leu Arg 565 570 575

   96 gcc ctg gac ttc age ggc aat gca ctg ggc cat atg tgg gcc gag gga 1920

   Ala Leu Asp Phe Ser Gly Asn Ala Leu Gly His Met Trp Ala Glu Gly

   580 585 590 gac etc tat ctg cac ttc ttc caa ggc ctg agc'ggt ttg ate tgg ctg 1968

   Asp Leu Tyr Leu His Phe Phe Gin Gly Leu Ser Gly Leu He Trp Leu 595 600 ^■ 605 gac ttg tec cag aad cgc ctg cac ace etc ctg ccc caa ace ctg cgc 2016

   Asp Leu Ser Gin Asn Arg Leu His Thr Leu Leu Pro Gin Thr Leu Arg 610 615 620 aac etc ccc aag age eta cag gtg ctg cgt etc cgt gac aat tac ctg 2064 Asn Leu Pro Lys Ser Leu Gin Val Leu Arg Leu Arg Asp Asn Tyr Leu

   625 630 635 640 gcc ttc ttt aag tgg tgg age etc cac ttc ctg ccc aaa ctg gaa gtc 2112

   Ala Phe Phe Lys Trp Trp Ser Leu His Phe Leu Pro Lys Leu Glu Val 645 650 655 etc gac ctg gca gga aac cag ctg aag gcc ctg ace aat ggc age ctg 2160

   Leu Asp Leu Ala Gly Asn Gin Leu Lys Ala Leu Thr Asn Gly Ser Leu

   660 665 670 cct get ggc ace egg etc egg agg ctg gat gtc age tgc aac age ate 2208

   Pro Ala Gly Thr Arg Leu Arg Arg Leu Asp Val Ser Cys Asn Ser He 675 680 685 age ttc gtg gcc ccc ggc ttc ttt tec aag gcc aag gag ctg cga gag 2256

   Ser Phe Val Ala Pro Gly Phe Phe Ser Lys Ala Lys Glu Leu Arg Glu 690 695 700 etc aac ctt age gcc aac gcc etc aag aca gtg gac cac tec tgg ttt 2304 Leu Asn Leu Ser Ala Asn Ala Leu Lys Thr Val Asp His Ser Trp Phe

   705 710 715 720 ggg ccc ctg gcg agt gcc ctg caa ata eta gat gta age gcc aac cct 2352

   Gly Pro Leu Ala Ser Ala Leu Gin He Leu Asp Val Ser Ala Asn Pro 725 730 735 ctg cac tgc gcc tgt ggg gcg gcc ttt atg gac ttc ctg ctg gag gtg 2400

   Leu His Cys Ala Cys Gly Ala Ala Phe Met Asp Phe Leu Leu Glu Val

   740 745 750 cag get gcc gtg ccc ggt ctg ccc age egg gtg aag tgt ggc agt ccg 2448 Gin Ala Ala Val Pro Gly Leu Pro Ser Arg Val Lys Cys Gly Ser Pro 755 760 765 ggc cag etc cag ggc etc age ate ttt gca cag gac ctg cgc etc tgc 2496 Gly Gin Leu Gin Gly Leu Ser He Phe Ala Gin Asp Leu Arg Leu Cys 770 775^' 780 ctg gat gag gcc etc tec tgg gac tgt ttc gcc etc teg ctg ctg get 2544 Leu Asp Glu Ala Leu Ser Trp Asp Cys Phe Ala Leu Ser Leu Leu Ala

   785 790 795 800 gtg get ctg ggc ctg ggt gtg ccc atg ctg cat cac etc tgt ggc tgg 2592

   97 Val Ala Leu Gly Leu Gly Val Pro Met Leu His His Leu Cys Gly Trp

   805 810 815 gac etc tgg tac tgc ttc cac ctg tgc ctg gcc tgg ctt ccc tgg egg 2640 Asp Leu Trp Tyr Cys Phe His Leu Cys Leu Ala Trp Leu Pro Trp Arg

   820 825 .' 830 ggg egg caa agt ggg cga gat gag gat gcc ctg ccc tac gat gcc ttc 2688

   Gly Arg Gin Ser Gly Arg Asp Glu Asp Ala Leu Pro Tyr Asp Ala Phe 835 ' _^ 840 845 gtg gtc ttc gac aaa acg cag age gca gtg gca gac tgg gtg tac aac 2736

   Val Val Phe Asp Lys Thr Gin Ser Ala Val Ala Asp Trp Val Tyr Asn

   850 855 860 gag ctt egg ggg cag ctg gag gag tgc cgt ggg cgc tgg gca etc cgc 2784

   Glu Leu Arg Gly Gin Leu Glu Glu Cys Arg Gly Arg Trp Ala Leu Arg

   865 870 875 880 ctg tgc ctg gag gaa cgc gac tgg ctg cct ggc aaa ace etc ttt gag 2832

   Leu Cys Leu Glu Glu Arg Asp Trp Leu Pro Gly Lys Thr Leu Phe Glu

   885 890 895 aac ctg tgg gcc teg gtc tat ggc age cgc aag acg ctg ttt gtg ctg 2880 Asn Leu Trp Ala Ser Val Tyr Gly Ser Arg Lys Thr Leu Phe Val Leu

   900 905 910 gcc cac acg gac egg gtc agt ggt etc ttg cgc gcc age ttc ctg ctg 2928

   Ala His Thr Asp Arg Val Ser Gly Leu Leu Arg Ala Ser Phe Leu Leu 915 920 925 gcc cag cag cgc ctg ctg gag gac cgc aag gac gtc gtg gtg ctg gtg 2976

   Ala Gin Gin Arg Leu Leu Glu Asp Arg Lys Asp Val Val Val Leu Val

   930 935 940 ate ctg age cct gac ggc cgc cgc tec cgc tat gtg egg ctg cgc cag 3024

   He Leu Ser Pro Asp Gly Arg Arg Ser Arg Tyr Val Arg Leu Arg Gin

   945 950 955 960 cgc etc tgc cgc cag agt gtc etc etc tgg ccc cac cag ccc agt ggt 3072

   Arg Leu Cys Arg Gin Ser Val Leu Leu Trp Pro His Gin Pro Ser Gly

   965 970 975 cag cgc age ttc tgg gcc cag ctg ggc atg gcc ctg ace agg gac aac 3120 Gin Arg Ser Phe Trp Ala Gin Leu Gly Met Ala Leu Thr Arg Asp Asn

   980 985 990 cac cac ttc tat aac egg aac ttc tgc cag gga ccc 'acg gcc gaa tag 3168

   His His Phe Tyr Asn Arg Asn Phe Cys Gin Gly Pro Thr Ala Glu 995 1000 1005

   <210> 43

   <211> 1055

   <212> PRT

   <213> Unknown

   <400> 43

   98 Met Pro Met Lys Trp Ser Gly Trp Arg Trp Ser Trp Gly Pro Ala Thr - 45 -40 -35

   His Thr Ala Leu Pro Pro Pro Gin Gly Phe Cys Arg Ser Ala Leu His -30 -25 -20

   Pro Leu Ser Leu Leu Val Gin Ala He Met Leu Ala Met Thr Leu Ala -15 -10 ' -5 -1 Leu Gly Thr Leu Pro' Ala Phe Leu Pro Cys Glu Leu Gin Pro His Gly 1 5 10 15

   Leu Val Asn Cys Asn Trp Leu Phe Leu Lys Ser Val Pro His Phe Ser 20 25 30

   Met Ala Ala Pro Arg Gly Asn Val Thr Ser Leu Ser Leu Ser Ser Asn 35 40 45

   Arg He His His Leu His Asp Ser Asp Phe Ala His Leu Pro Ser Leu 50 . 55 ^'60

   Arg His Leu Asn Leu Lys Trp Asn Cys Pro Pro Val Gly Leu Ser Pro

   65 70 75 80 Met His Phe Pro Cys His Met Thr He Glu Pro Ser Thr Phe Leu Ala

   85 90 95

   Val Pro Thr Leu Glu Glu Leu Asn Leu Ser Tyr Asn Asn He Met Thr 100 105 110

   Val Pro Ala Leu Pro Lys Ser Leu He. Ser Leu Ser Leu Ser His Thr 115 120 125

   Asn He Leu Met Leu Asp Ser Ala Ser Leu Ala Gly Leu His Ala Leu 130 135 140

   Arg Phe Leu Phe Met Asp Gly Asn Cys Tyr Tyr Lys Asn Pro Cys Arg 145 150 155 160 Gin Ala Leu Glu Val Ala Pro Gly Ala Leu Leu Gly Leu Gly Asn Leu

   165 170 175

   Thr His Leu Ser Leu Lys Tyr Asn Asn Leu Thr Val Val Pro Arg Asn 180 185 190

   Leu Pro Ser Ser Leu Glu Tyr Leu Leu Leu Ser Tyr Asn Arg He Val 195 200 205

   Lys Leu Ala Pro Glu Asp Leu Ala Asn Leu Thr Ala Leu Arg Val Leu 210 215 220

   Asp Val Gly Gly Asn Cys Arg Arg Cys Asp His Ala Pro Asn Pro Cys

   225 230 235 240 Met Glu Cys Pro Arg His Phe Pro Gin Leu His Pro Asp Thr Phe Ser

   245 250 255

   His Leu Ser Arg Leu Glu Gly -Leu Val Leu Lys Asp Ser Ser Leu Ser

   99 260 265 270

   Trp Leu Asn Ala Ser Trp Phe Arg Gly Leu Gly Asn Leu Arg Val Leu 275 280 285

   Asp Leu Ser Glu Asn Phe Leu Tyr Lys Cys He Thr Lys Thr Lys Ala 290 295 ^{' ''} 300

   Phe Gin Gly Leu Thr Gin Leu Arg Lys Leu Asn Leu Ser Phe Asn Tyr 305 ' 310 315 320

   Gin Lys Arg Val Ser Phe Ala His Leu Ser Leu Ala Pro Ser Phe Gly 325 330 335 Ser Leu Val Ala Leu Lys Glu Leu Asp Met His Gly He Phe Phe Arg 340 345 350

   Ser Leu Asp Glu Thr Thr Leu Arg Pro Leu Ala Arg Leu Pro Met Leu 355 360 365

   Gin Thr Leu Arg Leu Gin Met Asn Phe He Asn Gin Ala Gin Leu Gly 370 375 380

   He Phe Arg Ala Phe Pro Gly Leu Arg Tyr Val Asp Leu Ser Asp Asn 385 390 395 400

   Arg He Ser Gly Ala Ser Glu Leu Thr Ala Thr Met Gly Glu Ala Asp 405 410 415 Gly Gly Glu Lys Val Trp Leu Gin Pro Gly Asp Leu Ala Pro Ala Pro

   420 425 430

   Val Asp Thr Pro Ser Ser Glu Asp Phe Arg Pro Asn Cys Ser Thr Leu 435 440 445

   Asn Phe Thr Leu Asp Leu Ser Arg Asn Asn Leu Val Thr Val Gin Pro 450 455 460

   Glu Met Phe Ala Gin Leu Ser His Leu Gin Cys Leu Arg Leu Ser His 465 470 475 480

   Asn Cys He Ser Gin Ala Val Asn Gly Ser Gin Phe Leu Pro Leu Thr

   485 490 495 Gly Leu Gin Val Leu Asp Leu Ser His Asn Lys Leu Asp Leu Tyr His 500 505 510

   Glu His Ser Phe Thr Glu Leu Pro Arg Leu Glu Ala Leu Asp Leu Ser 515 520 525

   Tyr Asn Ser Gin Pro Phe Gly Met Gin Gly Val Gly His Asn Phe Ser 530 535 540

   Phe Val Ala His Leu Arg Thr Leu Arg His Leu Ser Leu Ala His Asn 545 550 555 560

   Asn He His Ser Gin Val Ser Gin Gin Leu Cys Ser Thr Ser Leu Arg

   565 570 575

   100 Ala Leu Asp Phe Ser Gly Asn Ala Leu Gly His Met Trp Ala Glu Gly 580 585 590

   Asp Leu Tyr Leu His Phe Phe Gin Gly Leu Ser Gly Leu He Trp Leu 595 600 ^■' 605

   Asp Leu Ser Gin Asn Arg Leu His Thr Leu Leu Pro Gin Thr Leu Arg 610 615 620

   Asn Leu Pro Lys Ser Leu Gin Val Leu Arg Leu Arg Asp Asn Tyr Leu 625 630 635 640

   Ala Phe Phe Lys Trp Trp Ser Leu His Phe Leu Pro Lys Leu Glu Val 645 650 655

   Leu Asp Leu Ala Gly Asn Gin Leu Lys Ala Leu Thr Asn Gly Ser Leu

   660 665 670 Pro Ala Gly Thr Arg Leu Arg Arg Leu Asp Val Ser Cys Asn Ser He

   675 680 685

   Ser Phe Val Ala Pro Gly Phe Phe Ser Lys Ala Lys Glu Leu Arg Glu 690 695 700

   Leu Asn Leu Ser Ala Asn Ala Leu Lys Thr Val Asp His Ser Trp Phe 705 710 715 720

   Gly Pro Leu Ala Ser Ala Leu Gin He Leu Asp Val Ser Ala Asn Pro 725 730 735

   Leu His Cys Ala Cys Gly Ala Ala Phe Met Asp Phe Leu Leu Glu Val

   740 745 750 Gin Ala Ala Val Pro Gly Leu Pro Ser Arg Val Lys Cys Gly Ser Pro 755 760 765

   Gly Gin Leu Gin Gly Leu Ser He Phe Ala Gin Asp Leu Arg Leu Cys

   770 775 780

   Leu Asp Glu Ala Leu Ser Trp Asp Cys Phe Ala Leu Ser Leu Leu Ala

   785 790 795 800

   Val Ala Leu Gly Leu Gly Val Pro Met Leu His His Leu Cys Gly Trp 805 810 815

   Asp Leu Trp Tyr Cys Phe His Leu Cys Leu Ala Trp Leu Pro Trp Arg 820 825 830 Gly Arg Gin Ser Gly Arg Asp Glu Asp Ala Leu Pro Tyr Asp Ala Phe

   835 840 845

   Val Val Phe Asp Lys Thr Gin Ser Ala Val Ala Asp Trp Val Tyr Asn 850 855 860

   Glu Leu Arg Gly Gin Leu Glu Glu Cys Arg Gly Arg Trp Ala Leu Arg

   865 870 875 880

   101 Leu Cys Leu Glu Glu Arg Asp Trp Leu Pro Gly Lys Thr Leu Phe Glu 885 890 895

   Asn Leu Trp Ala Ser Val Tyr Gly Ser Arg Lys Thr Leu Phe Val Leu 900 905 910

   Ala His Thr Asp Arg Val Ser Gly Leu Leu Arg Ala Ser Phe Leu Leu 915 920 ^• 925 Ala Gin Gin Arg Le Leu Glu Asp Arg Lys Asp Val Val Val Leu Val 930 935 940

   He Leu Ser Pro Asp Gly Arg Arg Ser Arg Tyr Val Arg Leu Arg Gin 945 950 955 960

   Arg Leu Cys Arg Gin Ser Val Leu Leu Trp Pro His Gin Pro Ser Gly 965 970 975

   Gin Arg Ser Phe Trp Ala Gin Leu Gly Met Ala Leu Thr Arg Asp Asn 980 985 990

   His His Phe Tyr Asn Arg Asn Phe Cys Gin Gly Pro Thr Ala Glu 995 1000 1005

   <210> 44

   <211> 2289

   <212> DNA

   <213> Unknown

   <220>

   <223> Description of Unknown Organism: rodent; surmised Mus musculus <220>

   <221> CDS

   <222> (1)..(2079)

   <400> 44 aac ctg tec ttc aat tac cgc aag aag gta tec ttt gcc cgc etc cac 48

   Asn Leu Ser Phe Asn Tyr Arg Lys Lys Val Ser Phe Ala Arg Leu His 1 5 10 15 ctg gca agt tec ttt aag aac ctg gtg tea ctg cag gag ctg aac atg 96 Leu Ala Ser Ser Phe Lys Asn Leu Val Ser Leu Gin Glu Leu Asn Met

   20 25 30 aac ggc ate ttc ttc cgc ttg etc aac aag tac acg etc aga tgg ctg 144 Asn Gly He Phe Phe Arg Leu Leu Asn Lys Tyr Thr Leu Arg Trp Leu 35 40 45 gcc gat ctg ccc aaa etc cac act ctg cat ctt caa atg aac ttc ate 192 Ala Asp Leu Pro Lys Leu His Thr Leu His Leu Gin Met Asn Phe He 50 55 60 aac cag gca cag etc age ate ttt ggt ace ttc cga gcc ctt cgc ttt 240 Asn Gin Ala Gin Leu Ser He Phe Gly Thr Phe Arg Ala Leu Arg Phe 65 70 75 80

   102 gtg gac ttg tea gac aat cgc ate agt ggg cct tea acg ctg tea gaa 288

   Val Asp Leu Ser Asp Asn Arg He Ser Gly Pro Ser Thr Leu Ser Glu

   85 90 95 gcc ace cct gaa gag gca gat gat gca gag cag.'gag gag ctg ttg tct 336

   Ala Thr Pro Glu Glu Ala Asp Asp Ala Glu Gin^' Glu Glu Leu Leu Ser

   100 ^' 105 ' 110 gcg gat cct cac cca' get ccg ctg age ace cct get tct aag aac ttc 384

   Ala Asp Pro His Pro Ala Pro Leu Ser Thr Pro Ala Ser Lys Asn Phe

   115 120 125 atg gac agg tgt aag aac ttc aag ttc aac atg gac ctg tct egg aac 432 Met Asp Arg Cys Lys Asn Phe Lys Phe Asn Met Asp Leu Ser Arg Asn

   130 135 140 aac ctg gtg act ate aca gca gag atg ttt gta aat etc tea cgc etc 480

   Asn Leu Val Thr He Thr Ala Glu Met Phe Val Asn Leu Ser Arg Leu 145 150 155 160 cag tgt ctt age ctg age cac aac tea att gca cag get gtc aat ggc 528

   Gin Cys Leu Ser Leu Ser His Asn Ser He Ala Gin Ala Val Asn Gly

   165 170 175 tct cag ttc ctg ccg ctg ace ggt ctg cag gtg eta gac ctg tec cac 576

   Ser Gin Phe Leu Pro Leu Thr Gly Leu Gin Val Leu Asp Leu Ser His

   180 185 190 aat aag ctg gac etc tac cac gag cac tea ttc acg gag eta cca cga 624

   Asn Lys Leu Asp Leu Tyr His Glu His Ser Phe Thr Glu Leu Pro Arg

   195 200 205 ctg gag gcc ctg gac etc age tac aac age cag ccc ttt age atg aag 672 Leu Glu Ala Leu Asp Leu Ser Tyr Asn Ser Gin Pro Phe Ser Met Lys

   210 215 220 ggt ata ggc cac aat ttc agt ttt gtg ace cat ctg tec atg eta cag 720

   Gly He Gly His Asn Phe Ser Phe Val Thr His Leu Ser Met Leu Gin 225 230 235 240 age ctt age ctg gca cac aat gac att cat ace cgt gtg tec tea cat 768

   Ser Leu Ser Leu Ala His Asn Asp He His Thr Arg Val Ser Ser His

   245 250 255 etc aac age aac tea gtg agg ttt ctt gac ttc age ggc aac ggt atg 816

   Leu Asn Ser Asn Ser Val Arg Phe Leu Asp Phe Ser Gly Asn Gly Met

   260 265 270 ggc cgc atg tgg gat gag ggg ggc ctt tat etc cat ttc ttc caa ggc 864

   Gly Arg Met Trp Asp Glu Gly Gly Leu Tyr Leu His Phe Phe Gin Gly

   275 280 285 ctg agt ggc gtg ctg aag ctg gac ctg tct caa aat aac ctg cat ate 912 Leu Ser Gly Val Leu Lys Leu Asp Leu Ser Gin Asn Asn Leu His He

   290 295 300 etc egg ccc cag aac ctt gac aac etc ccc aag age ctg aag ctg ctg 960

   103 Leu Arg Pro Gin Asn Leu Asp Asn Leu Pro Lys Ser Leu Lys Leu Leu 305 310 315 320 age etc cga gac aac tac eta tct ttc ttt aac tgg ace agt ctg tec 1008 Ser Leu Arg Asp Asn Tyr Leu Ser Phe Phe Asn Trp Thr Ser Leu Ser

   325 330 . 335 ttc eta ccc aac ctg gaa gtc eta gac ctg gca ggc aac cag eta aag 1056 Phe Leu Pro Asn Leu Glu Val Leu Asp Leu Ala Gly Asn Gin Leu Lys 340 ' 345 350 gcc ctg ace aat ggc ace ctg cct aat ggc ace etc etc cag aaa etc 1104

   Ala Leu Thr Asn Gly Thr Leu Pro Asn Gly Thr Leu Leu Gin Lys Leu 355 360 365 gat gtc agt age aac agt ate gtc tct gtg gcc ccc ggc ttc ttt tec 1152

   ^*Asp Val Ser Ser Asn Ser He Val Ser Val Ala Pro Gly Phe Phe Ser 370 375 380 aag gcc aag gag ctg cga gag etc aac ctt age gcc aac gcc etc aag 1200 Lys Ala Lys Glu Leu Arg Glu Leu Asn LeU Ser Ala Asn Ala Leu Lys 385 390 395 400 aca gtg gac cac tec tgg ttt ggg ccc att gtg atg aac ctg aca gtt 1248 Thr Val Asp His Ser Trp Phe Gly Pro He Val Met Asn Leu Thr Val

   405 410 415^* eta gac gtg aga age aac cct ctg cac tgt gcc tgt ggg gca gcc ttc 1296 Leu Asp Val Arg Ser Asn Pro Leu His Cys Ala Cys Gly Ala Ala Phe 420 425 430 gta gac tta ctg ttg gag gtg cag ace aag gtg cct ggc ctg get aat 1344

   Val Asp Leu Leu Leu Glu Val Gin Thr Lys Val Pro Gly Leu Ala Asn

   435 440 445 ggt gtg aag tgt ggc age ccc ggc cag ctg cag ggc cgt age ate ttc ^•» 1392

   Gly Val Lys Cys Gly Ser Pro Gly Gin Leu Gin Gly Arg Ser He Phe 450 455 460 gcg cag gac ctg egg ctg tgc ctg gat gag gtc etc tct tgg gac tgc 1440 Ala Gin Asp Leu Arg Leu Cys Leu Asp Glu Val Leu Ser Trp Asp Cys 465 470 475 480 ttt ggc ctt tea etc ttg get gtg gcc gtg ggc atg gtg gtg cct ata 1488^" Phe Gly Leu Ser Leu Leu Ala Val Ala Val Gly Met Val Val Pro He

   485 490 495 ctg cac cat etc tgc ggc tgg gac gtc tgg tac tgt ttt cat ctg tgc 1536 Leu His His Leu Cys Gly Trp Asp Val Trp Tyr Cys Phe His Leu Cys 500 505 510 ctg gca tgg eta cct ttg eta gcc cgc age cga cgc age gcc caa act 1584 Leu Ala Trp Leu Pro Leu Leu Ala Arg Ser Arg Arg Ser Ala Gin Thr 515 520 525 etc cct tat gat gcc ttc gtg gtg ttc gat aag gca cag age gca gtt 1632 Leu Pro Tyr Asp Ala Phe Val Val Phe Asp Lys Ala Gin Ser Ala Val 530 535 ^■ 540

   104 gcc gac tgg gtg tat aac gag ctg egg gtg egg ctg gag gag egg cgc 1680

   Ala Asp Trp Val Tyr Asn Glu Leu Arg Val Arg Leu Glu Glu Arg Arg

   545 550 555 560 ggc cgc tgg gca etc cgc ctg tgc ctg gag gac cga gat tgg ctg cct 1728

   Gly Arg Trp Ala Leu Arg Leu Cys ^"Leu Glu Asp Arg Asp Trp Leu Pro 565 570 ' 575 ggc cag acg etc ttc gag aac etc tgg get tec ate tat ggg age cgc 1776

   Gly Gin Thr Leu Phe Glu Asn Leu Trp Ala Ser He Tyr Gly Ser Arg 580 585 590 aag act eta ttt gtg ctg gcc cac acg gac cgc gtc agt ggc etc ctg 1824 Lys Thr Leu Phe Val Leu Ala His Thr Asp Arg Val Ser Gly Leu Leu 595 600 605 cgc ace age ttc ctg ctg get cag cag cgc ctg ttg gaa gac cgc aag 1872

   Arg Thr Ser Phe Leu Leu Ala Gin Gin Arg Leu Leu Glu Asp Arg Lys 610 615 620 gac gtg gtg gtg.ttg gtg ate ctg cgt ccg gat gcc cac cgc tec cgc 1920

   Asp Val Val Val Leu Val He Leu Arg Pro Asp Ala His Arg Ser Arg

   625 630 635 640 tat gtg cga ctg cgc cag cgt etc tgc cgc cag agt gtg etc ttc tgg 1968

   Tyr Val Arg Leu Arg Gin Arg Leu Cys Arg Gin Ser Val Leu Phe Trp 645 650 655 ccc cag cag ccc aac ggg cag ggg ggc ttc tgg gcc cag ctg agt aca 2016

   Pro Gin Gin Pro Asn Gly Gin Gly Gly Phe Trp Ala Gin Leu Ser Thr 660 665 670 gcc ctg act agg gac aac cgc cac ttc tat aac cag aac ttc tgc egg 2064 Ala Leu Thr Arg Asp Asn Arg His Phe Tyr Asn Gin Asn Phe Cys Arg 675 680 685 gga cct aca gca gaa tagctcagag caacagctgg aaacagctgc atcttcatgt 2119 G-ly Pro Thr Ala Glu 690 ctggttcceg agttgctctg cctgecttgc tctgtettac tacaccgcta tttggcaagt 2179 gegcaatata tgctaceaag 'ccaecaggce eaeggagcaa aggttggctg taaagggtag 2239 ttttcttccc atgcatcttt caggagagtg aagatagaca ccaaacccac 2289

   <210> 45 <211> 693

   <212> PRT

   <213> Unknown

   <400> 45 Asn Leu Ser Phe Asn Tyr Arg Lys Lys Val Ser Phe Ala Arg Leu His 1 " 5 10 15

   Leu Ala Ser Ser Phe Lys Asn Leu Val Ser Leu Gin Glu Leu Asn Met

   105 20 25 30

   Asn Gly He Phe Phe Arg Leu Leu Asn Lys Tyr Thr Leu Arg Trp Leu 35 40 45

   Ala Asp Leu Pro Lys Leu His Thr Leu His Leu 'Gin Met Asn Phe He 50 55 60

   Asn Gin Ala Gin Leu Ser He Phe Gly Thr Phe Arg Ala Leu Arg Phe 65 ^' 70 75 80

   Val Asp Leu Ser Asp Asn Arg He Ser Gly Pro Ser Thr Leu Ser Glu 85 ^• 90 95 Ala Thr Pro Glu Glu Ala Asp Asp Ala Glu Gin Glu Glu Leu Leu Ser 100 105 110

   Ala Asp Pro His Pro Ala Pro Leu Ser Thr Pro Ala Ser Lys Asn Phe 115 120 125

   Met Asp Arg Cys Lys Asn Phe Lys Phe Asn Met Asp Leu Ser Arg Asn 130 135 140

   Asn Leu Val Thr He Thr Ala Glu Met Phe Val Asn Leu Ser Arg Leu 145 150 ^J) 160

   Gin Cys Leu Ser Leu Ser His Asn Ser He Ala Gin Ala Val Asn Gly

   165 170 175 Ser Gin Phe Leu Pro Leu Thr Gly Leu Gin Val Leu Asp Leu Ser His 180 185 190

   Asn Lys Leu Asp Leu Tyr His Glu His Ser Phe Thr Glu Leu Pro Arg 195 200 205

   Leu Glu Ala Leu Asp Leu Ser Tyr Asn Ser Gin Pro Phe Ser Met Lys 210 215 220

   Gly He Gly His Asn Phe Ser Phe Val Thr His Leu Ser Met Leu Gin 225 230 235 . 240

   Ser Leu Ser Leu Ala His Asn Asp He His Thr Arg Val Ser Ser His

   245 250 255 Leu Asn Ser Asn Ser Val Arg Phe Leu Asp Phe Ser Gly Asn Gly Met 260 265 270

   Gly Arg Met Trp Asp Glu Gly Gly Leu Tyr Leu His Phe Phe Gin Gly 275 280 285

   Leu Ser Gly Val Leu Lys Leu Asp Leu Ser Gin Asn Asn Leu His He 290 295 300

   Leu Arg Pro Gin Asn Leu Asp Asn Leu Pro Lys Ser Leu Lys Leu Leu 305 310 315 320

   Ser Leu Arg Asp Asn Tyr Leu Ser Phe Phe Asn Trp Thr Ser Leu Ser

   325 330 335

   106 Phe Leu Pro Asn Leu Glu Val Leu Asp Leu Ala Gly Asn Gin Leu Lys 340 345 350

   Ala Leu Thr Asn Gly Thr Leu Pro Asn Gly Thr Leu Leu Gin Lys Leu 355 360 365

   Asp Val Ser Ser Asn Ser He Val Ser Val Ala Pro Gly Phe Phe Ser 370 375 380

   Lys Ala Lys Glu Leu Arg Glu Leu Asn Leu Ser Ala Asn Ala Leu Lys 385 390 395 400

   Thr Val Asp His Ser Trp Phe Gly Pro He Val Met Asn Leu Thr Val 405 410 415

   Leu Asp Val Arg Ser Asn Pro Leu His Cys Ala Cys Gly Ala Ala Phe 420 425 430 Val Asp Leu Leu Leu Glu Val Gin Thr Lys Val Pro Gly Leu Ala Asn 435 440 445

   Gly Val Lys Cys Gly Ser Pro Gly Gin Leu Gin Gly Arg Ser He Phe 450 455 460

   Ala Gin Asp Leu Arg Leu Cys Leu Asp Glu Val Leu Ser Trp Asp Cys 465 470 475 480

   Phe Gly Leu Ser Leu Leu Ala Val Ala Val Gly Met Val Val Pro He 485 490 495

   Leu His His Leu Cys Gly Trp Asp Val Trp Tyr Cys Phe His Leu Cys 500 505 510 Leu Ala Trp Leu Pro Leu Leu Ala Arg Ser Arg Arg Ser Ala Gin Thr 515 520 525

   Leu Pro Tyr Asp Ala Phe Val Val Phe Asp Lys Ala Gin Ser Ala Val 530 535 540

   Ala Asp Trp Val Tyr Asn Glu Leu Arg Val Arg Leu Glu Glu Arg Arg 545 550 555 560

   Gly Arg Trp Ala Leu Arg Leu Cys Leu. Glu Asp Arg Asp Trp Leu Pro 565 570 575

   Gly Gin Thr Leu Phe Glu Asn Leu Trp Ala Ser He Tyr Gly Ser Arg 580 585 590 Lys Thr Leu Phe Val Leu Ala His Thr Asp Arg Val Ser Gly Leu Leu 595 600 605

   Arg Thr Ser Phe Leu Leu Ala Gin Gin Arg Leu Leu Glu Asp Arg Lys 610 615 620

   Asp Val Val Val Leu Val He Leu Arg Pro Asp Ala His Arg Ser Arg

   625 630 635 640

   107 Tyr Val Arg Leu Arg Gin Arg Leu Cys Arg Gin Ser Val Leu Phe Trp 645 650 655

   Pro Gin Gin Pro Asn Gly Gin Gly Gly Phe Trp Ala Gin Leu Ser Thr 660 665 670

   Ala Leu Thr Arg Asp Asn Arg His Phe Tyr Asn Gin Asn Phe Cys Arg 675 680 ' 685 Gly Pro Thr Ala Glu 690

   108