AU782108B2 - Human 7TM proteins receptors and polynucleotides encoding the same - Google Patents

Description

WO 01/18207 PCT/US00/24591 HUMAN 7TM PROTEIN RECEPTORS AND POLYNUCLEOTIDES ENCODING THE SAME The present invention claims priority to U.S. Provisional Applications Ser. Nos. 60/153.366, filed 9/10/99 and 60/165,510, filed 11/15/99 which are herein incorporated by reference in their entirety.

1. INTRODUCTION The present invention relates to the discovery, identification and characterization of novel human polynucleotides that encode proteins and membrane associated receptors. The invention encompasses the described polynucleotides, host cell expression systems, the encoded proteins, fusion proteins, polypeptides and peptides, antibodies to the encoded proteins and peptides, and genetically engineered animals that lack the disclosed genes, or over express the disclosed sequences, or antagonists and agonists of the proteins, and other compounds that modulate the expression or activity of the proteins encoded by the disclosed genes that can be used for diagnosis, drug screening, clinical trial monitoring, and/or the treatment of physiological or behavioral disorders.

2. BACKGROUND OF THE INVENTION Membrane receptor proteins are integral components of the mechanism through which cells sense their surroundings, regulate cellular functions, and maintain physiological homeostasis. Accordingly, membrane receptor proteins are often involved in signal transduction pathways that control cell physiology, chemical communication, and gene expression.

A particularly relevant class of membrane receptors are those typically characterized by the presence of 7 conserved transmembrane domains that are interconnected by nonconserved hydrophilic loops. Such, "7TM receptors" include a superfamily of receptors known as G-protein coupled receptors (GPCRs). GPCRs are typically involved in signal transduction pathways involving G-proteins. As such, the GPCR family WO 01/18207 PCT/US00/24591 includes many receptors that are known to serve as drug targets for therapeutic agents.

3. SUMMARY OF THE INVENTION The present invention relates to the discovery, identification and characterization of nucleotides that encode novel GPCRs, and the corresponding amino acid sequences of the novel GPCRs. The GPCRs described for the first time herein, are transmembrane proteins that span the cellular membrane and are involved in signal transduction after ligand binding. The described GPCRs have structural motifs found in the 7TM receptor family. The GPCR mRNA transcripts are expressed, inter alia, in placenta, lung, kidney, liver, and pancreas, cells, among others. The novel human GPCRs described herein, encode proteins of 1,250, 1,221, 718, 1,112, 1,249, 1,220, 717, 1,111, 1,250, 1,221, 718, 1,112, 541, 512, 8, 403, 1,222, 1,193, 690, 1,084, 1,221, 1,192, 689, 1,083, 1,222, 1,193, 690, 1,084, and 1,192 amino acids in length (see SEQ ID NOS: 2, 4, 6, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, and 58 respectively). The described GPCRs have the characteristic seven transmembrane regions (of about 20-30 amino acids), as well as several predicted cytoplasmic domains. As evidenced by the alternative 5' regions, and splice junctions of the open reading frames presented in the Sequence Listing, the transcription of the described novel GPCRs can apparently initiate from one of several different promoters present within the genome. Depending on which promoter is used, the described novel GPCRs (NGPCRs) can have one of several distinct amino acid sequences at or near the amino terminal region of the protein.

Additionally contemplated are murine homologs of the described NGPCRs and corresponding "knockout" ES cells that are produced using conventional methods (see, for example, PCT Applic. No. PCT/US98/03243, filed February 20, 1998, herein incorporated by reference). Accordingly, an additional aspect of the present invention includes knockout cells and animals WO 01/18207 PCT/US00/24591 having genetically engineered mutations in the gene(s) encoding the presently described NGPCRs.

The invention encompasses the nucleotides presented in the Sequence Listing, host cells expressing such nucleotides, the expression products of such nucleotides, and: (a) nucleotides that encode mammalian homologs of the described NGPCRs, including the specifically described human NGPCRs, and the human NGPCR gene products; nucleotides that encode one or more portions of the NGPCRs that correspond to functional domains, and the polypeptide products specified by such nucleotide sequences, including but not limited to the novel regions of the described extracellular domain(s) (ECD), one or more transmembrane domain(s) (TM) first disclosed herein, and the cytoplasmic domain(s) isolated nucleotides that encode mutants, engineered or naturally occurring, of the described NGPCRs in which all or a part of at least one of the domains is deleted or altered, and the polypeptide products specified by such nucleotide sequences, including but not limited to soluble receptors in which all or a portion of the TM is deleted, and nonfunctional receptors in which all or a portion of the CD is deleted; nucleotides that encode fusion proteins containing the coding region from an NGPCR, or one of its domains an extracellular domain) fused to another peptide or polypeptide.

The invention also encompasses agonists and antagonists of the NGPCRs, including small molecules, large molecules, mutant NGPCR proteins, or portions thereof that compete with the native NGPCR, and antibodies, as well as nucleotide sequences that can be used to inhibit the expression of the described NGPCR antisense and ribozyme molecules, and gene or regulatory sequence replacement constructs) or to enhance the expression of the described NGPCR gene expression constructs that place the described gene under the control of a strong promoter system), and transgenic animals that express a NGPCR transgene or "knock-outs" that do not express a functional NGPCR.

WO 01/18207 PCT/US0O/24591 Further, the present invention also relates to methods for the use of the described NGPCR gene and/or NGPCR gene products for the identification of compounds that modulate, act as agonists or antagonists, of NGPCR gene expression and or NGPCR gene product activity. Such compounds can be used as therapeutic agents for the treatment of various symptomatic representations of biological disorders or imbalances.

4. DESCRIPTION OF THE SEQUENCE LISTING AND FIGURES The Sequence Listing provides the polynucleotide sequences of the described NGPCRs, and the amino acid sequences encoded thereby.

5. DETAILED DESCRIPTION OF THE INVENTION The human NGPCRs described for the first time herein are novel proteins that are expressed, inter alia, in placenta, lung, liver, pancreas, spinal cord, spleen, thymus, lymph node, adrenal gland, stomach, salivary gland, stomach, mammary gland, thyroid, heart, brain, testis, kidney, adipose, esophagus, rectum, pericardium, trachea, and gene trapped human cells. In view of the tissues that may express the NGPCRs, the described human NGPCRs may be important targets for the therapeutic treatment of, inter alia, diabetes, abnormal body weight or obesity, atherosclerosis, heart disease, abnormal blood pressure, cancer, and any associated symptoms.

The described NGPCRs are transmembrane proteins that fall within the 7TM family of receptors. As with other GPCRs, signal transduction is triggered when a ligand binds to the receptor. Interfering with the binding of the natural ligand, or neutralizing or removing the ligand, or interference with its binding to a NGPCR will effect NGPCR mediated signal transduction. Because of their biological significance, 7TM proteins, and particularly GPCRs, have been subjected to intense scientific and commercial scrutiny (see, for example, U.S. Applic. Ser. Nos. 08/820,521, filed March 19, 1997, and WO 01/18207 PCT/US00/24591 08/833,226, filed April 17, 1997 both of which are herein incorporated by reference in their entirety).

The invention encompasses the use of the described NGPCR nucleotides, NGPCR proteins and peptides as antagonists that inhibit receptor activity or expression, or agonists that activate receptor activity or increase its expression in the diagnosis and treatment of disease. The invention also encompasses the use of antibodies and anti-idiotypic antibodies (including Fab fragments), preferably humanized monoclonal antibodies, or binding fragments, domains, or fusion proteins thereof which bind to NGPCR nucleotides, proteins or peptides and act as therapeutic NGPCR agonists or antagonists.

In particular, the invention described in the subsections below encompasses NGPCR polypeptides or peptides corresponding to functional domains of NGPCR ECD, TM or CD), mutated, truncated or deleted NGPCRs NGPCRs missing one or more functional domains or portions thereof, such as, AECD, ATM and/or ACD), NGPCR fusion proteins a NGPCR or a functional domain of a NGPCR, such as the ECD, fused to an unrelated protein or peptide such as an immunoglobulin constant region, IgFc), nucleotide sequences encoding such products, and host cell expression systems that can produce such NGPCR products.

The invention also encompasses compounds or nucleotide constructs that inhibit expression of a NGPCR gene (transcription factor inhibitors, antisense and ribozyme molecules, or gene or regulatory sequence replacement constructs), or promote expression of a NGPCR expression constructs in which NGPCR coding sequences are operatively associated with expression control elements such as promoters, promoter/enhancers, etc.). The invention also relates to host cells and animals genetically engineered to express the human NGPCRs (or mutants thereof) or to inhibit or "knockout" expression of the animal's endogenous NGPCR genes.

The NGPCR proteins or peptides, NGPCR fusion proteins, NGPCR nucleotide sequences, antibodies, antagonists and WO 01/18207 PCT/US00/24591 agonists can be useful for the detection of mutant NGPCRs or inappropriately expressed NGPCRs for the diagnosis of disease.

The NGPCR proteins or peptides, NGPCR fusion proteins, NGPCR nucleotide sequences, host cell expression systems, antibodies, antagonists, agonists and genetically engineered cells and animals can be used for screening for drugs (or high throughput screening of combinatorial libraries) effective in the treatment of the symptomatic or phenotypic manifestations resulting from perturbation of the normal function of a NGPCR in the body. The use of engineered host cells and/or animals can offer an advantage in that such systems allow not only for the identification of compounds that bind to an ECD of a NGPCR, but can also identify compounds that affect the signal transduced by an activated NGPCR.

One feature of the described NGPCR proteins is that the 7TM region of the protein is typically present at the Cterminal portion of a protein (for example, beginning at about amino acid 710 of SEQ ID NO: 2) that can incorporate a large upstream open reading frame that is substantially similar to a variety of other proteins such as bone morphogenic protein, several proteases, etc. Given that, in lower organisms, ORFs encoding receptor ligands can be linked to the ORF encoding the cognate receptor, it is possible that the presently described upstream ORF encodes a product (or cleavage product) that can serve as a receptor ligand in the body. Accordingly, an additional embodiment of the present invention includes soluble protein products or ligands that are encoded by at least a portion of the described novel polynucleotide sequences.

Finally, the NGPCR protein products (especially soluble derivatives such as peptides corresponding to a NGPCR ECD, the upstream ORF, or truncated polypeptides lacking one or more TM domains) and fusion protein products (especially NGPCR-Ig fusion proteins, fusions of a NGPCR, or a domain of a NGPCR, ECD, ATM to an IgFc), antibodies and antiidiotypic antibodies (including Fab fragments), antagonists or agonists (including compounds that modulate signal WO 01/18207 PCT/US00/24591 transduction which may act on downstream targets in a NGPCRmediated signal transduction pathway) can be used for therapy of such diseases. For example, the administration of an effective amount of soluble NGPCR ECD, ATM, or an ECD-IgFc fusion protein or an anti-idiotypic antibody (or its Fab) that mimics the NGPCR ECD would "mop up" or "neutralize" the endogenous NGPCR ligand, and prevent or reduce binding and receptor activation. Nucleotide constructs encoding such NGPCR products can be used to genetically engineer host cells to express such products in vivo; these genetically engineered cells function as "bioreactors" in the body delivering a continuous supply of a NGPCR, a NGPCR peptide, soluble ECD or ATM or a NGPCR fusion protein that will "mop up" or neutralize a NGPCR ligand. Nucleotide constructs encoding functional NGPCRs, mutant NGPCRs, as well as antisense and ribozyme molecules can be used in "gene therapy" approaches for the modulation of NGPCR expression. Thus, the invention also encompasses pharmaceutical formulations and methods for treating biological disorders.

Various aspects of the invention are described in greater detail in the subsections below.

5.1 NGPCR POLYNUCLEOTIDES The cDNA sequences and deduced amino acid sequences of the described human proteins are presented in the Sequence Listing.

The NGPCR polynucleotides of the present invention include: the human DNA sequences presented in the Sequence Listing and additionally contemplate any nucleotide sequence encoding a contiguous and functional NGPCR open reading frame (ORF) that hybridizes to a complement of the DNA sequences presented in the Sequence Listing under highly stringent conditions, hybridization to filter-bound DNA in 0.5 M NaHPO 4 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65 0 C, and washing in 0.1xSSC/0.1% SDS at 68 0 C (Ausubel F.M. et al., eds., 1989, Current Protocols in Molecular Biology, Vol. I, Green Publishing Associates, Inc., and John Wiley sons, Inc., New WO 01/18207 PCT/US00/24591 York, at p. 2.10.3) and encodes a functionally equivalent gene product. Additionally contemplated are any nucleotide sequences that hybridize to the complement of the DNA sequences that encode and express an amino acid sequence presented in the Sequence Listing under moderately stringent conditions, washing in 0.2xSSC/0.1% SDS at 42 0 C (Ausubel et al., 1989, supra), yet which still encode a functionally equivalent NGPCR gene product. Functional equivalents of NGPCR include naturally occurring NGPCRs present in other species, and mutant NGPCRs whether naturally occurring or engineered (by site directed mutagenesis, gene shuffling, directed evolution as described in, for example, U.S. Patent No. 5,837,458, herein incorporated by reference). The invention also includes degenerate variants of the disclosed sequences.

Additionally contemplated are polynucleotides encoding NGPCR ORFs, or their functional equivalents, encoded by polynucleotide sequences that are about 99, 95, 90, or about percent similar or identical to corresponding regions of the nucleotide sequences of the Sequence Listing (as measured by BLAST sequence comparison analysis using, for example, the GCG sequence analysis package (Madison, Wisconsin) using standard default settings).

The invention also includes nucleic acid molecules, preferably DNA molecules, that hybridize to, and are therefore the complements of, the described NGPCR nucleotide sequences.

Such hybridization conditions may be highly stringent or less highly stringent, as described above. In instances wherein the nucleic acid molecules are deoxyoligonucleotides ("DNA oligos"), such molecules (and particularly about 16 to about 100 base long, about 20 to about 80, or about 34 to about base long, or any variation or combination of sizes represented therein incorporating a contiguous region of sequence first disclosed in the present Sequence Listing, can be used in conjunction with the polymerase chain reaction (PCR) to screen libraries, isolate clones, and prepare cloning and sequencing templates, etc. Alternatively, such NGPCR WO 01/18207 PCT/US0O/24591 oligonucleotides can be used as hybridization probes for screening libraries, and assessing gene expression patterns (particularly using a micro array or high-throughput "chip" format). Additionally, a series of the described NGPCR oligonucleotide sequences, or the complements thereof, can be used to represent all or a portion of the described NGPCR encoding nucleotides. The oligonucleotides, typically between about 16 to about 40 (or any whole number within the stated range) nucleotides in length can partially overlap each other and/or a NGPCR sequence may be represented using oligonucleotides that do not overlap. Accordingly, the described NGPCR polynucleotide sequences shall typically comprise at least about two or three distinct oligonucleotide sequences of at least about 18, and preferably about nucleotides in length that are each first disclosed in the described Sequence Listing. Such oligonucleotide sequences can begin at any nucleotide present within a sequence in the Sequence Listing and proceed in either a sense orientation vis-a-vis the described sequence or in an antisense orientation.

For oligonucleotides probes, highly stringent conditions may refer, to washing in 6xSSC/0.05% sodium pyrophosphate at 37 0 C (for 14-base oligos), 48 0 C (for 17-base oligos), 55 0 C (for 20-base oligos), and 60°C (for 23-base oligos). These nucleic acid molecules may encode or act as NGPCR antisense molecules, useful, for example, in NGPCR gene regulation (for and/or as antisense primers in amplification reactions of NGPCR gene nucleic acid sequences). With respect to NGPCR gene regulation, such techniques can be used to regulate biological functions. Further, such sequences may be used as part of ribozyme and/or triple helix sequences, also useful for NGPCR gene regulation.

Additionally, the antisense oligonucleotides may comprise at least one modified base moiety which is selected from the group including but not limited to 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, WO 01/18207 WO 0118207PCTIUSOO/2459 1 5-carboxymethylaminomethyl-2 -thiouridine, dihydrouracil, beta-Dgalactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2, 2-dimethylguanine, 2-methyladenine, 2 -methylguanine, 3 -methylcytosine, N6-adenine, 7-methyl guanine, 5-methoxyaminomethyl-2-thiouracil, beta- D-manno sylqueos ine, 5 '-methoxycarboxymethyluracil, 2-methylthio-N6-isopentenyladenine, oxyacetic acid wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid 2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine.

The antisense oligonucleotide may also comprise at least one modified sugar moiety selected from the group including but not limited to arabinose, 2-f luoroarabinose, xylulose, and hexose.

In yet another embodiment, the antisense oligonucleotide comprises at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof.

In yet another embodiment, the antisense oligonucleotide is an ca-anomeric oligonucleotide. An c-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual 1-units, the strands run parallel to each other (Gautier et al., 1987, Nuci. Acids Res. 15:6625-6641). The oligonucleotide is methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res.

15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330).

Oligonucleotides of the invention may be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from WO 01/18207 PCT/US00/24591 Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides may be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc.

Low stringency conditions are well known to those of skill in the art, and will vary predictably depending on the specific organisms from which the library and the labeled sequences are derived. For guidance regarding such conditions see, for example, Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual (and periodic updates thereof), Cold Springs Harbor Press, and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. Alternatively, suitably labeled NGPCR nucleotide probes can be used to screen a human genomic library using appropriately stringent conditions or by PCR.

The identification and characterization of human genomic clones is helpful for identifying polymorphisms, determining the genomic structure of a given locus/allele, and designing diagnostic tests. For example, sequences derived from regions adjacent to the intron/exon boundaries of the human gene can be used to design primers for use in amplification assays to detect mutations within the exons, introns, splice sites splice acceptor and/or donor sites), etc., that can be used in diagnostics and pharmacogenomics.

Further, a NGPCR gene homolog may be isolated from nucleic acid from the organism of interest by performing PCR using two degenerate oligonucleotide primer pools designed on the basis of amino acid sequences within the NGPCR gene product disclosed herein. The template for the reaction may be total RNA, mRNA, and/or cDNA obtained by reverse transcription of mRNA prepared from, for example, human or non-human cell lines or tissue, such as brain, known or suspected to express a NGPCR gene allele.

The PCR product can be subcloned and sequenced to ensure that the amplified sequences represent the sequence of the WO 01/18207 PCT/US00/24591 desired NGPCR gene. The PCR fragment can then be used to isolate a full length cDNA clone by a variety of methods. For example, the amplified fragment may be labeled and used to screen a cDNA library, such as a bacteriophage cDNA library.

Alternatively, the labeled fragment may be used to isolate genomic clones via the screening of a genomic library.

PCR technology can also be utilized to isolate full length cDNA sequences. For example, RNA may be isolated, following standard procedures, from an appropriate cellular or tissue source one known, or suspected, to express a NGPCR gene, such as, for example, brain tissue). A reverse transcription (RT) reaction may be performed on the RNA using an oligonucleotide primer specific for the most 5' end of the amplified fragment for the priming of first strand synthesis.

The resulting RNA/DNA hybrid may then be "tailed" using a standard terminal transferase reaction, the hybrid may be digested with RNase H, and second strand synthesis may then be primed with a complementary primer. Thus, cDNA sequences upstream of the amplified fragment may easily be isolated.

For a review of cloning strategies which may be used, see Sambrook et al., 1989, supra.

A cDNA of a mutant NGPCR gene can be isolated, for example, by using PCR. In this case, the first cDNA strand may be synthesized by hybridizing an oligo-dT oligonucleotide to mRNA isolated from tissue known or suspected to be expressed in an individual putatively carrying a mutant NGPCR allele, and by extending the new strand with reverse transcriptase. The second strand of the cDNA is then synthesized using an oligonucleotide that hybridizes specifically to the 5' end of the normal gene. Using these two primers, the product is then amplified via PCR, optionally cloned into a suitable vector, and subjected to DNA sequence analysis through methods well known to those of skill in the art. By comparing the DNA sequence of the mutant NGPCR allele to that of the normal NGPCR allele, the mutation(s) responsible for the loss or alteration of function of the mutant NGPCR gene product can be ascertained.

WO 01/18207 PCT/US00/24591 Alternatively, a genomic library can be constructed using DNA obtained from an individual suspected of or known to carry the mutant NGPCR allele, or a cDNA library can be constructed using RNA from a tissue known, or suspected, to express the mutant NGPCR allele. A normal NGPCR gene, or any suitable fragment thereof, can then be labeled and used as a probe to identify the corresponding mutant NGPCR allele in such libraries. Clones containing the mutant NGPCR gene sequences may then be purified and subjected to sequence analysis according to methods well known to those of skill in the art.

Additionally, an expression library can be constructed utilizing cDNA synthesized from, for example, RNA isolated from a tissue known, or suspected, to express a mutant NGPCR allele in an individual suspected of or known to carry such a mutant allele. In this manner, gene products made by the putatively mutant tissue may be expressed and screened using standard antibody screening techniques in conjunction with antibodies raised against the normal NGPCR gene product, as described, below, in Section 5.3. (For screening techniques, see, for example, Harlow, E. and Lane, eds., 1988, "Antibodies: A Laboratory Manual", Cold Spring Harbor Press, Cold Spring Harbor.) Additionally, screening can be accomplished by screening with labeled NGPCR fusion proteins, such as, for example, alkaline phosphatase-NGPCR (AP-NGPCR) or NGPCR-AP fusion proteins. In cases where a.NGPCR mutation results in an expressed gene product with altered function as a result of a missense or a frameshift mutation), a polyclonal set of antibodies to NGPCR are likely to cross-react with the mutant NGPCR gene product. Library clones detected via their reaction with such labeled antibodies can be purified and subjected to sequence analysis according to methods well known to those of skill in the art.

The invention also encompasses nucleotide sequences that encode mutant NGPCRs, peptide fragments of the NGPCRs, truncated NGPCRs, and NGPCR fusion proteins. These include, but are not limited to nucleotide sequences encoding mutant WO 01/18207 PCT/US00/24591 NGPCRs described in section 5.2 infra; polypeptides or peptides corresponding to one or more ECD, TM and/or CD domains of the NGPCR or portions of these domains; truncated NGPCRs in which one or two of the domains is deleted, a soluble NGPCR lacking the TM or both the TM and CD regions, or a truncated, nonfunctional NGPCR lacking all or a portion of a, for example, CD region. Nucleotides encoding fusion proteins may include, but are not limited to, full length NGPCR sequences, truncated NGPCRs, or nucleotides encoding peptide fragments of NGPCR fused to an unrelated protein or peptide, such as for example, a transmembrane sequence, which anchors the NGPCR ECD to the cell membrane; an Ig Fc domain which increases the stability and half life of the resulting fusion protein NGPCR-Ig) in the bloodstream; or an enzyme, fluorescent protein, luminescent protein which can be used as a marker.

The invention also encompasses DNA vectors that contain any of the foregoing NGPCR coding sequences and/or their complements antisense); DNA expression vectors that contain any of the foregoing NGPCR coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences; and genetically engineered host cells that contain any of the foregoing NGPCR coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences in the host cell. As used herein, regulatory elements include but are not limited to inducible and noninducible promoters, enhancers, operators and other elements known to those skilled in the art that drive and regulate expression. Such regulatory elements include but are not limited to the human cytomegalovirus (hCMV) immediate early gene, regulatable, viral promoters (particularly retroviral LTR promoters), the early or late promoters of adenovirus, the lac system, the trD system, the TAC system, the TRC system, the major operator and promoter regions of phage A, the control regions of fd coat protein, the promoter for 3-phosphoglycerate kinase (PGK), the promoters of acid WO 01/18207 PCT/US00/24591 phosphatase, and the promoters of the yeast a-mating factors.

Vectors incorporating foreign regulatory elements can also be used in conjunction with gene targeting technology to induce or activate the expression of endogenous NGPCRs by gene activation of the introduction of suitable transcription factors.

Additionally contemplated uses for the described sequences include the engineering of constitutively "on" variants for use in cell assays and genetically engineered animals using the methods and applications described in U.S.

Patent Applications Ser Nos. 60/110,906, 60/106,300, 60/094,879, and 60/121,851 all of which are herein incorporated by reference in their entirety.

5.2 NGPCR PROTEINS AND POLYPEPTIDES NGPCR proteins, polypeptides and peptide fragments, mutated, truncated or deleted forms of the NGPCR and/or NGPCR fusion proteins can be prepared for a variety of uses, including but not limited to use as agonist or antagonist, for the generation of antibodies, as reagents in diagnostic assays, the identification of other cellular gene products related to a NGPCR, as reagents in assays for screening for compounds that can be as pharmaceutical reagents useful in the therapeutic treatment of mental, biological, or medical disorders and disease.

The Sequence Listing discloses the amino acid sequences encoded by the described NGPCR genes. The NGPCRs have initiator methionines in DNA sequence contexts consistent with translation initiation sites, followed by hydrophobic signal sequences typical of membrane associated proteins. The sequence data presented herein indicate that alternatively spliced forms of the NGPCRs exist (which may or may not be tissue specific).

The NGPCR amino acid sequences of the invention include the nucleotide and amino acid sequences presented in the Sequence Listing as well as analogues and derivatives thereof.

WO 01/18207 PCT/US00/24591 Further, corresponding NGPCR homologues from other species are encompassed by the invention. In fact, any NGPCR protein encoded by the NGPCR nucleotides described in Section 5.1, above, is within the scope of the invention, as are any novel polynucleotide sequences encoding all or any novel portion of an amino acid sequence presented in the Sequence Listing. The degenerate nature of the genetic code is well known, and, accordingly, each amino acid presented in the Sequence Listing, is generically representative of the well known nucleic acid "triplet" codon, or in many cases codons, that can encode the amino acid. As such, as contemplated herein, the amino acid sequences presented in the Sequence Listing, when taken together with the genetic code (see, for example, Table 4-1 at page 109 of "Molecular Cell Biology", 1986, J.

Darnell et al. eds., Scientific American Books, New York, NY, herein incorporated by reference) are generically representative of all the various permutations and combinations of nucleic acid sequences that can encode such amino acid sequences.

The invention also encompasses proteins that are functionally equivalent to the NGPCR encoded by the nucleotide sequences described in Section 5.1, as judged by any of a number of criteria, including but not limited to the ability to bind a ligand for NGPCR, the ability to effect an identical or complementary signal transduction pathway, a change in cellular metabolism ion flux, tyrosine phosphorylation, etc.) or change in phenotype when the NGPCR equivalent is present in an appropriate cell type (such as the amelioration, prevention or delay of a biochemical, biophysical, or overt phenotype. Such functionally equivalent NGPCR proteins include but are not limited to additions or substitutions of amino acid residues within the amino acid sequence encoded by the NGPCR nucleotide sequences described above, in Section 5.1, but which result in a silent change, thus producing a functionally equivalent gene product. Amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, WO 01/18207 PCT/US00/24591 and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid.

While random mutations can be made in NGPCR DNA (using random mutagenesis techniques well known to those skilled in the art) and the resulting mutant NGPCRs tested for activity, site-directed mutations of the NGPCR coding sequence can be engineered (using site-directed mutagenesis techniques well known to those skilled in the art) to generate mutant NGPCRs with increased function, higher binding affinity for the target ligand, and/or greater signaling capacity; or decreased function, and/or decreased signal transduction capacity. One starting point for such analysis is by aligning the disclosed human sequences with corresponding gene/protein sequences from, for example, other mammals in order to identify amino acid sequence motifs that are conserved between different species. Non-conservative changes can be engineered at variable positions to alter function, signal transduction capability, or both. Alternatively, where alteration of function is desired, deletion or non-conservative alterations of the conserved regions identical amino acids) can be engineered. For example, deletion or non-conservative alterations (substitutions or insertions) of the various conserved transmembrane domains.

Other mutations to the NGPCR coding sequence can be made to generate NGPCRs that are better suited for expression, scale up, etc. in the host cells chosen. For example, cysteine residues can be deleted or substituted with another amino acid in order to eliminate disulfide bridges; N-linked glycosylation sites can be altered or eliminated to achieve, for example, expression of a homogeneous product that is more easily recovered and purified from yeast hosts which are known WO 01/18207 PCT/US00/24591 to hyperglycosylate N-linked sites. To this end, a variety of amino acid substitutions at one or both of the first or third amino acid positions of any one or more of the glycosylation recognition sequences which occur in the ECD (N-X-S or N-X-T), and/or an amino acid deletion at the second position of any one or more such recognition sequences in the ECD will prevent glycosylation of the NGPCR at the modified tripeptide sequence. (See, Miyajima et al., 1986, EMBO J.

5(6):1193-1197).

Peptides corresponding to one or more domains of the NGPCR ECD, TM, CD, etc.), truncated or deleted NGPCRs NGPCR in which a ECD, TM and/or CD is deleted) as well as fusion proteins in which a full length NGPCR, a NGPCR peptide, or truncated NGPCR is fused to an unrelated protein, are also within the scope of the invention and can be designed on the basis of the presently disclosed NGPCR nucleotide and NGPCR amino acid sequences. Such fusion proteins include but are not limited to IgFc fusions which stabilize the NGPCR protein or peptide and prolong half-life in vivo; or fusions to any amino acid sequence that allows the fusion protein to be anchored to the cell membrane, allowing an ECD to be exhibited on the cell surface; or fusions to an enzyme, fluorescent protein, or luminescent protein which provide a marker function.

While the NGPCR polypeptides and peptides can be chemically synthesized see Creighton, 1983, Proteins: Structures and Molecular Principles, W.H. Freeman Co., large polypeptides derived from a NGPCR and full length NGPCRs can be advantageously produced by recombinant DNA technology using techniques well known in the art for expressing nucleic acid containing NGPCR gene sequences and/or coding sequences. Such methods can be used to construct expression vectors containing a NGPCR nucleotide sequences described in Section 5.1 and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. See, for WO 01/18207 PCT/US00/24591 example, the techniques described in Sambrook et al., 1989, supra, and Ausubel et al., 1989, supra. Alternatively, RNA corresponding to all or a portion of a transcript encoded by a NGPCR nucleotide sequence may be chemically synthesized using, for example, synthesizers. See, for example, the techniques described in "Oligonucleotide Synthesis", 1984, Gait, M.J.

ed., IRL Press, Oxford, which is incorporated by reference herein in its entirety.

A variety of host-expression vector systems may be utilized to express a NGPCR nucleotide sequences of the invention. Where the NGPCR peptide or polypeptide is a soluble derivative NGPCR peptides corresponding to an ECD; truncated or deleted NGPCR in which a TM and/or CD are deleted) the peptide or polypeptide can be recovered from the culture, from the host cell in cases where the NGPCR peptide or polypeptide is not secreted, and from the culture media in cases where the NGPCR peptide or polypeptide is secreted by the cells. However, such expression systems also encompass engineered host cells that express a NGPCR, or functional equivalent, in situ, anchored in the cell membrane. Purification or enrichment of NGPCR from such expression systems can be accomplished using appropriate detergents and lipid micelles and methods well known to those skilled in the art. However, such engineered host cells themselves may be used in situations where it is important not only to retain the structural and functional characteristics of the NGPCR, but to assess biological activity, in drug screening assays.

Expression systems that can be used for purposes of the invention include, but are not limited to, microorganisms such as bacteria E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing NGPCR nucleotide sequences; yeast Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing NGPCR nucleotide sequences; insect cell systems infected with recombinant virus expression vectors baculovirus) WO 01/18207 PCT/US00/24591 containing NGPCR sequences; plant cell systems infected with recombinant virus expression vectors cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors Ti plasmid) containing NGPCR nucleotide sequences; or mammalian cell systems COS, CHO, BHK, 293, 3T3) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells metallothionein promoter) or from mammalian viruses the adenovirus late promoter; the vaccinia virus 7.5K promoter).

In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the NGPCR gene product being expressed. For example, when a large quantity of such a protein is to be produced, for the generation of pharmaceutical compositions of NGPCR protein or for raising antibodies to a NGPCR protein, for example, vectors that direct the expression of high levels of fusion protein products that are readily purified may be desirable.

Such vectors include, but are not limited, to the E. coli expression vector pUR278 (Ruther et al., 1983, EMBO J.

2:1791), in which a NGPCR coding sequence may be ligated individually into the vector in frame with the lacZ coding region so that a fusion protein is produced; pIN vectors (Inouye Inouye, 1985, Nucleic Acids Res. 13:3101-3109; Van Heeke Schuster, 1989, J. Biol. Chem. 264:5503-5509); and the like. pGEX vectors may also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption to glutathione-agarose beads followed by elution in the presence of free glutathione. The PGEX vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

In an insect system, Autographa californica nuclear polyhidrosis virus (AcNPV) is used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda WO 01/18207 PCT/USOO/24591 cells. A NGPCR gene coding sequence may be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter).

Successful insertion of NGPCR gene coding sequence will result in inactivation of the polyhedrin gene and production of nonoccluded recombinant virus virus lacking the proteinaceous coat coded for by the polyhedrin gene). These recombinant viruses are then used to infect Spodoptera frugiperda cells in which the inserted gene is expressed see Smith et al., 1983, J. Virol. 46: 584; Smith, U.S.

Patent No. 4,215,051).

In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the NGPCR nucleotide sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a nonessential region of the viral genome region El or E3) will result in a recombinant virus that is viable and capable of expressing a NGPCR gene product in infected hosts See Logan Shenk, 1984, Proc. Natl. Acad. Sci. USA 81:3655- 3659). Specific initiation signals may also be required for efficient translation of inserted NGPCR nucleotide sequences.

These signals include the ATG initiation codon and adjacent sequences. In cases where an entire NGPCR gene or cDNA, including its own initiation codon and adjacent sequences, is inserted into the appropriate expression vector, no additional translational control signals may be needed. However, in cases where only a portion of a NGPCR coding sequence is inserted, exogenous translational control signals, including, perhaps, the ATG initiation codon, must be provided.

Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous WO 01/18207 PCT/US00/24591 translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (See Bittner et al., 1987, Methods in Enzymol. 153:516-544) In addition, a host cell strain may be chosen that modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications glycosylation) and processing cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include, but are not limited to, CHO, VERO, BHK, HeLa, COS, MDCK, 293, 3T3, WI38, and in particular, choroid plexus cell lines.

For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the NGPCR sequences described above may be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements promoter, enhancer sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media.

The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form WO 01/18207 PCT/US00/24591 foci which in turn can be cloned and expanded into cell lines.

This method may advantageously be used to engineer cell lines which express the NGPCR gene product. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that affect the endogenous activity of the NGPCR gene product.

A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler, et al., 1977, Cell 11:223), hypoxanthine-guanine phosphoribosyltransferase (Szybalska Szybalski, 1962, Proc.

Natl. Acad. Sci. USA 48:2026), and adenine phosphoribosyltransferase (Lowy, et al., 1980, Cell 22:817) genes can be employed in tk-, hgprt- or aprt- cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler, et al., 1980, Natl. Acad. Sci. USA 77:3567; O'Hare, et al., 1981, Proc.

Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance to mycophenolic acid (Mulligan Berg, 1981, Proc. Natl. Acad.

Sci. USA 78:2072); neo, which confers resistance to the aminoglycoside G-418 (Colberre-Garapin, et al., 1981, J. Mol.

Biol. 150:1); and hygro, which confers resistance to hygromycin (Santerre, et al., 1984, Gene 30:147).

Alternatively, any fusion protein may be readily purified by utilizing an antibody specific for the fusion protein being expressed. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht, et al., 1991, Proc. Natl. Acad. Sci. USA 88: 8972-8976). In this system, the gene of interest is subcloned into a vaccinia recombination plasmid such that the gene's open reading frame is translationally fused to an amino-terminal tag consisting of six histidine residues. Extracts from cells infected with recombinant vaccinia virus are loaded onto Ni 2 nitriloacetic acid-agarose columns and histidine-tagged proteins are selectively eluted with imidazole-containing buffers.

NGPCR gene products can also be expressed in transgenic WO 01/18207 PCTIUS00/24591 animals. Animals of any species, including, but not limited to, worms, mice, rats, rabbits, guinea pigs, pigs, micro-pigs, birds, goats, and non-human primates, baboons, monkeys, and chimpanzees may be used to generate NGPCR transgenic animals.

Any technique known in the art may be used to introduce a NGPCR transgene into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to pronuclear microinjection (Hoppe, P.C. and Wagner, 1989, U.S. Pat. No. 4,873,191); retrovirus mediated gene transfer into germ lines (Van der Putten et al., 1985, Proc.

Natl. Acad. Sci., USA 82:6148-6152); gene targeting in embryonic stem cells (Thompson et al., 1989, Cell 56:313-321); electroporation of embryos (Lo, 1983, Mol Cell. Biol. 3:1803- 1814); and sperm-mediated gene transfer (Lavitrano et al., 1989, Cell 57:717-723); etc. For a review of such techniques, see Gordon, 1989, Transgenic Animals, Intl. Rev. Cytol.

115:171-229, which is incorporated by reference herein in its entirety.

The present invention provides for transgenic animals that carry the NGPCR transgene in all their cells, as well as animals which carry the transgene in some, but not all their cells, mosaic animals or somatic cell transgenic animals. The transgene may be integrated as a single transgene or in concatamers, head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, for example, the teaching of Lasko et al., 1992, Proc. Natl. Acad. Sci. USA 89:6232-6236. The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

When it is desired that the NGPCR gene transgene be integrated into the chromosomal site of the endogenous NGPCR gene, gene targeting is preferred. Briefly, when such a technique is to be utilized, vectors containing some nucleotide sequences homologous to the endogenous NGPCR gene WO 01/18207 PCT/US00/24591 are designed for the purpose of integrating, via homologous recombination with chromosomal sequences, into and disrupting the function of the nucleotide sequence of the endogenous NGPCR gene "knockout" animals).

The transgene may also be selectively introduced into a particular cell type, thus inactivating the endogenous NGPCR gene in only that cell type, by following, for example, the teaching of Gu et al., 1994, Science, 265:103-106. The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

Once transgenic animals have been generated, the expression of the recombinant NGPCR gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to assay whether integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include but are not limited to Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and RT-PCR.

Samples of NGPCR gene-expressing tissue, may also be evaluated immunocytochemically using antibodies specific for the NGPCR transgene product.

5.3 ANTIBODIES TO NGPCR PROTEINS Antibodies that specifically recognize one or more epitopes of a NGPCR, or epitopes of conserved variants of a NGPCR, or peptide fragments of a NGPCR are also encompassed by the invention. Such antibodies include but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab') 2 fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.

The antibodies of the invention may be used, for example, in the detection of NGPCR in a biological sample and may, WO 01/18207 PCT/USOO/24591 therefore, be utilized as part of a diagnostic or prognostic technique whereby patients may be tested for abnormal amounts of NGPCR. Such antibodies may also be utilized in conjunction with, for example, compound screening schemes, as described, below, in Section 5.5, for the evaluation of the effect of test compounds on expression and/or activity of a NGPCR gene product. Additionally, such antibodies can be used in conjunction gene therapy to, for example, evaluate the normal and/or engineered NGPCR-expressing cells prior to their introduction into the patient. Such antibodies may additionally be used as a method for the inhibition of abnormal NGPCR activity. Thus, such antibodies may, therefore, be utilized as part of weight disorder treatment methods.

For the production of antibodies, various host animals may be immunized by injection with the NGPCR, an NGPCR peptide one corresponding the a functional domain of the receptor, such as an ECD, TM or CD), truncated NGPCR polypeptides (NGPCR in which one or more domains, a TM or CD, has been deleted), functional equivalents of the NGPCR or mutants of the NGPCR. Such host animals may include but are not limited to rabbits, mice, and rats, to name but a few.

Various adjuvants may be used to increase the immunological response, depending on the host species, including but not limited to Freund's adjuvant (complete and incomplete), mineral salts such as aluminum hydroxide or aluminum phosphate, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and Corynebacterium parvum. Alternatively, the immune response could be enhanced by combination and or coupling with molecules such as keyhole limpet hemocyanin, tetanus toxoid, diptheria toxoid, ovalbumin, cholera toxoin or fragments thereof. Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of the immunized animals.

WO 01/18207 PCT/US00/24591 Monoclonal antibodies, which are homogeneous populations of antibodies to a particular antigen, may be obtained by any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique of Kohler and Milstein, (1975, Nature 256:495-497; and U.S. Patent No.

4,376,110), the human B-cell hybridoma technique (Kosbor et al., 1983, Immunology Today 4:72; Cole et al., 1983, Proc.

Natl. Acad. Sci. USA 80:2026-2030), and the EBV-hybridoma technique (Cole et al., 1985, Monoclonal Antibodies And Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof. The hybridoma producing the mAb of this invention may be cultivated in vitro or in vivo.

Production of high titers of mAbs in vivo makes this the presently preferred method of production.

In addition, techniques developed for the production of "chimeric antibodies" (Morrison et al., 1984, Proc. Natl.

Acad. Sci., 81:6851-6855; Neuberger et al., 1984, Nature, 312:604-608; Takeda et al., 1985, Nature, 314:452-454) by splicing the genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity can be used (see U.S. Patents Nos. 6,075,181 and 5,877,397 which are herein incorporated by reference in their entirety). A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region.

Alternatively, techniques described for the production of single chain antibodies Patent 4,946,778; Bird, 1988, Science 242:423-426; Huston et al., 1988, Proc. Natl. Acad.

Sci. USA 85:5879-5883; and Ward et al., 1989, Nature 334:544- 546) can be adapted to produce single chain antibodies against NGPCR gene products. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region WO 01/18207 PCT/US00/24591 via an amino acid bridge, resulting in a single chain polypeptide.

Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, such fragments include but are not limited to: the F(ab') 2 fragments which can be produced by pepsin digestion of the antibody molecule and the Fab fragments which can be generated by reducing the disulfide bridges of the F(ab') 2 fragments. Alternatively, Fab expression libraries may be constructed (Huse et al., 1989, Science, 246:1275-1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.

Antibodies to a NGPCR can, in turn, be uti generate antiidiotype antibodies that "mimic" a given NGPCR, using techniques well known to those skilled in the art. (See, Greenspan Bona, 1993, FASEB J 7(5):437-444; and Nissinoff, 1991, J. Immunol. 147(8):2429-2438). For example antibodies which bind to a NGPCR ECD.and competitively inhibit the binding of a ligand of NGPCR can be used to generate antiidiotypes that "mimic" a NGPCR ECD and, therefore, bind and neutralize a ligand. Such neutralizing anti-idiotypes or Fab fragments of such anti-idiotypes can be used in therapeutic regimens involving the NGPCR signaling pathway.

5.4 DIAGNOSIS OF ABNORMALITIES RELATED TO A NGPCR A variety of methods can be employed for the diagnostic and prognostic evaluation of disorders related to NGPCR function, and for the identification of subjects having a predisposition to such disorders.

Such methods may, for example, utilize reagents such as the NGPCR nucleotide sequences described in Section 5.1, and NGPCR antibodies, as described, in Section 5.3. Specifically, such reagents may be used, for example, for: the detection of the presence of NGPCR gene mutations, or the detection of either over- or under-expression of NGPCR mRNA relative to a given phenotype; the detection of either an over- or an under-abundance of NGPCR gene product relative to a given phenotype; and the detection of perturbations or WO 01/18207 PCT/US00/24591 abnormalities in the signal transduction pathway mediated by

NGPCR.

The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one specific NGPCR nucleotide sequence or NGPCR antibody reagent described herein, which may be conveniently used, in clinical settings, to diagnose patients exhibiting body weight disorder abnormalities.

For the detection of NGPCR mutations, any nucleated cell can be used as a starting source for genomic nucleic acid.

For the detection of NGPCR gene expression or NGPCR gene products, any cell type or tissue in which the NGPCR gene is expressed, such as, for example, brain or adipose cells, may be utilized.

Nucleic acid-based detection techniques are described, below, in Section 5.4.1. Peptide detection techniques are described, below, in Section 5.4.2.

5.4.1 DETECTION OF NGPCR NUCLEOTIDES AND TRANSCRIPTS- Mutations within a NGPCR gene can be detected by utilizing a number of techniques. Nucleic acid from any nucleated cell can be used as the starting point for such assay techniques, and may be isolated according to standard nucleic acid preparation procedures which are well known to those of skill in the art.

DNA may be used in hybridization or amplification assays of biological samples to detect abnormalities involving NGPCR gene structure, including point mutations, insertions, deletions and chromosomal rearrangements. Such assays may include, but are not limited to, Southern analyses, single stranded conformational polymorphism analyses (SSCP), and PCR analyses.

Such diagnostic methods for the detection of NGPCR genespecific mutations can involve for example, contacting and incubating nucleic acids including recombinant DNA molecules, cloned genes or degenerate variants thereof, obtained from a sample, derived from a patient sample or other WO 01/18207 PCT/US00/24591 appropriate cellular source, with one or more labeled nucleic acid reagents including recombinant DNA molecules, cloned genes or degenerate variants thereof, as described in Section 5.1, under conditions favorable for the specific annealing of these reagents to their complementary sequences within a given NGPCR gene. Preferably, the lengths of these nucleic acid reagents are at least 15 to 30 nucleotides. After incubation, all non-annealed nucleic acids are removed from the nucleic acid:NGPCR molecule hybrid. The presence of nucleic acids which have hybridized, if any such molecules exist, is then detected. Using such a detection scheme, the nucleic acid from the cell type or tissue of interest can be immobilized, for example, to a solid support such as a membrane, or a plastic surface such as that on a microtiter plate or polystyrene beads. In this case, after incubation, nonannealed, labeled nucleic acid reagents of the type described in Section 5.1 are easily removed. Detection of the remaining, annealed, labeled NGPCR nucleic acid reagents is accomplished using standard techniques well-known to those in the art. The NGPCR gene sequences to which the nucleic acid reagents have annealed can be compared to the annealing pattern expected from a normal NGPCR gene sequence in order to determine whether a NGPCR gene mutation is present.

Alternative diagnostic methods for the detection of NGPCR gene specific nucleic acid molecules, in patient samples or other appropriate cell sources, may involve their amplification, by PCR (the experimental embodiment set forth in Mullis, 1987, U.S. Patent No. 4,683,202), followed by the detection of the amplified molecules using techniques well known to those of skill in the art. The resulting amplified sequences can be compared to those which would be expected if the nucleic acid being amplified contained only normal copies of a NGPCR gene in order to determine whether a NGPCR gene mutation exists.

Additionally, well-known genotyping techniques can be performed to identify individuals carrying NGPCR gene mutations. Such techniques include, for example, the use of WO 01/18207 PCT/US00/24591 restriction fragment length polymorphisms (RFLPs), which involve sequence variations in one of the recognition sites for the specific restriction enzyme used.

Additionally, improved methods for analyzing DNA polymorphisms which can be utilized for the identification of NGPCR gene mutations have been described which capitalize on the presence of variable numbers of short, tandemly repeated DNA sequences between the restriction enzyme sites. For example, Weber Pat. No. 5,075,217, which is incorporated herein by reference in its entirety) describes a DNA marker based on length polymorphisms in blocks of (dC-dA)n-(dG-dT)n short tandem repeats. The average separation of (dC-dA)n-(dGdT)n blocks is estimated to be 30,000-60,000 bp. Markers which are so closely spaced exhibit a high frequency coinheritance, and are extremely useful in the identification of genetic mutations, such as, for example, mutations within a given NGPCR gene, and the diagnosis of diseases and disorders related to NGPCR mutations.

Also, Caskey et al. Pat. No. 5,364,759, which is incorporated herein by reference in its entirety) describe a DNA profiling assay for detecting short tri and tetra nucleotide repeat sequences. The process includes extracting the DNA of interest, such as the NGPCR gene, amplifying the extracted DNA, and labeling the repeat sequences to form a genotypic map of the individual's DNA.

The level of NGPCR gene expression can also be assayed by detecting and measuring NGPCR transcription. For example, RNA from a cell type or tissue known, or suspected to express the NGPCR gene, such as brain, may be isolated and tested utilizing hybridization or PCR techniques such as are described, above. The isolated cells can be derived from cell culture or from a patient. The analysis of cells taken from culture may be a necessary step in the assessment of cells to be used as part of a cell-based gene therapy technique or, alternatively, to test the effect of compounds on the expression of a NGPCR gene. Such analyses may reveal both quantitative and qualitative aspects of the expression pattern WO 01/18207 PCT/US00/24591 of the NGPCR gene, including activation or inactivation of NGPCR gene expression.

In one embodiment of such a detection scheme, cDNAs are synthesized from the RNAs of interest by reverse transcription of the RNA molecule into cDNA). A sequence within the cDNA is then used as the template for a nucleic acid amplification reaction, such as a PCR amplification reaction, or the like. The nucleic acid reagents used as synthesis initiation reagents primers) in the reverse transcription and nucleic acid amplification steps of this method are chosen from among the NGPCR nucleic acid reagents described in Section 5.1. The preferred lengths of such nucleic acid reagents are at least 9-30 nucleotides. For detection of the amplified product, the nucleic acid amplification may be performed using radioactively or nonradioactively labeled nucleotides. Alternatively, enough amplified product may be made such that the product may be visualized by standard ethidium bromide staining, by utilizing any other suitable nucleic acid staining method, or by sequencing.

Additionally, it is possible to perform such NGPCR gene expression assays "in situ", directly upon tissue sections (fixed and/or frozen) of patient tissue obtained from biopsies or resections, such that no nucleic acid purification is necessary. Nucleic acid reagents such as those described in Section 5.1 may be used as probes and/or primers for such in situ procedures (See, for example, Nuovo, 1992, "PCR In Situ Hybridization: Protocols And Applications", Raven Press, NY).

Alternatively, .if a sufficient quantity of the appropriate cells can be obtained, standard Northern analysis can be performed to determine the level of mRNA expression of the NGPCR gene.

WO 01/18207 PCT/US00/24591 5.4.2 DETECTION OF NGPCR GENE PRODUCTS Antibodies directed against wild type or mutant NGPCR gene products or conserved variants or peptide fragments thereof, which are discussed, above, in Section 5.3, may also be used as diagnostics and prognostics, as described herein.

Such diagnostic methods, may be used to detect abnormalities in the level of NGPCR gene expression, or abnormalities in the structure and/or temporal, tissue, cellular, or subcellular location of the NGPCR, and may be performed in vivo or in vitro, such as, for example, on biopsy tissue.

For example, antibodies directed to epitopes of the NGPCR ECD can be used in vivo to detect the pattern and level of expression of the NGPCR in the body. Such antibodies can be labeled, with a radio-opaque or other appropriate compound and injected into a subject in order to visualize binding to the NGPCR expressed in the body using methods such as X-rays, CAT-scans, or MRI. Labeled antibody fragments, the Fab or single chain antibody comprising the smallest portion of the antigen binding region, are preferred for this purpose to promote crossing the blood-brain barrier and permit labeling NGPCRs expressed in the brain.

Additionally, any NGPCR fusion protein or NGPCR conjugated protein whose presence can be detected, can be administered. For example, NGPCR fusion or conjugated proteins labeled with a radio-opaque or other appropriate compound can be administered and visualized in vivo, as discussed, above for labeled antibodies. Further such NGPCR fusion proteins as alkaline phosphatase-NGPCR (AP-NGPCR) or NGPCR-AP fusion proteins can be utilized for in vitro diagnostic procedures.

Alternatively, immunoassays or fusion protein detection assays, as described above, can be utilized on biopsy and autopsy samples in vitro to permit assessment of the expression pattern of the NGPCR. Such assays are not confined to the use of antibodies that define a NGPCR ECD, but can include the use of antibodies directed to epitopes of any of the domains of a NGPCR, the ECD, the TM and/or CD. The WO 01/18207 PCT/US00/24591 use of each or all of these labeled antibodies will yield useful information regarding translation and intracellular transport of the NGPCR to the cell surface, and can identify defects in processing.

The tissue or cell type to be analyzed will generally include those which are known, or suspected, to express a NGPCR gene, such as, for example, brain cells. The protein isolation methods employed herein may, for example, be such as those described in Harlow and Lane (Harlow, E. and Lane, D., 1988, "Antibodies: A Laboratory Manual", Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York), whi'ch is incorporated herein by reference in its entirety. The isolated cells can be derived from cell culture or from a patient. The analysis of cells taken from culture may be a necessary step in the assessment of cells that could be used as part of a cell-based gene therapy technique or, alternatively, to test the effect of compounds on the expression of a NGPCR gene.

For example, antibodies, or fragments of antibodies, such as those described, above, in Section 5.3, useful in the present invention may be used to quantitatively or qualitatively detect the presence of NGPCR gene products or conserved variants or peptide fragments thereof. This can be accomplished, for example, by immunofluorescence techniques employing a fluorescently labeled antibody (see below, this Section) coupled with light microscopic, flow cytometric, or fluorimetric detection. Such techniques are especially preferred if such NGPCR gene products are expressed on the cell surface.

The antibodies (or fragments thereof) or NGPCR fusion or conjugated proteins useful in the present invention may, additionally, be employed histologically, as in immunofluorescence, immunoelectron microscopy or non-immuno assays, for in situ detection of NGPCR gene products or conserved variants or peptide fragments thereof, or for NGPCR binding (in the case of labeled NGPCR ligand fusion protein).

WO 01/18207 PCTUS00/24591 In situ detection may be accomplished by removing a histological specimen from a patient, and applying thereto a labeled antibody or fusion protein of the present invention.

The antibody (or fragment) or fusion protein is preferably applied by overlaying the labeled antibody (or fragment) onto a biological sample. Through the use of such a procedure, it is possible to determine not only the presence of the NGPCR gene product, or conserved variants or peptide fragments, or NGPCR binding, but also its distribution in the examined tissue. Using the present invention, those of ordinary skill will readily perceive that any of a wide variety of histological methods (such as staining procedures) can be modified in order to achieve such in situ detection.

Immunoassays and non-immunoassays for NGPCR gene products or conserved variants or peptide fragments thereof will typically comprise incubating a sample, such as a biological fluid, a tissue extract, freshly harvested cells, or lysates of cells which have been incubated in cell culture, in the presence of a detectably labeled antibody capable of identifying NGPCR gene products or conserved variants or peptide fragments thereof, and detecting the bound antibody by any of a number of techniques well-known in the art.

The biological sample may be brought in contact with and immobilized onto a solid phase support or carrier such as nitrocellulose, or other solid support which is capable of immobilizing cells, cell particles or soluble proteins. The support may then be washed with suitable buffers followed by.

treatment with the detectably labeled NGPCR antibody or NGPCR ligand fusion protein. The solid phase support may then be washed with the buffer a second time to remove unbound antibody or fusion protein. The amount of bound label on solid support may then be detected by conventional means.

By "solid phase support or carrier" is intended any support capable of binding an antigen or an antibody. Wellknown supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and WO 01/18207 PCT/US0O/24591 magnetite. The nature of the carrier can be either soluble to some extent or insoluble for the purposes of the present invention. The support material may have virtually any possible structural configuration so long as the coupled molecule is capable of binding to an antigen or antibody.

Thus, the support configuration may be spherical, as in a bead, or cylindrical, as in the inside surface of a test tube, or the external surface of a rod. Alternatively, the surface may be flat such as a sheet, test strip, etc. Preferred supports include polystyrene beads. Those skilled in the art will know many other suitable carriers for binding antibody or antigen, or will be able to ascertain the same by use of routine experimentation.

The binding activity of a given lot of NGPCR antibody or NGPCR ligand fusion protein may be determined according to well known methods. Those skilled in the art will be able to determine operative and optimal assay conditions for each determination by employing routine experimentation.

With respect to antibodies, one of the ways in which the NGPCR antibody can be detectably labeled is by linking the same to an enzyme and use in an enzyme immunoassay (EIA) (Voller, "The Enzyme Linked Immunosorbent Assay (ELISA)", 1978, Diagnostic Horizons 2:1-7, Microbiological Associates Quarterly Publication, Walkersville, MD); Voller, A. et al., 1978, J. Clin. Pathol. 31:507-520; Butler, 1981, Meth.

Enzymol. 73:482-523; Maggio, E. 1980, Enzyme Immunoassay, CRC Press, Boca Raton, FL,; Ishikawa, E. et al., 1981, Enzyme Immunoassay, Kgaku Shoin, Tokyo). The enzyme that is bound to the antibody will react with an appropriate substrate, preferably a chromogenic substrate, in such a manner as to produce a chemical moiety which can be detected, for example, by spectrophotometric, fluorimetric or by visual means. Enzymes which can be used to detectably label the antibody include, but are not limited to, malate dehydrogenase, staphylococcal nuclease, isomerase, yeast alcohol dehydrogenase, alphaglycerophosphate, dehydrogenase, triose phosphate isomerase, WO 01/18207 PCT/US00/24591 horseradish peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase and acetylcholinesterase. The detection can be accomplished by colorimetric methods which employ a chromogenic substrate for the enzyme. Detection may also be accomplished by visual comparison of the extent of enzymatic reaction of a substrate in comparison with similarly prepared standards.

Detection may also be accomplished using any of a variety of other immunoassays. For example, by radioactively labeling the antibodies or antibody fragments, it is possible to detect NGPCR through the use of a radioimmunoassay (RIA) (see, for example, Weintraub, Principles of Radioimmunoassays, Seventh Training Course on Radioligand Assay Techniques, The Endocrine Society, March, 1986; which is incorporated by reference herein). The radioactive isotope can be detected by such means as the use of a gamma counter or a scintillation counter or by autoradiography.

It is also possible to label the antibody with a fluorescent compound. When the fluorescently labeled antibody is exposed to light of the proper wave length, its presence can then be detected due to fluorescence. Among the most commonly used fluorescent labeling compounds are fluorescein isothiocyanate, rhodamine, phycoerythrin, phycocyanin, allophycocyanin, o-phthaldehyde and fluorescamine.

The antibody can also be detectably labeled using fluorescence emitting metals such as 152 Eu, or others of the lanthanide series. These metals can be attached to the antibody using such metal chelating groups as diethylenetriaminepentacetic acid (DTPA) or ethylenediaminetetraacetic acid (EDTA).

The antibody also can be detectably labeled by coupling it to a chemiluminescent compound. The presence of the chemiluminescent-tagged antibody is then determined by detecting the presence of luminescence that arises during the course of a chemical reaction. Examples of particularly useful chemiluminescent labeling compounds are luminol, WO 01/18207 PCT/US00/24591 isoluminol, theromatic acridinium ester, imidazole, acridinium salt and oxalate ester.

Likewise, a bioluminescent compound may be used to label the antibody of the present invention. Bioluminescence is a type of chemiluminescence found in biological systems in, which a catalytic protein increases the efficiency of the chemiluminescent reaction. The presence of a bioluminescent protein is determined by detecting the presence of luminescence. Important bioluminescent compounds for purposes of labeling are luciferin, luciferase and aequorin.

SCREENING ASSAYS FOR COMPOUNDS THAT MODULATE NGPCR EXPRESSION OR ACTIVITY The following assays are designed to identify compounds that interact with bind to) NGPCRs (including, but not limited to an ECD or CD of a NGPCR), compounds that interact with bind to) intracellular proteins that interact with NGPCR (including but not limited to the TM and CD of NGPCR), compounds that interfere with the interaction of NGPCR with transmembrane or intracellular proteins involved in NGPCRmediated signal transduction, and to compounds which modulate the activity of NGPCR gene modulate the level of NGPCR gene expression) or modulate the level of NGPCR. Assays may additionally be utilized which identify compounds which bind to NGPCR gene regulatory sequences promoter sequences) and which may modulate NGPCR gene expression. See e.g., Platt, 1994, J. Biol. Chem. 269:28558-28562, which is incorporated herein by reference in its entirety.

The compounds which may be screened in accordance with the invention include but are not limited to peptides, antibodies and fragments thereof, and other organic compounds peptidomimetics) that bind to an ECD of a NGPCR and either mimic the activity triggered by the natural ligand agonists) or inhibit the activity triggered by the natural ligand antagonists); as well as peptides, antibodies or fragments thereof, and other organic compounds WO 01/18207 PCTUSOO/24591 that mimic the ECD of the NGPCR (or a portion thereof) and bind to and "neutralize" natural ligand.

Such compounds can include, but are not limited to, peptides such as, for example, soluble peptides, including but not limited to members of random peptide libraries; (see, Lam, K.S. et al., 1991, Nature 354:82-84; Houghten, R.

et al., 1991, Nature 354:84-86), and combinatorial chemistryderived molecular library made of D- and/or L- configuration amino acids, phosphopeptides (including, but not limited to members of random or partially degenerate, directed phosphopeptide libraries; see, Songyang, Z. et al., 1993, Cell 72:767-778), antibodies (including, but not limited to, polyclonal, monoclonal, humanized, anti-idiotypic, chimeric or single chain antibodies, and FAb, F(ab') 2 and FAb expression library fragments, and epitope-binding fragments thereof), and small organic or inorganic molecules.

Other compounds that can be screened in accordance with the invention include but are not limited to small organic molecules that are able to cross the blood-brain barrier, gain entry into an appropriate cell in the choroid plexus, the hypothalamus, etc.) and affect the expression of a NGPCR gene or some other gene involved in the NGPCR signal transduction pathway by interacting with the regulatory region or transcription factors involved in gene expression); or such compounds that affect the activity of the NGPCR by inhibiting or enhancing the enzymatic activity of a CD) or the activity of some other intracellular factor involved in the NGPCR signal transduction pathway.

Computer modeling and searching technologies permit identification of compounds, or the improvement of already identified compounds, that can modulate NGPCR expression or activity. Having identified such a compound or composition, the active sites or regions are identified. Such active sites might typically be ligand binding sites. The active site can be identified using methods known in the art including, for example, from the amino acid sequences of peptides, from the nucleotide sequences of nucleic acids, or from study of WO 01/18207 PCT/US00/24591 complexes of the relevant compound or composition with its natural ligand. In the latter case, chemical or X-ray crystallographic methods can be used to find the active site by finding where on the factor the complexed ligand is found.

Next, the three dimensional geometric structure of the active site is determined. This can be done by known methods, including X-ray crystallography, which can determine a complete molecular structure. On the other hand, solid or liquid phase NMR can be used to determine certain intramolecular distances. Any other experimental method of structure determination can be used to obtain partial or complete geometric structures. The geometric structures may be measured with a complexed ligand, natural or artificial, which may increase the accuracy of the active site structure determined.

If an incomplete or insufficiently accurate structure is determined, the methods of computer based numerical modeling can be used to complete the structure or improve its accuracy.

Any recognized modeling method may be used, including parameterized models specific to particular biopolymers such as proteins or nucleic acids, molecular dynamics models based on computing molecular motions, statistical mechanics models based on thermal ensembles, or combined models. For most types of models, standard molecular force fields, representing the forces between constituent atoms and groups, are necessary, and can be selected from force fields known in physical chemistry. The incomplete or less accurate experimental structures can serve as constraints on the complete and more accurate structures computed by these modeling methods.

Finally, having determined the structure of the active site, either experimentally, by modeling, or by a combination, candidate modulating compounds can be identified by searching databases containing compounds along with information on their molecular structure. Such a search seeks compounds having structures that match the determined active site structure and that interact with the groups defining the active site. Such WO 01/18207 PCT/US00/24591 a search can be manual, but is preferably computer assisted.

These compounds found from this search are potential NGPCR modulating compounds.

Alternatively, these methods can be used to identify improved modulating compounds from an already known modulating compound or ligand. The composition of the known compound can be modified and the structural effects of modification can be determined using the experimental and computer modeling methods described above applied to the new composition. The altered structure is then compared to the active site structure of the compound to determine if an improved fit or interaction results. In this manner systematic variations in composition, such as by varying side groups, can be quickly evaluated to obtain modified modulating compounds or ligands of improved specificity or activity.

Further experimental and computer modeling methods useful to identify modulating compounds based upon identification of the active sites of a NGPCR, and related transduction and transcription factors will be apparent to those of skill in the art.

Examples of molecular modeling systems are the CHARMm and QUANTA programs (Polygen Corporation, Waltham, MA). CHARMm performs the energy minimization and molecular dynamics functions. QUANTA performs the construction, graphic modeling and analysis of molecular structure. QUANTA allows interactive construction, modification, visualization, and analysis of the behavior of molecules with each other.

A number of articles review computer modeling of drugs interactive with specific proteins, such as Rotivinen, et al., 1988, Acta Pharmaceutical Fennica 97:159-166; Ripka, New Scientist 54-57 (June 16, 1988); McKinaly and Rossmann, 1989, Annu. Rev. Pharmacol. Toxiciol. 29:111-122; Perry and Davies, OSAR: Quantitative Structure-Activity Relationships in Drug Design pp. 189-193 (Alan R. Liss, Inc. 1989); Lewis and Dean, 1989 Proc. R. Soc. Lond. 236:125-140 and 141-162; and, with respect to a model receptor for nucleic acid components, Askew, et al., 1989, J. Am. Chem. Soc. 111:1082-1090. Other WO 01/18207 PCTUSOO/24591 computer programs that screen and graphically depict chemicals are available from companies such as BioDesign, Inc.

(Pasadena, Allelix, Inc. (Mississauga, Ontario, Canada), and Hypercube, Inc. (Cambridge, Ontario). Although these are primarily designed for application to drugs specific to particular proteins, they can be adapted to design of drugs specific to regions of DNA or RNA, once that region is identified.

Although described above with reference to design and generation of compounds which could alter binding, one could also screen libraries of known compounds, including natural products or synthetic chemicals, and biologically active materials, including proteins, for compounds which are inhibitors or activators.

Cell-based systems can also be used to identify compounds that bind NGPCRs as well as assess the altered activity associated with such binding in living cells. One tool of particular interest for such assays is green fluorescent protein which is described, inter alia, in U.S. Patent No.

5,625,048, herein incorporated by reference. Cells that may be used in such cellular assays include, but are not limited to, leukocytes, or cell lines derived from leukocytes, lymphocytes, stem cells, including embryonic stem cells, and the like. In addition, expression host cells cells, COS cells, CHO cells, OMK cells, fibroblasts, Sf9 cells) genetically engineered to express a functional NGPCR of interest and to respond to activation by the test, or natural, ligand, as measured by a chemical or phenotypic change, or induction of another host cell gene, can be used as an end point in the assay.

Compounds identified via assays such as those described herein may be useful, for example, in elaborating the biological function of a NGPCR gene product. Such compounds can be administered to a patient at therapeutically effective doses to treat any of a variety of physiological or mental disorders. A therapeutically effective dose refers to that amount of the compound sufficient to result in any WO 01/18207 PCT/US00/24591 amelioration, impediment, prevention, or alteration of any biological or overt symptom.

Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for determining the

LD

50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).

The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio

LD

50

/ED

50 Compounds which exhibit large therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the

ED

50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography.

Pharmaceutical compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers or excipients. Thus, the compounds and their physiologically acceptable salts and solvates may be formulated for WO 01/18207 PCT/US00/24591 administration by inhalation or insufflation (either through the mouth or the nose) or oral, buccal, parenteral, intracranial, intrathecal, or rectal administration.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants magnesium stearate, talc or silica); disintegrants potato starch or sodium starch glycolate); or wetting agents sodium lauryl sulphate).

The tablets may be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents lecithin or acacia); non-aqueous vehicles almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring, coloring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound.

For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable WO 01/18207 PCTUS00/24591 gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, in ampoules or in multidose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, sterile pyrogenfree water, before use.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

WO 01/18207 PCT/US00/24591 5.5.1 IN VITRO SCREENING ASSAYS FOR COMPOUNDS THAT BIND TO NGPCRs In vitro systems may be designed to identify compounds capable of interacting with binding to) NGPCR (including, but not limited to, a ECD or CD of NGPCR) Compounds identified may be useful, for example, in modulating the activity of wild type and/or mutant NGPCR gene products; may be useful in elaborating the biological function of the NGPCR; may be utilized in screens for identifying compounds that disrupt normal NGPCR interactions; or may in themselves disrupt such interactions.

The principle of the assays used to identify compounds that bind to the NGPCR involves preparing a reaction mixture of the NGPCR and the test compound under conditions and for a time sufficient to allow the two components to interact and bind, thus forming a complex which can be removed and/or detected in the reaction mixture. The NGPCR species used can vary depending upon the goal of the screening assay. For example, where agonists of the natural ligand are sought, the full length NGPCR, or a soluble truncated NGPCR, in which the TM and/or CD is deleted from the molecule, a peptide corresponding to a ECD or a fusion protein containing one or more NGPCR ECD fused to a protein or polypeptide that affords advantages in the assay system labeling, isolation of the resulting complex, etc.) can be utilized. Where compounds that interact with the cytoplasmic domain are sought to be identified, peptides corresponding to the NGPCR CD and fusion proteins containing the NGPCR CD can be used.

The screening assays can be conducted in a variety of ways. For example, one method to conduct such an assay would involve anchoring the NGPCR protein, polypeptide, peptide or fusion protein or the test substance onto a solid phase and detecting NGPCR/test compound complexes anchored on the solid phase at the end of the reaction. In one embodiment of such a method, the NGPCR reactant may be anchored onto a solid surface, and the test compound, which is not anchored, may be labeled, either directly or indirectly.

WO 01/18207 PCT/US00/24591 In practice, microtiter plates may conveniently be utilized as the solid phase. The anchored component may be immobilized by non-covalent or covalent attachments. Noncovalent attachment may be accomplished by simply coating the solid surface with a solution of the protein and drying.

Alternatively, an immobilized antibody, preferably a monoclonal antibody, specific for the protein to be immobilized may be used to anchor the protein to the solid surface. The surfaces may be prepared in advance and stored.

In order to conduct the assay, the nonimmobilized component is added to the coated surface containing the anchored component. After the reaction is complete, unreacted components are removed by washing) under conditions such that any complexes formed will remain immobilized on the solid surface. The detection of complexes anchored on the solid surface can be accomplished in a number of ways. Where the previously nonimmobilized component is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the previously nonimmobilized component is not pre-labeled, an indirect label can be used to detect complexes anchored on the surface; using a labeled antibody specific for the previously nonimmobilized component (the antibody, in turn, may be directly labeled or indirectly labeled with a labeled anti-Ig antibody).

Alternatively, a reaction can be conducted in a liquid phase, the reaction products separated from unreacted components, and complexes detected; using an immobilized antibody specific for a NGPCR protein, polypeptide, peptide or fusion protein or the test compound to anchor any complexes formed in solution, and a labeled antibody specific for the other component of the possible complex to detect anchored complexes.

Alternatively, cell-based assays can be used to identify compounds that interact with NGPCR. To this end, cell lines that express a NGPCR, or cell lines COS cells, CHO cells, fibroblasts, etc.) that have been genetically engineered to express a NGPCR by transfection or WO 01/18207 PCT/US00/24591 transduction of NGPCR DNA) can be used. Interaction of the test compound with, for example, a ECD of a NGPCR expressed by the host cell can be determined by comparison or competition with native ligand.

5.5.2 ASSAYS FOR INTRACELLULAR PROTEINS THAT INTERACT WITH NGPCRs Any method suitable for detecting protein-protein interactions can be employed for identifying transmembrane proteins or intracellular proteins that interact with a NGPCR.

Among the traditional methods which may be employed are co-immunoprecipitation, crosslinking and co-purification through gradients or chromatographic columns of cell lysates or proteins obtained from cell lysates and a NGPCR to identify proteins in the lysate that interact with the NGPCR. For these assays, the NGPCR component used can be a full length NGPCR, a soluble derivative lacking the membrane-anchoring region a truncated NGPCR in which a TM is deleted resulting in a truncated molecule containing a ECD fused to a CD), a peptide corresponding to a CD or a fusion protein containing a CD of a NGPCR. Once isolated, such an intracellular protein can be identified and can, in turn, be used, in conjunction with standard techniques, to identify proteins with which it interacts. For example, at least a portion of the amino acid sequence of an intracellular protein which interacts with a NGPCR can be ascertained using techniques well known to those of skill in the art, such as via the Edman degradation technique. (See, Creighton, 1983, "Proteins: Structures and Molecular Principles", W.H.

Freeman Co., pp.34-49). The amino acid sequence obtained may be used as a guide for the generation of oligonucleotide mixtures that can be used to screen for gene sequences encoding such intracellular proteins. Screening may be accomplished, for example, by standard hybridization or PCR techniques. Techniques for the generation of oligonucleotide mixtures and the screening are well-known. (See, e.g., Ausubel, supra, and PCR Protocols: A Guide to Methods and WO 01/18207 PCT/US00/24591 Applications, 1990, Innis, M. et al., eds. Academic Press, Inc., New York).

Additionally, methods may be employed which result in the simultaneous identification of genes which encode the transmembrane or intracellular proteins interacting with NGPCR. These methods include, for example, probing expression, libraries, in a manner similar to the well known technique of antibody probing of Xgtll libraries, using labeled NGPCR protein, or an NGPCR polypeptide, peptide or fusion protein, an NGPCR polypeptide or NGPCR domain fused to a marker an enzyme, fluor, luminescent protein, or dye), or an Ig-Fc domain.

One method which detects protein interactions in vivo, the two-hybrid system, is described in detail for illustration only and not by way of limitation. One version of this system has been described (Chien et al., 1991, Proc. Natl. Acad. Sci.

USA, 88:9578-9582) and is commercially available from Clontech (Palo Alto, CA).

Briefly, utilizing such a system, plasmids are constructed that encode two hybrid proteins: one plasmid consists of nucleotides encoding the DNA-binding domain of a transcription activator protein fused to a NGPCR nucleotide sequence encoding NGPCR, an NGPCR polypeptide, peptide or fusion protein, and the other plasmid consists of nucleotides encoding the transcription activator protein's activation domain fused to a cDNA encoding an unknown protein which has been recombined into this plasmid as part of a cDNA library.

The DNA-binding domain fusion plasmid and the cDNA library are transformed into a strain of the yeast Saccharomyces cerevisiae that contains a reporter gene HBS or lacZ) whose regulatory region contains the transcription activator's binding site. Either hybrid protein alone cannot activate transcription of the reporter gene: the DNA-binding domain hybrid cannot because it does not provide activation function and the activation domain hybrid cannot because it cannot localize to the activator's binding sites. Interaction of the two hybrid proteins reconstitutes the functional activator WO 01/18207 PCT/US00/24591 protein and results in expression of the reporter gene, which is detected by an assay for the reporter gene product.

The two-hybrid system or related methodology may be used to screen activation domain libraries for proteins that interact with the "bait" gene product. By way of example, and not by way of limitation, a NGPCR may be used as the bait gene product. Total genomic or cDNA sequences are fused to the DNA encoding an activation domain. This library and a plasmid encoding a hybrid of a bait NGPCR gene product fused to'the DNA-binding domain are cotransformed into a yeast reporter strain, and the resulting transformants are screened for those that express the reporter gene. For example, and not by way of limitation, a bait NGPCR gene sequence, such as the open reading frame of a NGPCR (or a domain of a NGPCR) can be cloned into a vector such that it is translationally fused to the DNA encoding the DNA-binding domain of the GAL4 protein.

These colonies are purified and the library plasmids responsible for reporter gene expression are isolated. DNA sequencing is then used to identify the proteins encoded by the library plasmids.

A cDNA library of the cell line from which proteins that interact with bait NGPCR gene product are to be detected can be made using methods routinely practiced in the art.

According to the particular system described herein, for example, the cDNA fragments can be inserted into a vector such that they are translationally fused to the transcriptional activation domain of GAL4. This library can be co-transformed along with the bait NGPCR gene-GAL4 fusion plasmid into a yeast strain which contains a lacZ gene driven by a promoter which contains GAL4 activation sequence. A cDNA encoded protein, fused to GAL4 transcriptional activation domain, that interacts with bait NGPCR gene product will reconstitute an active GAL4 protein and thereby drive expression of the HIS3 gene. Colonies which express HIS3 can be detected by their growth on petri dishes containing semi-solid agar based media lacking histidine. The cDNA can then be purified from these strains, and used to produce and isolate the bait NGPCR gene- WO 01/18207 PCT/US00/24591 interacting protein using techniques routinely practiced in the art.

5.5.3 ASSAYS FOR COMPOUNDS THAT INTERFERE WITH NGPCR/INTRACELLULAR OR NGPCR/ TRANSMEMBRANE MACROMOLECULE INTERACTION The macromolecules that interact with the NGPCR are referred to, for purposes of this discussion, as "binding partners". These binding partners are likely to be involved in the NGPCR signal transduction pathway. Therefore, it is desirable to identify compounds that interfere with or disrupt the interaction of such binding partners which may be useful in regulating the activity of a NGPCR and controlling disorders associated with NGPCR activity.

The basic principle of the assay systems used to identify compounds that interfere with the interaction between a NGPCR and its binding partner or partners involves preparing a reaction mixture containing NGPCR protein, polypeptide, peptide or fusion protein as described in Sections 5.5.1 and 5.5.2 above, and the binding partner under conditions and for a time sufficient to allow the two to interact and bind, thus forming a complex. In order to test a compound for inhibitory activity, the reaction mixture is prepared in the presence and absence of the test compound. The test compound may be initially included in the reaction mixture, or may be added at a time subsequent to the addition of the NGPCR moiety and its binding partner. Control reaction mixtures are incubated without the test compound or with a placebo. The formation of any complexes between the NGPCR moiety and the binding partner is then detected. The formation of a complex in the control reaction, but not in the reaction mixture containing the test compound, indicates that the compound interferes with the interaction of the NGPCR and the interactive binding partner.

Additionally, complex formation within reaction mixtures containing the test compound and normal NGPCR protein may also be compared to complex formation within reaction mixtures containing the test compound and a mutant NGPCR. This comparison may be important in those cases wherein it is WO 01/18207 PCT/US00/24591 desirable to identify compounds that specifically disrupt interactions of mutant, or mutated, NGPCRs but not normal NGPCRs.

The assay for compounds that interfere with the interaction of the NGPCR and binding partners can be conducted in a heterogeneous or homogeneous format. Heterogeneous assays involve anchoring either the NGPCR moiety product or the binding partner onto a solid phase and detecting complexes anchored on the solid phase at the end of the reaction. In homogeneous assays, the entire reaction is carried out in a liquid phase. In either approach, the order of addition of reactants can be varied to obtain different information about the compounds being tested. For example, test compounds that interfere with the interaction by competition can be identified by conducting the reaction in the presence of the test substance; by adding the test substance to the reaction mixture prior to, or simultaneously with, a NGPCR moiety and interactive binding partner. Alternatively, test compounds that disrupt preformed complexes, e.g. compounds with higher binding constants that displace one of the components from the complex, can be tested by adding the test compound to the reaction mixture after complexes have been formed. The various formats are described briefly below.

In a heterogeneous assay system, either a NGPCR moiety or an interactive binding partner, is anchored onto a solid surface, while the non-anchored species is labeled, either directly or indirectly. In practice, microtiter plates are conveniently utilized. The anchored species may be immobilized by non-covalent or covalent attachments. Noncovalent attachment may be accomplished simply by coating the solid surface with a solution of the NGPCR gene product or binding partner and drying. Alternatively, an immobilized antibody specific for the species to be anchored may be used to anchor the species to the solid surface. The surfaces may be prepared in advance and stored.

In order to conduct the assay, the partner of the immobilized species is exposed to the coated surface with or WO 01/18207 PCT/US00/24591 without the test compound. After the reaction is complete, unreacted components are removed by washing) and any complexes formed will remain immobilized on the solid surface.

The detection of complexes anchored on the solid surface can be accomplished in a number of ways. Where the nonimmobilized species is pre-labeled, the detection of label immobilized on the surface indicates that complexes were formed. Where the non-immobilized species is not pre-labeled, an indirect label can be used to detect complexes anchored on the surface; using a labeled antibody specific for the initially non-immobilized species (the antibody, in turn, may be directly labeled or indirectly labeled with a labeled anti- Ig antibody). Depending upon the order of addition of reaction components, test compounds which inhibit complex formation or which disrupt preformed complexes can be detected.

Alternatively, the reaction can be conducted in a liquid phase in the presence or absence of the test compound, the reaction products separated from unreacted components, and complexes detected; using an immobilized antibody specific for one of the binding components to anchor any complexes formed in solution, and a labeled antibody specific for the other partner todetect anchored complexes. Again, depending upon the order of addition of reactants to the liquid phase, test compounds which inhibit complex or which disrupt preformed complexes can be identified.

In an alternate embodiment of the invention, a homogeneous assay can be used. In this approach, a preformed complex of a NGPCR moiety and an interactive binding partner is prepared in which either the NGPCR or its binding partners is labeled, but the signal generated by the label is quenched due to formation of the complex (see, U.S. Patent No. 4,109,496 by Rubenstein which utilizes this approach for immunoassays). The addition of a test substance that competes with and displaces one of the species from the preformed complex will result in the generation of a signal above background. In this way, test substances which disrupt WO 01/18207 PCT/US00/24591 NGPCR/intracellular binding partner interaction can be identified.

In a particular embodiment, a NGPCR fusion can be prepared for immobilization. For example, a NGPCR or a peptide fragment, corresponding to a CD, can be fused to a glutathione-S-transferase (GST) gene using a fusion vector, such as pGEX-5X-1, in such a manner that its binding activity is maintained in the resulting fusion protein. The interactive binding partner can be purified and used to raise a monoclonal antibody, using methods routinely practiced in the art and described above, in Section 5.3. This antibody can be labeled with the radioactive isotope 125I, for example, by methods routinely practiced in the art. In a heterogeneous assay, the GST-NGPCR fusion protein can be anchored to glutathione-agarose beads. The interactive binding partner can then be added in the presence or absence of the test compound in a manner that allows interaction and binding to occur. At the end of the reaction period, unbound material can be washed away, and the labeled monoclonal antibody can be added to the system and allowed to bind to the complexed components. The interaction between a NGPCR gene product and the interactive binding partner can be detected by measuring the amount of radioactivity that remains associated with the glutathione-agarose beads. A successful inhibition of the interaction by the test compound will result in a decrease in measured radioactivity.

Alternatively, the GST-NGPCR fusion protein and the interactive binding partner can be mixed together in liquid in the absence of the solid glutathione-agarose beads. The test compound can be added either during or after the species are allowed to interact. This mixture can then be added to the glutathione-agarose beads and unbound material is washed away.

Again the extent of inhibition of the NGPCR/binding partner interaction can be detected by adding the labeled antibody and measuring the radioactivity associated with the beads.

In another embodiment of the invention, these same techniques can be employed using peptide fragments that WO 01/18207 PCT/US00/24591 correspond to the binding domains of a NGPCR and/or the interactive or binding partner (in cases where the binding partner is a protein), in place of one or both of the full length proteins. Any number of methods routinely practiced in the art can be used to identify and isolate the binding sites.

These methods include, but are not limited to, mutagenesis of the gene encoding one of the proteins and screening for disruption of binding in a co-immunoprecipitation assay.

Compensatory mutations in the gene encoding the second species in the complex can then be selected. Sequence analysis of the genes encoding the respective proteins will reveal the mutations that correspond to the region of the protein involved in interactive binding. Alternatively, one protein can be anchored to a solid surface using methods described above, and allowed to interact with and bind to its labeled binding partner, which has been treated with a proteolytic enzyme, such as trypsin. After washing, a relatively short, labeled peptide comprising the binding domain may remain associated with the solid material, which can be isolated and identified by amino acid sequencing. Also, once the gene coding for the intracellular binding partner is obtained, short gene segments can be engineered to express peptide fragments of the protein, which can then be tested for binding activity and purified or synthesized.

For example, and not by way of limitation, a NGPCR gene product can be anchored to a solid material as described, above, by making a GST-NGPCR fusion protein and allowing it to bind to glutathione agarose beads. The interactive binding partner can be labeled with a radioactive isotope, such as and cleaved with a proteolytic enzyme such as trypsin.

Cleavage products can then be added to the anchored GST-NGPCR fusion protein and allowed to bind. After washing away unbound peptides, labeled bound material, representing the intracellular binding partner binding domain, can be eluted, purified, and analyzed for amino acid sequence by well-known methods. Peptides so identified can be produced synthetically WO 01/18207 PCTUS00/24591 or fused to appropriate facilitative proteins using recombinant DNA technology.

The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings.

Such modifications are intended to fall within the scope of the appended claims. All of the cited references, publications, patents and patent applications are herein incorporated by reference in their entirety.

Throughout this specification and the claims, unless the context requires otherwise, the word "comprise" and its variations, such as "comprises" and "comprising, will be understood to imply the inclusion of a stated integer or step i 0::0 or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference to any prior art in this specification is not, and should not be taken as an acknowledgement or any form of suggestion that such art forms part of the common general knowledge in Australia.

EDITORIAL NOTE APPLICATION NUMBER 75759/00 The following sequence listing pages 1 87 are part of the description. The claims pages follow on pages 57 58.

WO 01/18207 WO 0118207PCT/USOO/2459 1 SEQUENCE LISTING <110> Turner, C. Alexander Jr.

Nehis, m~ichael Friedrich, Glenn Scoville, John Zambrowicz, Brian Sands, Arthur T.

<120> Novel Human 7TM Proteins and Receptors and Polynucleotides Encoding the Same <130> LEX-0041-PCT <150> US 60/153,366 <151> 1999-09-10 <150> US 60/165,510 <151> 1999-11-15 <160> 59 <170> FastSEQ for Windows Version <210> 1 <211> 3753 <212> DNA <213> homo sapiens <400> 1 atgtttcgct cagatcgaat ttcttatttg ctttatatat tgccgagtgg ttttgtccaa tacccaaaca gccaggcttg ataacattta, acgactttga cttgataatg gagagagcca aactcaagtg cgaatgagat ggtttcaatg ccagctacat ccccagacat cagatgctta agtgctttca. cactctgctt gctttctcct actcaaatgc ggctactttc tatccatttc gaaaaagaag acatttttgc ttgggctcta ttggtgtaaa attagtaaag ttattcctgg gtctctctaa aaggggacat atcctctcca acctcagctg tggaatatcc caaacctagc atcccgctcc cagcagcaga actgtaaact ctcctagtac agaatcgata aacaaaggaa atccttcgtc accctgaggt ttccaaaatt ggaactacac gaggacaaga ttaaagtcaa cttctagttt acaatgctac ctcctaaaaa ataatgagtc caactgggtc attgtcttgc ccttctgaat acgttcttc ttttacaatg ctaccaaccc ttaaaagaag caaatgaagt ttaacctcag ccaatattac gaaaacattg atataacact gtggagc tgc: catgtgtgtt cccttctggg catgtggacg cat tgaagaa gactaaattt gcatgtgtcc cagagt tgcc ccaggtatct tgaagcaacc atccttcaca tgat tcaaaa agaaagcttt tttcaaaaga gaa tgggaaa ttataacttt taatgtgaaa tctgaaagct ac tggccagc tacaccacce tgatggaatt aaaagtacag ggtttatgtc gagaagcctt caacaatact cttggatgaa catggaggaa ttgtccagac attggtaacc tgctaaccag caacattgtg tggc tcaact cattggaaat cctcactcag acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagt tggcc caattgc tca tgtttgttga gaacagctct aactatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tg tgcagacc actgtcacca atctatagaa agcaaggtgg gttaatatca gagga tgagc aatttagaag ggcttgaggc cccaaaggct aagcctggct tactggggac attttaaatt gaacaggtca ctaatgaata ggaagcccag cagtgtgggg ctccatgcta ccaccggtta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat a tgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat tcgactggca taagCtgtgg tggggaccct ctaacatgcc tatccgtagt cagaatggct gttttcacct caaggttggt gaaaaatcat tacatacagt actactggcc tttctgcttc ctgttgatat taactgctga aaagaattgt tat tttctaa tcctctcctg atgtgccaac ccctaacgac tatcattcag ctcattatcc cctatcattt cc agaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acctgtcaaa gaataattct tgattctacc aaatgaaatt gaatgccaaa aaatgacttc ttcctacctg ctgtcaagct tgttactaac gattcagaac caattcaacc gagtgctgga gctttgggcc tcagcagaag gaatgtgaga atc tatccaa tcggatatgt ctccaactgt tgggcagaac gaataaagaa tatcttaagc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1 87 WO 01/18207 WO 0118207PCT[USOO/2459 1 agttcagaca gccttcaaga ctcagcgtat ccaagcaata gcatctgtaa gttagaagag caaagaaaaa aatctgaagg cccatctgtg ggatgtgttg acacactttg actaaagtcc gcaactctcc t tgatgaacc atcacctcct cttctggcaa aaagtattta ttgcctgcct aaagaaagtt ttttatgtga attgtggtaa gaagaagtgt tggggttttg atcttcaatt gttcagaaac gattggagta ttgtcttcaa tctaccacct tcaaaactgg gataaggtca tcagacacct gtgacttgct tagacctaaa catccctgtt atgaatcgta ttttgcctcc cacagtttac ctttagtgag atcctgttca ccttctggga cacacagaga gagttctgat tcactttcat tgacatatgt tgagcacagc tcaatgtgga cctttacctg acacttacat tagtggtgtc atgggaaaga cctgtgctgg tggtgcagat taaggaacc t cattCtttgc cattacaagg agtggcggcg agacagc tac gctccattgg atttcaaaag cccatgctga agggttattg tcagccacag tgagtcatct tagcacatca accagggaca tttccagatg aaacttactt tttcttcaac ttatgtgatg aataaaaatc tctgaacaaa ttcagatgca ggaccttcca cagctatatt tgcttttgag cctgctgttc tggactttgc gatggggc ta tcgccgatac agttgttcta aaaaggtgat gtattttgga ctgtgggagg gcgcagtg Lg c tggggaccc ct tat ttat a gcatctctgc caatatcatc ttccaactca gaatagccac tggagatcaa caatgctcat cacaaagttt tctgaagctt catgtgaata aatgcaattt gattttgaga gagaatttaa aaaac tggac gcgtgcagta aaacatacaa aacaaaagtt agtgagacag agaagtgcc t gggtgtggaa aaattgcgaa ctgaatctcc attgctgttg gaagcaattc attctaaaat gcgagcagaa gaattctgtt gtcatgtttt aa tggcaaga gttagcttga ttaaatatcc ttcatcttcc tgtggtagat aagaaaagtt acctatctta acagacagtg acatcaatca tcagacaact taa taaaaacaat ttacaactcg caaattttag gtggacaagt gtccagaaga ttttccagga ttggaaacat gaactcagga ttggaggatg tctgcctgtg cacagttaga tatctgctat gggattatcc tcttcctcct cagtcctgtt acatgtacat tctgcatcat acaacaatga ggattcaaga ttctgaacat gaagcaaccg cctttctgtt cct tcatgta actgtgctat ttcggttagc ctgataatct catccaaatc cttccatgga tccctgtcca tctataaaaa tgatgaattg gaacttggct cat tggtctt ggatccactg ttctgtatta tgtaggaccc tactatccag agtgcatcat gaacacgtca taaccacttc tgcaagaaac tttttcagca ctccaaaatc agatggctgg gcatttcttc tgc t ctagt t tggctggggt agtctatgga tccagtcata tgccatgttc gaccctgaga gggcatgaca cCtcttCtc gaaggagaa t agataactca aggaaaatct taaatccagc caagtccttg tcaggtcatt tattatcatg 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3753 <210> 2 <211> 1250 <212> PRT <213> homo sapiens <400> 2 Met Phe Arg Ser Asp Arg Met Trp Ser Ser Pro Leu Leu Phe Leu Phe Ala Ser Ala Val Trp Gly Cys Ala Asn Cys His Trp Lys Trp Lys Pro 10 Tyr Ile Met Cys Val Pro His Arg Val Val Leu Ser Asn Pro Ser Gin Ile Gly Thr Phe Thr Ser Pro Tyr Pro Asn Pro Asn Ser Ala Thr Cys Met Trp Thr Phe Asn Asp Phe Leu Ser Leu Asp Leu Arg Ala Pro Tyr Ile Ile Asp Ile Glu Asp Ser Asn Gly Ser Gin Pro Asn Cys Thr Lys Phe 110 Ala Asn Glu Ile Tyr Cys Gly Met His 100 Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Val Ser 130 Phe Ser Ser Tyr Ilie Arg 145 Pro Gin Thr Ser Ile Pro Giu Leu 180 Gly His Glu Asp Ser Asp Phe 135 Val Ala Val 150 Asp Ala Tyr Ile Gin Lys Ser Leu Arg Asn Phe Asn Ala Lys Val Ile Gin Val Ala Lys Ala Phe Thr Phe Glu Ala Ser Ile Ser 175 Thr Lys Val 190 Asn Ala Ser Ser Asp Trp Thr Phe Ser Tyr Ser 2 87 WO 01/18207 Phe Ser 225 Giu Trp Giu Giy Gly 305 Ile Gin Asn Aia Pro 385 Arg Val1 Val Tyr Lys 465 Leu Ile Arg Giu Val1 545 Phe Ile Asn Ile Ile 625 Ser Ile Asn Gly 200 Giy Leu Glu Ile Thr 280 Asn Leu Asn Pro Leu 360 Thr Val Asp His Thr 440 His Asp Asn Asn Arg 520 Trp, Pro Leu Ala Asn 600 Ile Met Giu Ile Ala 680 Phe Lys Leu Ser Gly 265 Ile Gin Trp Val Asn 345 Ile Leu Thr Gly Pro 425 Phe Leu Giu Asn Asn 505 Gin Pro Giy Val Asn 585 Leu Val1 Asn Ser

ASP

665 Leu Ser Ser 220 Ala Gin Phe Val1 Ile 300 Thr Asn Leu Pro Aia 380 Met Tyr Lys Trp Giy 460 Leu Leu Leu His Gin 540 Aia Trp Aia Ala Giu 620 Ser Giu Ser Ser Leu 700 Tyr Pro Cys Arg 270 Pro Ser Asn Val1 Ala 350 Aia Val Vali Ile Gin 430 Tyr

ASP

Leu Giy Giu 510 LeU Ser Arg Pro Gin 590 Ile Asn Ile Leu Ser 670 Leu Ser PCTUSOO/24591 Leu Lys 240 Val Tyr Asn Lys Lys 320 Trp Ser Leu Ser Asn 400 Val1 Lys Vai Ile Aia 480 Ile Leu Met Tyr Cys 560 Asp Leu Asn Asp Ser 640 Thr Vai Pro Asn 3 87 WO 01/18207 WO 0118207PCT/1JS0012459 I Glu Ser Tyr Phe Gin Met Asp Phe Giu Ser Giy Gin Val Asp Pro Leu 705 710 715 720 Ala Ser Val Ile Leu Pro Pro Asn Leu Leu Giu Asn Leu Ser Pro Giu 725 730 735 Asp Ser Val Leu Val Arg Arg Ala Gin Phe Thr Phe Phe Asn Lys Thr 740 745 750 Gly Leu Phe Gin Asp Val Gly Pro Gin Arg Lys Thr Leu Val Ser Tyr 755 760 765 Val Met Ala Cys Ser Ile Gly Asi Ile Thr Ile Gin Asn Leu Lys Asp 770 775 780 Pro Val Gin Ile Lys Ilie Lys His Thr Arg Thr Gin Glu Val His His 785 790 795 800 Pro Ile Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser Phe Giy Giy 805 810 815 Trp Asn Thr Ser Gly Cys Val Ala His Arg Asp Ser Asp Ala Ser Giu 820 825 830 Thr Val Cys Leu Cys Asn His Phe Thr His Phe Gly Val Leu Met Asp 835 840 845 Leu Pro Arg Ser Ala Ser Gin Leu Asp Ala Arg Asn Thr Lys Val Leu 850 855 860 Thr Phe Ile Ser Tyr Ile Gly Cys Gly Ile Ser Ala Ile Phe Ser Aia 865 870 875 880 Ala Thr Leu Leu Thr Tyr Val Ala Phe Giu Lys Leu Arg Arg Asp Tyr 885 890 895 Pro Ser Lys Ilie Leu Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn 900 905 910 Leu Leu Phe Leu Leu Asp Gly Trp Ilie Thr Ser Phe Asn Val Asp Gly 915 920 925 Leu Cys Ile Ala Val Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr 930 935 940 Phe Thr Trp Met Gly Leu Giu Ala Ile His Met Tyr Ile Ala Leu Val 945 950 955 960 Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile 965 970 975 Ilie Gly Trp Giy Leu Pro Ala Leu Val Val Ser Val Val Leu Ala Ser 980 985 990 Arg Asn Asn Asn Glu Val Tyr Giy Lys Giu Ser Tyr Gly Lys Giu Lys 995 1000 1005 Gly Asp Giu Phe Cys Trp Ile Gin Asp Pro Val Ile Phe Tyr Val Thr 1010 1015 1020 Cys Ala Giy Tyr Phe Gly Val Met Phe Phe Leu Asn Ile Ala Met Phe 1025 1030 1035 1040 Ilie Vai Val Met Val Gin Ile Cys Gly Arg Asn Gly Lys Arg Ser Asn 1045 1050 1055 Arg Thr Leu Arg Giu Giu Val Leu Arg Asn Leu Arg Ser Val Val Ser 1060 1065 1070 Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp 1075 1080 1085 Gly Pro Leu Asn Ilie Pro Phe Met Tyr Leu Phe Ser Ilie Phe Asn Ser 1090 1095 1100 Leu Gin Gly Leu Phe Ile Phe Ilie Phe His Cys Ala met Lys Giu Asn 1105 1110 ills 1120 Val Gin Lays Gin Trp Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu 1125 1130 1135 Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys 1140 1145 1150 Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser Ilie Gly Ser 1155 1160 1165 Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr 1170 1175 1180 Phe Lys Arg Asn Ser His Thr Asp Ser Ala Ser Met Asp Lys Ser Leu 1185 1190 1195 1200 Ser Lys Leu Ala His Ala Asp Gly Asp Gin Thr Ser Ile Ilie Pro Val 4 87 WO 01/18207 WO 0118207PCT/USOO/24591 1205 1210 1215 His Gin Val Ilie Asp Lys Val Lys Gly Tyr Cys Asn Ala His Ser Asp 1220 1225 1230 Asn Phe Tyr Lys Asn Ilie Ilie Met Ser Asp Thr Phe Ser His Ser Thr 1235 1240 1245 Lys Phe 1250 <210> 3 <211> 3666 <212> DNA <213> homo sapiens <400> 3 atgtttcgct ttcttatttg tgccgagtgg tacccaaaca ataacattta cttgataatg aactcaagtg ggtttcaatg ccccagacat agtgctttca gctttCtcct ggctactttc gaaaaagaag ttgggctcta attagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc actgtaaact agaatcgata atccttcgtc ttccaaaatt gaggacaaga cttctagttt ctcctaaaaa caactgggtc ccttctgaat ttttacaatg ttaaaagaag ttaacctcag gaaaacattg agttcagaca gccttcaaga ctcagcgtat ccaagcaata gcatctgtaa gt tagaagag caaagaaaaa aatctgaagg cccatctgtg ggatgtgttg acacactttg ac taaagtcc gcaactctcc ttgatgaacc atcacctcct cttctggcaa aaagtattta cagatcgaat ctttatatat ttttgtccaa gccaggcttg acgactttga gagagagcca cgaatgagat ccagctacat cagatgctta cactctgctt actcaaatgc tatccatttc acatttttgc ttggtgtaaa ttattcctgg aaggggacat acctcagctg caaacctagc cagcagcaga ctcctagtac aacaaaggaa accctgaggt ggaactacac ttaaagtcaa acaatgctac ataa tgagtc attgtcttgc acgttcttcc ctaccaaccc caaa tgaagt ccaatattac atataacact gtgacttgct tagacctaaa catccctgtt atgaatcgta ttttgcctcc cacagtttac ctttagtgag atcctgttca ccttctggga cacacagaga gagt tc tgat tcactttcat tgacatatgt tgagcacagc tcaatgtgga cctttacctg acacttacat gtggagctgc catgtgtgtt cccttctggg catgtggacg cattgaagaa gactaaattt gcatgtgtcc cagagttgcc ccaggtatct tgaagcaacc atccttcaca tgat tcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct actggccagc tacaccaccc tgatggaatt aaaagtacag ggtttatgtc gagaagcctt caacaatact cttggatgaa ca tggaggaa ttgtccagac attggtaacc tgctaaccag caacattgtg tggctcaact tgagtcatct tagcacatca accagggaca tttccagatg aaacttactt tttcttcaac ttatgtgatg aataaaaatc tctgaacaaa ttcagatgca ggaccttcca cagctatatt tgcttttgag cctgctgttc tggactttgc gatggggcta tcgccgatac cattggaaat cctcactcag acctttactt c tccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctc t aactatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc actgtcacca atctatagaa agcaaggtgg gttaatatca gaggatgagc aatt tagaag ggctt gaggc cccaaaggc C aagcctggct tactggggac attttaaatt gaacaggtca ctaatgaata tctgaagctt catgtgaata aatgcaattt gattttgaga gagaat ttaa aaaactggac gcgtgcagta aaacatacaa aacaaaagtt agtgagacag agaagtgcct gggtgtggaa aaattgcgaa c tgaatc Ccc attgctgttg gaagcaattc attctaaaat ggaagcccag cagtgtgggg ctccatgcta ccaccggtta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat tcgac tggca Caagctgtgg tggggaccc C ctaacatgcc tatccgtagt cagaatggct gttttcacct caaggttggt gaaaaatcat tacatacagt actactggcc tttctgcttc ctgt tga tat taactgctga aaagaattgt tattttctaa taaaaacaa C ttacaac tcg caaattttag gtggacaagt gtccagaaga ttttccagga ttggaaacat gaactcagga ttggaggatg tctgectgtg cacagttaga tatctgctat gggattatcc tcttcctcct cagtcctgtt acatgtacat tctgcatcat tcctctcctg atgtgccaac ccc taacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acctgtcaaa gaataattct tgatC c tacc aaatgaaatt gaatgccaaa aaatgacttc ttcctacctg ctgtcaagct tgttactaac gat Ccagaac caattcaacc gagtgctgga gctttgggcc tcagcagaag gaatgtgaga atctatccaa tcggatatgt ctccaactgt tgggcagaac gaataaagaa tatcttaagc tgatgaattg gaacttggct cattggtctt ggatccactg ttctgtatta tgtaggacc tactatccag agtgcatcat gaacacgtca taaccacttc tgcaagaaac tttttcagca ctccaaaatc agatggctgg gcatttcttc tgctctagtt tggctggggt 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 87 WO 01/18207 WO 0118207PCTIUSOO/24591 ttgcctgcct tagtggtgtc aaagaaagtt atgggaaaga ttttatgtga cctgtgctgg attgtggtaa tggtgcagat gaagaagtgt taaggaacct tggggttttg cattctttgc atcttcaatt cattacaagg gttcagaaac agtggcggcg gattggagta agacagctac ttgtcttcaa gctccattgg tctaccacct atttcaaaag aacaaaagtg gatcactcag tgctga <210> 4 <211> 1221 <212> PRT <213> homo sapiens agttgttcta aaaaggtgat gtat tttgga ctgtgggagg gcgcagtgtg ctggggaccc ct tat ttata gcatctctgc caatatcatc ttccaactca gaatagccac acagtgcttc gcgagcagaa gaattctgtt gtcatgtttt aatggcaaga gttagcttga ttaaatatcc ttcatcttcc tgtggtagat aagaaaagt t acctatctta acagataatg catggacaag acaacaatga ggattcaaga ttctgaacat gaagcaaccg cctttctgtt ccttcatgta actgtgctat ttcggttagc ctgataatct catccaaatc tctcctatga tccttgtcaa agtc tatgga tccagtcata tgccatgttc gaccctgaga gggcatgaca cctcttctcC gaaggagaat aga taactca aggaaaatct taaatccagc gcattccttc aactggccca 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3666 <400> 4 Met Phe 1 Ser Pro Ser Ala Ser Gly Gin Ala Ile Thr Asp Ser Ala Thr Val Ser 130 Ser Tyr 145 Pro Gin Ilie Pro Gly His Phe Thr 210 Ser Ilie 225 Giu Lys Trp Asn Giu Thr Gly Lys 290 Gly Asp 305 Ile Leu Gin Asn Ser Leu Trp Phe Met Asn Ser 100 Lys Ser Arg Ser Leu 180 Asp Leu Asp Asp Ser 260 Pro Leu Tyr Asn Phe Cys His Tyr Ile Arg Val Pro Asn Pro Thr Glu Ala Ser Gin Ser Ser Gin Lys Arg Asn 155 Ser Val 170 Cys Phe Phe Ser Aia Lys Asn Asn 235 Phe Giu 250 Val Asn Ser Lys Asn Giu Asn Phe 315 Lys Gly 330 Leu Ala Trp Val1 Ser Pro Ile Cys Phe 110 Giu Phe Vali Ser Thr 190 Asn Tyr Pro Cys Arg 270 Pro Ser Asn Val Ala 6 87 WO 01/18207 Asn Ala Pro 385 Arg Val1 Val1 Tyr Lys 465 Leu Ile Arg Glu Val 545 Phe Ile Asn Ile Ile 625 Ser Ile Asn Gly Glu 705 Ala Asp Gly Val Pro 785 Pro Trp Thr Leu 360 Thr Val Asp His Thr 440 His Asp As n Asn Arg 520 Trp Pro Leu Ala Asn 600 Ile Met Glu Ile Ala 680 Phe Phe Asn Ala Pro 760 Asn His Leu Ala Phe 840 Ala 365 Thr Pro Arg Val Asn 445 Glu Val Glu Asp Cys 525 Pro Ser Gly Asn Asn 605 Glu Asn Ala Thr Ser 685 Pro Val Leu Phe Leu 765 Asn Glu Ser Asp Val 845 PCTIUSOO/24591 Leu Ser Asn 400 Val Lys Val Ile Ala 480 Ile Leu Met Tyr Cys 560 Asp Leu Asn Asp Ser 640 Thr Val Pro Asn Leu 720 Glu Thr Tyr Asp His 800 Gly Glu Asp 7 87 WO 01/18207 WO 0118207PCT/USOO/2459 1 Leu Pro Arg Ser Ala Ser Gin Leu Asp Ala Arg Asn Thr Lys Val Leu 850 855 860 Thr Phe Ilie Ser Tyr Ilie Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala 865 870 875 880, Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg Arg Asp Tyr 885 890 895 Pro Ser Lys Ile Leu Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn 900 905 910 Leu Leu Phe Leu Leu Asp Gly Trp Ilie Thr Ser Phe Asn Val Asp Gly 915 920 925 Leu Cys Ilie Ala Val Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr 930 935 940 Phe Thr Trp Met Giy Leu Giu Ala Ile His met Tyr Ile Ala Leu Val 945 950 955 960 Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile 965 970 975 Ilie Gly Trp Gly Leu Pro Ala Leu Val Val Ser Val Val Leu Ala Ser 980 985 990 Arg Asn Asn Asn Giu Val Tyr Gly Lys Giu Ser Tyr Gly Lys Glu Lys 995 1000 1005 Giy Asp Giu Phe Cys Trp Ilie Gin Asp Pro Val Ile Phe Tyr Vai Thr 1010 1015 1020 Cys Aia Giy Tyr Phe Gly Val Met Phe Phe Leu Asn Ile Ala Met Phe 1025 1030 1035 1040 Ile Val Val Met Val Gin Ilie Cys Gly Arg Asn Gly Lys Arg Ser Asn 1045 1050 1055 Arg Thr Leu Arg Giu Giu Val Leu Arg Asn Leu Arg Ser Val Val Ser 1060 1065 1070 Leu Thr Phe Leu Leu Gly Met Thr Trp, Giy Phe Ala Phe Phe Ala Trp 1075 1080 1085 Giy Pro Leu Asn Ilie Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser 1090 1095 1100 Leu Gin Gly Leu Phe Ile Phe Ile Phe His Cys Ala Met Lys Giu Asn 1105 1110 1115 1120 Val Gin Lys Gin Trp Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu 1125 1130 1135 Aia Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys 1140 1145 1150 Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser Ile Gly Ser 1155 1160 1165 Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr 1170 1175 1180 Phe Lys Arg Asn Ser His Thr Asp Asn Val Ser Tyr Giu His Ser Phe 1185 1190 1195 1200 Asn Lys Ser Gly Ser Leu Arg Gin Cys Phe His Gly Gin Val Leu Val 1205 1210 1215 Lys Thr Gly Pro Cys 1220 <210> <211> 2157 <212> DNA <213> homo sapiens <400> atgtttcgct cagatcgaat gtggagctgc cattggaaat ggaagcccag tcctctcctg ttcttatttg ctttatatat catgtgtgtt cctcactcag cagtgtgggg atgtgccaac 120 tgccgagtgg ttttgtccaa cccttctggg acctttactt ctccatgcta. ccctaacgac 180 tacccaaaca gccaggcttg catgtggacg ctccgagccc ccaccggtta tatcattcag 240 ataacattta acgactttga cattgaagaa. gctcccaatt gcatttatga ctcattatcc 300 ctegataatg gagagagcca gactaaattt tgtggagcaa ctgccaaagg cctatcattt 360 aactcaagtg cgaatgagat gcatgtgtcc ttttCaagtg actttagcat ccagaagaaa 420 ggtttcaatg ccagctacat cagagttgcc gtgtccttaa ggaatcaaaa ggtcatttta 480 8 87 WO 01/18207 WO 0118207PCTIUSOO/24591 ccccagacat agtgctttca gctttCtcct ggctactttc gaaaaagaag ttgggctcta attagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc actgtaaact agaatcgata atccttcgtc ttccaaaatt gaggacaaga cttctagttt ctcctaaaaa caactgggtc ccttctgaat ttttacaatg ttaaaagaag t taacctcag gaaaacattg agttcagaca gccttcaaga ctcagcgtat ccaagcaata cagatgctta cactctgctt actcaaatgc tatccatttc acatttttgc ttiggtgtaaa ttattcctgg aaggggacat acctcagctg caaacctagc cagcagcaga ctcctagtac aacaaaggaa accc tgaggt ggaactacac ttaaagtcaa acaatgctac ataatgagtc attgtcttgc acgttcttcc ctaccaaccc caaatgaagt ccaatattac atataacact gtgacttgct tagacc taaa catccctgtt at gaa tcgt a ccaggtatct tgaagcaacc atccttcaca tgat tcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct ac tggccagc tacaccaccc tgatggaatt aaaagtacag ggtttatgtc gagaagcctt caacaatac t cttggatgaa catggaggaa t tgtccagac attggtaacc tgctaaccag caacattgtg tggctcaact tgagtcatct tagcacatca accagggaca tttccaggta gttgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aactatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc actgtcacca atctatagaa agcaaggtgg gttaatatca gaggatgagc aatttagaag ggcttgaggc cccaaaggct aagcctggct tactggggac attttaaatt gaacaggtca c taatgaata tctgaagctt catgtgaata aatgcaattt atgagccagt gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg qctccaatca attttaccat tcgactggca taagctgtgg tggggaccct ctaacatgcc tatccgtagt cagaatggct gttttcacct caaggttggt gaaaaatcat tacatacagt actactggcc tttctgcttc ctgttgatat taactgctga a aa gaat tgt tattttctaa taaaaacaat ttacaactcg caaattttag ggtttctttc tccagagctc tgattggaca ggccaagagt a cctg tcaaa gaataattct tgattctacc aaatgaaatt gaatgccaaa aaatgacttc t tcctacctg ctgtcaagct tgttactaac gat tcagaac caattcaacc gag tgc tgga gctttgggCC tcagcagaag gaatgtgaga atctatccaa tcggatatgt ctccaactgt tgggcagaac gaa taaagaa tatcttaagc tgatgaat tg gaacttggct cattggtctt attttaa 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2157 <210> 6 <211> 718 <212> PRT <213> homo sapiens <400> 6 Met Phe Arg Ser Asp Arg Met Trp Ser His Trp Lys Trp Lys Pro Ser Pro Leu Ser Ala Val Ser Gly Thr Phe Leu Phe Ala Ile Met Cys Gly Cys Ala Arg Val Val Val Pro His Ser Asn Pro Pro Asn Ser Phe Thr Ser Pro Tyr Pro Asn Asp Gin Ala Leu Cys Met Trp Ile Thr Phe Asn Asp Ser Leu Ala Thr Ala 115 Val Ser Phe 130 Ser Tyr Ilie Asp Phe Asp Leu Asp Asn Gly Leu Ser Arg Ala Pro Thr Gly 75 Ile Glu Glu Ala Pro 90 Gly Glu Ser Gin Thr 105 Phe Asn Ser Ser Ala Tyr Ile Ile Gin Asn Cys Ile Tyr Lys Phe Cys Gly 110 Asn Glu met His 125 Gly Phe Asn Ala Ser Ser Asp Arg Val Ala Phe 135 Val1 Ile Gin Lys Ser Leu Arg Lys Val Ile Gin Thr Ser Ala Tyr Gin Val Ilie Pro Giu Leu Ala Phe Thr Ser Val Ala 170 Cys Phe Glu Phe Ser Tyr Lys Ser Ile Ser 175 Ala Thr Lys Vai 190 Ser Asn Ala Ser 205 Gly Tyr Phe Leu Gly His Glu 195 Phe Thr Gin 210 Ser Asp Trp Leu Leu Ser Phe 215 Lys Ala Lys 9 87 WO 01/18207 Lys 230 Phe Gly Asp Gly Phe 310 Ser Asn Ser Leu Pro 390 Arg Leu Asn Ser Leu 470 Ala Leu Asn Tyr Asp 550 Asn Lys Gly Lys Thr 630 Leu Phe Asn Ser Val 710 PCTIUSOO/24591 Lys 240 Val1 Tyr Asn Lys Lys 320 Trp Ser Leu Ser Asn 400 Val1 Lys Val Ile Al a 480 Ile Leu Met Tyr Cys 560 Asp Leu Asn Asp Ser 640 Thr Val1 Pro Asn 87 WO 01/18207 WO 0118207PCT[USOO/24591 <210> 7 <211> 3339 <212> DNA <213> homo sapiens <400> 7 atgtttcgct ttcttatttg tgccgagtgg tacccaaaca ataacattta cC tga taa tg aactcaagtg ggtttcaatg ccccagacat agtgctttca gctttctcct ggctactttc gaaaaagaag ttgggctcta attagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc actgtaaact agaatcgata atccttcgtc ttccaaaatt gaggacaaga cttctagttt ctcctaaaaa caactgggtc ccttcCtgaat ttttacaatg C taaaagaag ttaacctcag gaaaacattg agttcagaca gccttcaaga c Ccagcgtat ccaagcaata gcatctgtaa gttagaagag caaagaaaaa aatc tgaagg cccatctgtg ggatgtgttg acacactttg actaaagtcc gcaactctcc ttgatgaacc atcacctcct cttctggcaa aaag CattCta Ctgcctgcct aaagaaagtt ttttatgtga attgtggtaa gaagaagtgt tggggttttg atcttcaatt cagatcgaat ctttatatat tttCC geccaa gccaggcttg acgactttga gagagagcca cgaatgagat ccagctacat cagatgctta cactctgctt actcaaatgc tatccatttc acatttttgc C tggtgtaaa ttattcctgg aaggggacat acctcagctg caaacctagc cagcagcaga ctcctagtac aacaaaggaa accctgaggt ggaactacac ttaaagtcaa acaatgctac ataatgagtC attgtcttgc acgttcttcc ctaccaaccc caaatgaagt ccaatattac atataacact gtgacttgct tagacctaaa catccctgtt atgaatcgta tttgcctcc cacagtttac ctttagtgag atcctgttca ccttctggga cacacagaga gagttctgat tcactttcat tgacatatgt tgagcacagc tcaatgtgga cctttacctg acacttacat tagtggtgtc atgggaaaga cctgtgctgg Cggtgcagat taaggaacct cattctttgc cat Cacaagg gtggagc Cgc catgtgtgtt cccttctggg catgtggacg cattgaagaa gactaaattt gcatgtgtcc cagagttgcc ccaggtatct tgaagcaacc atccttcaca tgattcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct ac tggccagc tacaccaccc tgatggaatt aaaagtacag ggtttatgtc gagaagcctt caacaatact cttggatgaa catggaggaa ttgtccagac attggtaacc tgctaaccag caacattgtg tggctcaact tgagtcatct tagcacatca accagggaca ttCtccaga tg aaacttactt tttcttcaac ttatgtgatg aataaaaatc tctgaacaaa ttcagatgca ggacct tcca cagctatatt Cgcttttgag cctgctgttc tggactttgc gatggggcta tcgccgatac agttgttcta aaaaggtgat gtattttgga ctgtgggagg gcgcagtgtg c tggggaccc taagataaat cattggaaat cctcactcag acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aactatgaaa Ctgttgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc ac Cgtcacca at cta tagaa agcaaggtgg gttaatatca gaggatgagc aatttagaag ggcttgaggc cccaaaggct aagcctggct tactggggac atttaaatt gaacaggtca ctaatgaata tctgaagctt catgtgaata aatgcaattt gattttgaga gagaatttaa aaaactggac gcgtgcagta aaacatacaa aacaaaagtt agtgagacag agaagtgcct gggtgtggaa 4aattgcgaa ctgaatctcc attgctgttg gaagcaat Cc atCc taaaa C gcgagcagaa gaattctgtt gtcatgCCCC aatggcaaga gttagcttga ttaaatatcc tgtacatga ggaagcccag cagtgtgggg ctccatgcta ccacc gg ta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcat gccttgtttg cagttccatg gctccaatca atttaccat Ccgactggca taagctgtgg tggggaccct ctaacatgcc tatccgtagt cagaatggct gttttcacct caaggttggt gaaaaatcat tacatacagt actac Cggcc tttctgcttc ctgttgatat C aactCgc tga aaagaattgt tat tttctaa taaaaacaat ttacaactcg caaat tttag gtggacaagt gtccagaaga Ctttccagga t tggaaacat gaactcagga ttggaggatg tctgcctgtg cacagttaga tatctgctat gggattatcc tcttcctcct cagtcctgtt acatgtacat tctgcatcat acaacaatga ggattcaaga ttctgaacat gaagcaaccg ccttctgtt ccttcatgta tcctctcctg atg tgccaac ccctaacgac tatcattcag ctcattatcc cctatcatC ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acc tgtcaaa gaataattct tgattctacc aaatgaaatt gaatgccaaa aaatgacttc ttcctacctg ctgtcaagct tgttactaac gattcagaac caattcaac gagtgc Cgga gctttgggCC tcagcagaag gaatgtgaga atctatccaa Cc ggatCa tg C ctccaactgt tgggcagaac gaataaagaa Catcttaagc tgatgaattg gaacttggct cat Cggtct C ggatccactg ttctgtatta tgtaggaccc tactatccag agtgcatcat gaacacgtca taaccactc tgcaagaaac tttttcagca ctccaaaatc agatggctgg gcatttcttc tgctctagtt tggctggggt agtctatgga tccagtcata tgccatgttc gaccc tgaga gggca egaca cctcttctc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3339 11 87 WO 01/18207 PCT/USOO/24591 <210> 8 <211> 1112 <212> PRT <213> homo sapiens <400> 8 Met Phe Arg Ser Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys Pro 1 5 10 Ser Pro Leu Leu Phe Leu Phe Ala Lieu Tyr Ie Met Cys Val Pro His 25 Ser Ala Val Tip Gly Cys Ala Asn Cys Arg Val Val Leu Ser Asn Pro 40 Ser Gly Thr Phe Thr Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Ser 55 Gin Ala Cys Met Trp Thr Leu Arg Ala Pro Thr Gly Tyr Ile Ile Gin 70 75 Ile Thr Phe Asn Asp Phe Asp Ile Giu Giu Ala Pro Asn Cys Ile Tyr 90 Asp Ser Leu Ser Leu Asp Asn Gly Giu Ser Gin Thr Lys Phe Cys Gly 100 105 110 Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Ala Asn Giu Met His 115 120 125 Val Ser Phe Ser Ser Asp Phe Ser Ile Gin Lys Lys Gly Phe Asn Ala 130 135 140 Ser Tyr Ile Arg Val Ala Val Ser Leu Arg Asn Gin Lys Vai Ile Leu 145 150 155 160 Pro Gin Thr Ser Asp Aia Tyr Gin Val Ser Val Ala Lys Ser Ile Ser 165 170 175 Ile Pro Glu Leu Ser Ala Phe Thr Leu Cys Phe Giu Ala Thr Lys Val I8O 185 190 Gly His Glu Asp Ser Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser 195 200 205 Phe Thr Gin Leu Leu Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu 210 215 220 Ser Ilie Ser Asp Ser Lys Cys Leu Leu Asn Asn Ala Leu Pro Val Lys 225 230 235 240 Giu Lys Giu Asp Ilie Phe Ala Giu Ser Phe Glu Gin Leu Cys Leu Val 245 250 255 Tip Asn Asn Ser Leu Gly Ser Ile Gly Val Asn Phe Lys Arg Asn Tyr 260 265 270 Giu Thr Val Pro Cys Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn 275 280 285 Gly Lys Leu Leu Leu Gly Ser Asn Gin Asn Glu Ile Val Ser Leu Lys 290 295 300 Gly Asp Ilie Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asn Ala Lys 305 310 315 320 Ile Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Asn Val Val Asp Tip 325 330 335 Gln Asn Asp Phe Tip Asn Ile Pro Asn Leu Ala Leu Lys Ala Giu Ser 340 345 350 Asn Leu Ser Cys Gly Ser Tyr Leu Ile Pro Leu Pro Ala Ala Giu Leu 355 360 365 Ala Ser Cys Ala Asp Leu Gly Thr Leu Cys Gin Ala Thr Vai Asn Ser 370 375 380 Pro Ser Thr Thr Pro Pro Thr Val Thr Thr Asn Met Pro Val Thr Asn 385 390 395 400 Arg Ile Asp Lys Gin Arg Asn Asp Gly Ile Ile Tyr Arg Ile Ser Val 405 410 415 Val Ilie Gin Asn Ile Leu Arg His Pro Giu Val Lys Val Gin Ser Lys 420 425 430 Val Ala Glu Trp Lell Asn Ser Thr Phe Gin Asn Tip Asn Tyr Thr Val 435 440 445 Tyr Val Val Asn Ie Ser Phe His Leu Ser Ala Gly Giu Asp Lys Ile 12 87 WO 01/18207 Lys 465 Leu Ile Arg Giu Val1 545 Phe Ile Asn Ile Ile 625 Ser Ile Asn Gly Glu 705 Ala Asp Gly Val Pro 785 Pro Trp, Thr Leu Thr 865 Ala Pro Leu Leu Phe 945 Lys Val Gin His 515 Pro Pro Asn Asn Thr 595 Giu Leu Asp Giu Thr 675 Asn Tyr Vali Val1 Phe 755 Ala Gin Cys Thr Cys 835 Arg Ile Leu Lys Phe 915 Ile Trp Leu 470 Ala Leu Asn Tyr Asp 550 Asn Lys Giy Lys Thr 630 Leu Phe Asn Ser Met 710 Pro Arg Val1 Ile Ile 790 Trp Cys Asn Ser Ile 870 Tyr Met Asp Ala Leu 950 Asp Asn Asn Arg 520 Trp Pro Leu Ala Asn 600 Ile Met Giu Ile Ala 680 Phe Phe Asn Ala Pro 760 Asn His Leu Ala Phe 840 Leu Cys Ala Leu Trp 920 Leu Ala Leu Gly Giu 510 Leu Ser Arg Pro Gin 590 Ile Asn le Leu Ser 670 Leu Ser Asp Ser Asn 750 Val Leu Val1 Phe Ala 830 Leu Lys Phe Arg Phe 910 Val1 Leu Ala PCT/USOO/24591 Ala 480 Ile Leu Met Tyr Cys 560 Asp Leu Asn Asp Ser 640 Thr Val1 Pro Asn Leu 720 Glu Thr Tyr Asp His 800 Gly Giu Asp Leu Ala 880 Tyr Asn Giy Thr Val 960 13 87 WO 01/18207 WO 0118207PCT/USOO/24591 Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile 965 970 975 Ilie Gly Trp Gly Leu Pro Ala Leu Val Val Ser Vai Val Leu Ala Ser 980 985 990 Arg Asn Asn 995 Asn Giu Val Tyr Gly Lys 1000 Ile Gin Asp 1015 Gly Cys 1025 Ile Asp Giu 1010 Ala Gly Val Val.

Phe Cys Trp Glu Ser Tyr Gly Lys Giu Lys 1005 Pro Val le Phe Tyr Val Thr 1020 Phe Leu Asn. Ile Ala Met Phe Tyr Phe Gly Val Met Phe 1030 Met Val Gin Ile Cys Gly 1045 1035 Arg Asn 1050 Gly Lys 1040 Arg Ser Asn 1055 Vai Val Ser 1070 Arg Thr Leu Leu Thr Phe 1075 Gly Pro Leu 1090 Leu Gin Gly 1105 Arg Giu Glu Val Leu Arg 1060 1065 Leu Leu Gly Met Thr Trp 1080 Asn Ile Pro Phe Met Tyr 1095 Lys Ile Asn Cys Thr 1110 ksn Leu Arg Ser 31y Phe Ala Phe Phe Ala Trp 1085 Leu Phe Ser Ile Phe Asn Ser 1100 <210> 9 <211> 3750 <212> DNA <213> homo sapiens <400> 9 atgtttcgct ttcttatttg cgagtggttt ccaaacagcc acatttaacg gataatggag tcaagtgcga ttcaatgcca cagacatcag gctttcacac ttctcctact tactttctat aaagaagaca ggctctattg agtaaagtta tctctaaaag ctctccaacc aatatcccaa ccgctcccag gtaaactctc atcgataaac cttcgtcacc caaaattgga gacaagat ta ctagtttaca ctaaaaaata ctgggtcatt tctgaatacg tacaatgcta aaagaagcaa acc tcagc ca aacattgata tcagacagtg ttcaagatag agcgtatcat agcaataatg cagatcgaat ctttatatat tgtccaaccc aggcttgcat actttgacat agagccagac atgagatgca gctacatcag atgcttacca tc tgc t ttga caaatgcatc ccatttctga tttttgcaga gtgtaaattt ttcc tgggaa gggacattta tcagctgtaa acctagctct cagcagaac t ctagtactac aaaggaatga ctgaggtaaa actacacggt aagtcaagag atgc taccaa atgagtcct t gtcttgccat ttcttccttg ccaacccatt atgaagt tgc atattaccaa taacacttgg acttgcttga acctaaatag ccctgttacc aatcgtattt gtggagctgc catgtgtgtt ttc tgggacc gtggacgctc tgaagaagct taaattttgt tgtgtccttt agt tgccgtg ggtatctgtt agcaaccaaa cttcacacaa ttcaaaatgt aagctttgaa caaaagaaac tgggaaattg taactttcga tgtgaaaggg gaaagctgaa ggccagctgt accacccac t tggaattatc agtacagagc ttatgtcgtt aagccttgag caatactaat gga tgaaggc ggaggaaccc tccagacaag ggtaacctac taaccagatt cattgtggaa ctcaactcta gtcatcttct cacatcacat agggacaaat ccagatggat cat tggaaa t cctcactcag tttacttctc cgagccccca cccaattgca ggagcaactg tcaagtgact tccttaagga gcaaaaagca gttggccatg ttgctcagtt ttgttgaata cagctctgcc tatgaaacag ttgttgggct ctttggaatt aatgtagtcg agcaacctaa gcagacctgg gtcaccacta tatagaatat aaggtggcag aatatcagt t gatgagccaa ttagaaggaa ttgaggctac aaaggctac t cctggctttt tggggacctg ttaaatttaa caggtcaaaa atgaatatat gaagctttaa gtgaatatta gcaatttcaa tttgagagtg ggaagcccag tgtggggatg catgctaccc ccggttatat tttatgactc ccaaaggcct ttagcatcca atcaaaaggt tctctattcc aagacagtga ttggaaaggc atgcattacc ttgtttggaa ct cca tg tga ccaatcaaaa ttaccatgaa act ggcaaaa gctgtggttc ggaccctctg acatgcctgt ccgtagtgat aatggctcaa ttcacctgag ggttggtgct aaatcattca atacagtgaa actggccatc ctgcttCtcg ttgatatctc ctgctgatgg gaattgtgaa tttctaatat aaacaattga caactcggaa attttagcat gacaagtgga tcctctcctg tgccaactgc taacgactac cat tcaga ta attaticcctt atcatttaac gaagaaaggt cattttaccc agagctcagt ttggacagct caagagtggc tgtcaaagaa taattctttg ttctaccatt tgaaat tgtc tgccaaaatc tgacttctgg ctacctgatc tcaagctact tactaacaga tcagaacatc ttcaaccttc tgctggagag ttgggcCCtt gcagaagctc tgtgagacaa tatccaacct gatatgtttt caactgttta gcagaactta taaagaagaa cttaagcagt tgaattggcc cttggctctc tggtcttcca tccactggca 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 14 87 WO 01/18207 WO 0118207PCTIUSOO/2459 I tctgtaattt agaagagcac agaaaaactt ctgaaggatc atctgtgcct tgtgttgcac cactttggag aaagtcctca actctcctga atgaacctga acctccttca ctggcaacct gtatttaaca cctgccttag gaaagttatg tatgtgacct gtggtaatgg gaagtgttaa ggttttgcat ttcaattcat cagaaacagt tggag taaga tcttcaagct accacctatt aaactggccc aaggtcaagg gacaccttca tgcctccaaa agtttacttt tagtgagtta ctgttcaaat tc tgggatct acagagattc ttctga tgga ctttcatcag catatgttgc gcacagccct atgtggatgg ttacctggat cttacattcg tggtgtcagt ggaaagaaaa gtgctgggta tgcagatctg ggaacctgcg tctttgcctg tacaaggctt ggcggcggca cagc taccaa ccattggttc tcaaaaggaa atgc tgatgg gttattgcaa gccacagcac cttacttgag ct tcaacaaa tgtgatggcg aaaaatcaaa gaacaaaaac agatgcaag t cc ttccaaga ctatattggg ttttgagaaa gctgttcctg actttgcatt ggggc tagaa ccga tacat t tgttctagcg aggtgatgaa ttttggagtc tgggaggaa t cagtgtggtt gggaccctta at ttatattc tctctgctgt tatcatcaag caactcaacc tagccacaca agatcaaaca tgctcat tca aaagttttaa aatttaagtc actggacttt tgcagtattg catacaagaa aaaagttttg gagacagtct agtgcctcac tgtggaatat ttgcgaaggg aatctcctct gctgttgcag gcaattcaca ctaaaattct agcagaaaca ttctgttgga atgttttttc ggcaagagaa agcttgacct aatatcccc t atcttccact ggtagatttc aaaagttctg tatcttacat gacagtgctt tcaatcatcc gacaacttct cagaagattc tccaggatgt gaaacat tac ctcaggaagt gaggatggaa gcctgtgtaa agt tagatgc ctgctatttt attatccctc tcctcctaga tcctgttgca tgtacat tgc gcatcattgg acaatgaagt ttcaagatcc t gaacat tgc gcaaccggac ttctgttggg tcatgtacct gtgctatgaa ggttagcaga ataatctagg ccaaatctaa ccatggacaa ctgtccatca ataaaaatat tgtattagtt aggaccccaa tatccagaat gcatcatccc cacgtcagga ccacttcaca aagaaacac t ttcagcagca caaaatcttg tggctggatc tttcttcctt, tctagttaaa c tggggtt tg c tatggaaaa agtcatattt catgttcatt cctgagagaa catgacatgg cttctccatc ggagaatgtt taactcagat.

aaaatctttg atccagctct gtccttgtca ggtcattgat tatcatgtca 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3750 <210> <211> 1249 <212> PRT <213> homo sapiens <400> 10 Met Phe Arg Ser Asp 1 5 Ser Pro Leu Leu Phe Arg Met Trp Ser Leu Phe Ala Leu His Trp, Lys Trp Lys Pro Pro His Ile Met Cys Ser Val Trp Gly Gly Thr Phe Thr Ala Cys Met Trp Thr Phe Asn Asp Ser Leu Ser Leu 100 Thr Ala Lys Gly 115 Ser Phe Ser Ser Cys Ala Ser Pro Thr Leu Asn Cys Arg Val Val Leu Tyr Pro Asn Asp Tyr Asn Pro Ser Asn Ser Gin Arg Ala Pro Thr Tyr Ile Ile Gin Asp Ile Glu Giu Asn Cys Leu

ASP

Asn Gly Glu Ser Phe Asn 120 Phe Ser Ile Thr Lys Phe Ser Ala Asn Ile T'yr Asp Cys Gly Aia li0 Met His Val Asn Ala Ser Gin Lys Lys Arg Val Ala Ser Asp Ala 165 135 Val Ser 150 Tyr Gin Leu Arg Asn Val Ile Leu 'rhr Val Ser Lys Ser Ile Ser Ile 175 Pro Giu Leu Ser 180 His Giu Asp Ser 195 Thr Gin Leu Leu 210 Ile Ser Asp Ser Ala Phe Thr Leu Giu Ala Thr Asp Trp Thr Ser Tyr Ser Lys Val Giy 190 Ala Ser Phe Phe Leu Ser Ser Phe Lys Cys Giy 215 Leu Ala Lys Ser Leu Asn Asn Ala Leu Pro Val Lys Giu 87 WO 01/18207 225 Lys Asn Thr Lys Asp 305 Leu Asn Leu Ser Ser 385 Ile Ile Ala Val Val 465 Leu Gin Leu Glu Leu 545 Tyr Ser Leu Val Thr 625 Ser Asp Ile Thr Ser 705 Ser Ile Leu 260 Cys Leu Asn Leu Trp 340 dly Asp Pro Gin Ile 420 Leu Ile Ser Asn Leu 500 Vai Gly Pro Thr Leu 580 Asp Val Ser Asp Ala 660 Arg Ile Gin Leu Phe 245 Gly Asp Giy Phe Ser 325 Asn Ser Leu Pro Arg 405 Leu Asn Ser Leu Ala 485 Leu Asn Tyr Asp Asn 565 Lys Gly Lys Thr Leu 645 Phe Asn Ser Met Pro 725 Glu Ile Thr Asn 295 Leu Asn Pro Leu Thr 375 Val1 Asp His Thr His 455 Asp Asn Asn Arg Trp, 535 Pro Leu Ala Asn Ile 615 Met Glu Ile Ala Phe 695 Phe Asn Leu Asn 270 Gly Leu Al a Asp Glu 350 Giu Asn Thr Ser Ser 430 Thr Lys Trp Lys Gly 510 Ala Gl u Ile Val1 Ile 590 Thr Ile Leu Lys His 670 Leu Asn Pro Pro PCT/USOO/24591 240 Trp Giu Gly Gly Ile 320 Gin Asn Ala Pro Arg 400 Val Val Lys Leu 480 Ile Arg Glu Val Phe 560 Ile Asn le le Ser 640 le Asn Gly Glu Ala 720 Asp 16 87 WO 01/18207PC/S/25 PCT/USOO/24591 Ser Val Leu Vai Arg Arg Ala Gin Phe Thr Phe Phe Asn Lys Thr Gly 740 745 750 Leu Phe Gin Asp Val Gly Pro Gin Arg Lys Thr Leu Val Ser Tyr Val 755 760 765 Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gin Asn Leu Lys Asp Pro 770 775 780 Val Gin Ile Lys Ile Lys His Thr Arg Thr Gin Glu Val His His Pro 785 790 795 800 Ile Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly Trp 805 810 815 Asn Thr Ser Gly Cys Val Ala His Arg Asp Ser Asp Ala Ser Glu Thr 820 825 830 Val Cys Leu Cys Asn His Phe Thr His Phe Gly Val Leu Met Asp Leu 835 840 845 Pro Arg Ser Ala Ser Gin Leu Asp Ala Arg Asn Thr Lys Val Leu Thr 850 855 860 Phe Ile Ser Tyr Ile Giy Cys Gly Ile Ser Ala Ile Phe Ser Aia Aia 865 870 875 880 Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg Arg Asp Tyr Pro 885 890 895 Ser Lys Ile Leu Met Asn Leu Ser Thr Aia Leu Leu Phe Leu Asn Leu 900 905 910 Leu Phe Leu Leu Asp Gly Trp Ilie Thr Ser Phe Asn Vai Asp Gly Leu 915 920 925 Cys Ilie Ala Val Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr Phe 930 935 940 Thr Trp Met Gly Leu Giu Aia Ile His Met Tyr Ilie Ala Leu Val Lys 945 950 955 960 Val Phe Asn Thr Tyr Ilie Arg Arg Tyr Ile Leu Lys Phe Cys Ile Ile 965 970 975 Gly Trp Gly Leu Pro Ala Leu Val Val Ser Vai Val Leu Ala Ser Arg 980 985 990 Asn Asn Asn Giu Val Tyr Gly Lys Giu Ser Tyr Giy Lys Giu Lys Gly 995 1000 1005 Asp Glu Phe Cys Trp Ile Gin Asp Pro Val Ile Phe Tyr Val Thr Cys 1010 1015 1020 Ala Gly Tyr Phe Gly Val Met Phe Phe Leu Asn Ile Ala Met Phe Ile 1025 1030 1035 1040 Val Val Met Val Gin Ilie Cys Gly Arg Asn Gly Lys Arg Ser Asn Arg 1045 1050 1055 Thr Leu Arg Giu Glu Val Leu Arg Asn Leu Arg Ser Val Val Ser Leu 1060 1065 1070 Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp Gly 1075 1080 1085 Pro Leu Asn Ilie Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser Leu 1090 1095 1100 Gin Gly Leu Phe Ilie Phe Ile Phe His Cys Ala Met Lys Giu Asn Val 1105 1110 1115 1120 Gin Lys Gin Trp Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu Ala 1125 1130 1135 Asp Asn Ser Asp Trp, Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys Ser 1140 1145 1150 Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser Ile Giy Ser Asn 1155 1160 1165 Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr Phe 1170 1175 1180 Lys Arg Asn Ser His Thr Asp Ser Ala Ser Met Asp Lys Ser Leu Ser 1185 1190 1195 1200 Lys Leu Ala His Ala Asp Gly Asp Gin Thr Ser Ile Ile Pro Val His 1205 1210 1215 Gin Val Ile Asp Lys Val Lys Cly Tyr Cys Asn Ala His Ser Asp Asn 1220 1225 1230 Phe Tyr Lys Asn Ilie Ile Met Ser Asp Thr Phe Ser His Ser Thr Lys 17 87 WO 01/18207 WO 0118207PCT/USOO/24591 1235 1240 1245 <210> 11 <211> 3663 <212> DNA <213> homo sapiens <400> 11 atgtttcgct ttcttatttg cgagtggttt ccaaacagcc acatttaacg gataatggag tcaagtgcga t tcaatgcca cagacatcag gctttcacac ttctcctact tactttctat aaagaagaca ggctctattg agtaaagt ta tctctaaaag ctctccaacc aatatcccaa ccgctcccag gtaaac tc te atcgataaac cttcgtcacc caaaattgga gacaagat ta ctagtttaca ctaaaaaata ctgggtcatt tctgaatacg tacaatgcta aaagaagcaa acctcagcca aacattgata teagacagtg ttcaagatag agcgtatcat agcaataatg tctgtaattt agaagagcac agaaaaactt ct gaaggat c atctgtgcct tgtgttgcac cactttggag aaagtcctca actctcctga atgaacctga acctccttca ctggcaacct gtatttaaca cctgccttag gaaagttatg tatgtgacct gtggtaatgg cagatcgaat ctttatatat tgtccaaccc aggcttgcat actttgacat agagccagac atgagatgca gctacatcag atgcttacca tcigctttga caaa tgcatc ccatttctga t tt ttgcaga gtgtaaattt ttcctgggaa gggacattta tcagctgtaa acctagctct cagcagaact ctagtactac aaaggaatga ctgaggtaaa actacacggt aagtcaagag atgctaceaa atgagtcctt gtcttgccat ttcttccttg ccaacccat t atgaagt tgc atattaccaa taacact tgg acttgcttga acctaaatag ccctgttacc aatcgtattt tgcctccaaa agt ttac tt t tagtgagt ta ctgttcaaat tctgggatct acagagattc ttctgatgga ctttcatcag catatgttgc gcacagccct atgtggatgg ttacctggat cttacattcg tggtgtcagt ggaaagaaaa gtgctgggta tgcagatctg gtggagctgc catgtgtgtt ttctgggacc gtggacgctc tgaagaagct taaattttgt tgtgtccttt agt tgccgtg ggtatctgtt agcaaccaaa cttcacacaa ttcaaaatgt aagctttgaa caaaagaaac tgggaaattg taactttcga tgtgaaaggg gaaagctgaa ggccagctgt accacccact tggaattatc ag tacagagc ttatgtcgtt aagccttgag caatae taat gga tgaaggc ggaggaaccc tccagacaag ggtaacctac taaccagatt cattgtggaa c tcaac tcta gtcatcttct cacatcacat agggacaaat ccagatggat cttacttgag cttcaacaaa tgtgatggcg aaaaatcaaa gaacaaaaac agatgcaagt ccttccaaga ctatattggg ttttgagaaa gctgttectg actttgcatt ggggctagaa ccgatacatt tgttctagcg aggtgatgaa ttttggagtc tgggaggaat cattggaaat cctcactcag t t tac ttc tc cgagccccca cccaattgca ggagcaactg tcaagtgact tccttaagga gcaaaaagca gttggccatg ttgctcagtt ttgttgaata cagctctgcc tatgaaacag ttgttgggct ctttggaatt aatgtagtcg agcaacctaa gcagacctgg gtcaccacta tatagaatat aaggtggcag aatatcagtt gatgagccaa ttagaaggaa ttgaggctac aaaggctact cctggctttt tggggacctg ttaaatttaa caggtcaaaa atgaatatat gaagctttaa gtgaatatta gcaatttcaa tttgagagtg aatttaagtc actggacttt tgcagtattg catacaagaa aaaagttttg gagacagtct agtgccticac tgtggaatat ttgcgaaggg aatctcctct gctgttgcag gcaattcaca ctaaaattct agcagaaaca ttctgttgga atgttttttc ggcaagagaa ggaagcccag tgtggggatg eatigetacce ccggttatat tttatgactc ccaaaggcct ttagcatcca atcaaaaggt tctictattcc aagacagtga ttggaaaggc atgcattacc ttgtttggaa ttccatgtga ccaatcaaaa ttaccatgaa actggcaaaa gctgtggttc ggaccetctg acatgcctgt ccgtagtgat aatggctcaa ttcacctgag ggt tggtgct aaatcattca atacagtgaa actggccatc ctgcttctcg titgataticte ctgctgatgg gaattgtgaa tttctaatat aaacaattga caactcggaa attttagcat gacaagtgga cagaagattc tccaggatgt gaaaca ttac ctcaggaagt gagga tggaa gcctgtgtaa agt tagatgc ctgctatttt attatecte tcctcctaga tcctgttgca tgtacattgc gcatcattgg acaatgaagt ttcaagatcc tgaacattgc gcaaccggac tcctctcctg tgccaactgc ta a ga ctac cattcagata attatccctt atcatttaac gaagaaaggt cattittacc agagctcagt titggacagct caagagtggc tgtcaaagaa taattctttg titctaccatt tgaaattgtc tgccaaaatc tgacttctgg ctacctgatc tcaagctact tactaacaga tcagaacatc ttcaaccttc tgctggagag ttgggccctt gcagaagctc tgtgagacaa tatccaacct gata tgttt t caactgttta gcagaactta taaagaagaa cttaagcagt tgaattggcc cttggctctc tggtcttcca tccactggca tgtattagtt aggaccccaa tatccagaat gca teat ccc cacgtcagga ceaettcaca aagaaacact ttcagcagca caaaatcttg tiggetiggatc tttettcett tctagttaaa etggggtttg ctatggaaaa agteatattt catgttcatt cc tgagagaa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 18 87 WO 01/18207 WO 0118207PCTIUSOO/2459 1 gaagtgttaa ggaacctgcg cagtgtggtt agcttgacct ttctgttggg catgacatgg ggttttgcat tctttgcctg gggaccctta aatatcccct tCatgtaCCt cttctccatc ttcaattcat tacaaggctt atttatattc atcttccact gtgctatgaa ggagaatgtt cagaaacagt ggcggcggca tctctgctgt ggtagatttc ggttagcaga taactcagat tggagtaaga cagctaccaa tatcatcaag aaaagttctg ataatctagg aaaatctttg tcttcaagct ccattggttc caactcaacc tatcttacat ccaaatctaa atccagctct accacctatt tcaaaaggaa tagccacaca gataatgtct cctatgagca ttccttcaac aaaagtggat cactcagaca gtgcttccat ggacaagtcc ttgtcaaaac tggcccatgc tga <210> 12 <211> 1220 <212> PRT <213> homo sapiens 3240 3300 3360 3420 3480 3540 3600 3660 3663 <400> 12 Met PheI 1 Ser Pro I Ser Val Gly 'Phr 1 Ala Cys1 Thr PheI Ser Leu! Thr Ala I Ser Phe 130 Tyr Ile 1 145 Gin Thr Pro Glu I His Glu I Thr Gin 1 210 Ile Ser 1 225 Lys Glu I Asn Asn! Thr Val I Lys Leu I 290 Asp Ile 305 Leu Ser Asn Asp I Leu SerC Ser Cys I Asp Phe Cys Ser Thr Phe Asp Leu Asp Ala Ala 165 Ala Asp Ser Lys Phe 245 Gly Asp Gly Phe Ser 325 Asn Ser Leu 19 87 WO 01/18207 WO 0118207PCT/USOO/24591 370 Thr Asp Gin Giu Val 450 Lys Val G~n His Pro 530 Pro Asn Asn Thr Giu 610 Leu Asp Giu Thr Asn 690 Tyr Val Val Phe Ala 770 Gin Cys Thr Cys Arg 850 Ile 87 WO 01/18207 WO 0118207PCT[USOO/24591 Thr Leu Leu Thr Ser Lys Ile Leu 900 Leu Phe Leu Leu 915 Cys Ile Ala Val 930 Thr Trp Met Gly 945 Val Phe Asn Thr Val Ala Phe Giu Leu Arg Arg Asp Tyr Pro 895 Asn Leu Ser Asp Gly Trp Ile 920 Ala Val Leu Leu 935 Leu Giu Ala Ile Thr Ser His Phe His Met Leu Leu Phe Phe Asn Vai 925 Phe Leu Leu Leu A-sn Leu 910 Asp Gly Leu Ala Thr Phe 940 Tyr Ile Ala Leu Val Tyr 965 Pro A-rg Arg Tyr Lys Phe Cys Ile Ile 975 Gly Trp Gly A-sn Asn A-sn 995 Asp Giu Phe 1010 Ala Gly Tyr 1025 Val Val Met Thr Leu Arg Ala Leu Val Ser Val Val Ser Tyr Gly Leu Ala Ser Arg 990 Lys Giu Lys Gly 1005 Val Tyr Gly Lys Glu 1000 Cys Trp Ilie Gin Asp Pro 1015 Phe Gly Val Met Phe Phe 1030 Val Gin Ile Cys Gly Arg Vai Ile Phe Tyr Val 1020 Leu A-sn Ile A-ia Met 1035 Asn Gly Lys Arg Ser 1050 Leu Arg Ser Val Val Thr Cys Phe Ile 1040 A-sn A-rg 1055 Ser Leu 1045 Glu Glu Val Leu Arg A-sn 1060 Gly Met Thr 1065 Phe Ala Phe Thr Phe Leu Leu 1075 Trp Gly 1080 Phe 108' A-ia Trp Gly A-sn Ser Leu Glu A-sn Val Pro Leu A-sn Ile Pro Phe Met Tyr Leu Phe Ser Ile Phe 1090 1095 1100 Gin Glv Leu Phe Ilie Phe Ile Phe His Cys Ala Met Lys 1105 Gin Lys Gin Trp Asp A-sn Ser Asp 1140 Ser Asp A-sn Leu 1155 Ser Thr Tyr Leu 1170 Lys Arg Asn Ser 1110 A.rg A-rg 1125 Trp, Ser ;iy Lys Thr Ser His Leu Cys Lys Thr A-ia 1145 Ser Leu Ser 1160 Lys Ser Lys 1115 Cys Gly 1130 Thr A-sn Arg Ile Ser Ser Ser Ser Ser Ser 1120 Phe A-rg Leu Ala 1135 Ile Lys Lys Ser 1150 Ile Giy Ser Asn 1165 Thr Thr Tyr Phe His Ser Phe A-sn 1200 Val Leu Val Lys 1215 1175 His Thr Asp 1185 Lys Ser 1190 Gly Ser Leu Arg Gin 1205 1180 A-sn Vai Ser Tyr Giu 1195 Cys Phe His Gly Gin 1210 Thr Giy Pro Cys 1220 <210> 13 <211> 2154 <212> DNA <213> homo sapiens <400> 13 atgtttcgct ttcttatttg cgagtggttt ccaaacagcc acatttaacg gataatggag tcaagtgcga ttcaatgcca ca gac atcag gct t tcacac ttctcctact tactttctat cagatcgaat ctttatatat tgtccaaccc aggcttgcat actttgacat agagcc agac atgagatgca gctacatcag atgcttacca tctgctttga caaatgcatc ccatttctga gtggagctgc catgtgtgtt ttctgggacc gtggacgctc tgaagaagct taaattttgt tgtgtccttt agttgccgtg ggtatctgtt agcaaccaaa cttcacacaa t tcaaaatgt cattggaaat cc tcac tc ag tttacttctc cgagccccca cccaattgca ggagcaac tg tcaagtgac t tccttaagga gcaaaaagca gttggccatg ttgctcagtt ttgttgaata ggaagc ccag tgtggggatg catgctacc ccggttatat t t tatgact c ccaaaggcct ttagcatcca atcaaaaggt tctctattcc aagacagtga ttggaaaggc atgcattacc tcctctcctg tgccaactgc taacgac tac CattCagata attatccctt atcatttaac gaagaaaggt cattttaccc agagctcagt ttggacagct caagagtggc tgtcaaagaa 21 87 WO 01/18207 WO 0118207PCT/USOO/24591 aaagaagaca ggctctattg agtaaagt ta tctctaaaag ctc tccaacc aatatcccaa ccgctcccag gtaaactctc atcgataaac cttcgtcacc caaaattgga gacaagatta ctagtttaca ctaaaaaata ctgggtcatt tctgaatacg tacaatgcta aaagaagcaa acctcagcca aacattgata tcagacagtg ttcaagatag agcgtatcat.

agcaataatg tttttgcaga gtgtaaattt ttcctgggaa gggacattta tcagctgtaa acctagctct cagcagaac t ctagtactac aaaggaatga ctgaggtaaa actacacggt aagtcaagag atgctaccaa atgagtcct t gtcttgccat ttcttccttg ccaacccatt.

atgaagttgc atattaccaa taacacttgg acttgcttga acctaaatag ccc tg ttacc aatcgtattt aagc t ttgaa caaaagaaac tgggaaattg taactttcga tgtgaaaggg gaaagctgaa ggccagc tgt accacccact tggaattatc agtacagagc ttatgtcgtt aagccttgag caatactaat ggatgaaggc ggaggaaccc tccagacaag ggtaacctac taaccagatt cattgtggaa ctcaactcta gtcatcttct cacatcacat agggacaaat ccaggtaa tg cagctctgcc tatgaaacag ttgttgggct ctttggaatt aatgtagtcg agcaacc taa gcagacctgg gtcaccacta tatagaatat aaggtggcag aatatcagtt gatgagccaa ttagaaggaa ttgaggctac aaaggctact cctggctttt tggggacctg ttaaatt taa caggtcaaaa atgaatatat gaagctttaa gtgaatatta gcaatttcaa agccagtggt ttgtt tggaa ttccatgtga ccaatcaaaa ttaccatgaa ac tggcaaaa gctgtggttc ggaccctctg acatgcctgt ccgtagtgat aatggctcaa ttcacctgag ggttggtgct aaatcattca atacagtgaa act ggc ca tc ctgcttctcg ttgatatctc ctgctgatgg gaattgtgaa tttctaatat aaacaat tga caactcggaa attttagcat ttctttcatt taattctttg ttctaccatt tgaaattgtC tgccaaaatc tgacttctgg ctacctgatc tcaagctact tactaacaga tcagaacatc ttcaaccttc tgctggagag ttgggccctt gcagaagctc tgtgagacaa tatccaacct gatatgtttt caactgttta gcagaactta.

taaagaagaa cttaagcagt tgaattggc cttggctctc tggtcttcca ttaa 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2154 <210> 14 <211> 717 <212> PRT <213> homo sapiens <400> 14 Met Phe Arg Ser Asp Arg Met Trp 1 5 Ser Pro Leu Leu Phe Leu Phe Ala Ser Cys His 10 Leu Tyr Ile 25 Trp Lys Met Cys Ser Val Trp Gly Cys Gly Thr Phe Thr Ser 'Prp Lys Pro Val Pro His Asn Pro Ser Asn Ser Gin Ala Asn Cys Arg Val Val Leu 40 Pro Cys Tyr Pro Asn Asp Tyr Leu Arg Ala Pro Thr Gly Tlyr Ser Pro Met Trp Thr Ile Ile Gin Phe Asn Asp Asp Ile Glu Giu Ala Asn Cys Ser Leu Ser Leu 100 Thr Ala Lys Gly Asn Giy Glu Thr Lys Phe Ile Tyr Cys Gly 110 Met His Leu Ser Phe Ser Ala Asn Ser Phe 130 T1vr Ile Ser Asp Phe Gin Lys Lys Asn Ala Ser Arg Val Ala Val Leu Arg Asn Val Ile Leu Thr Ser Asp Gin Val Ser LYS Ser Ile Ser Ile 175 Pro Glu Leu Ser Phe Thr Leu Glu Ala Thr His Glu Asp 195 Thr Gin Leu Asp Trp Thr Ser Tyr Ser Lys Val Gly 190 Ala Ser Phe Phe Leu Ser Leu Ser Phe 210 Ile Ser Gly 215 Leu Aia Lys Ser Asp Ser Lys Leu Asn Asm, Pro Val Lys Giu Asp Ile Giu Ser Phe Glu 250 Leu Cys Leu 22 87 WO 01/18207 PCTUSOO/2459 1 Asn ASn Ser Leu Gly Ser Ile Gly Val Asn Phe Lys Arg Asn Tyr Giu 260 265 270 Thr Val Pro Cys Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn Gly 275 280 285 Lys Leu Leu Leu Gly Ser Asn Gin Asn Glu Ile Val Ser Leu Lys Gly 290 295 300 Asp Ile Tyr Asn Phe Arg Leu T-p, Asn Phe Thr Met Asn Ala Lys Ile 305 310 315 320 Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Asn Val Val Asp Trp, Gin 325 330 335 Asn Asp Phe Ti-p Asn Ile Pro Asn Leu Ala Leu Lys Ala Giu Ser Asn 340 345 350 Leu Ser Cys Gly Ser Tyr Leu Ilie Pro Leu Pro Ala Ala Giu Leu Ala 355 360 365 Ser Cys Ala Asp Leu Gly Thr Leu Cys Gin Ala Thi- Val Asn Ser Pro 370 375 380 Ser Thr Thr Pro Pro Thr Val Thi- Thr Asn Met Pro Val Thi- Asn Arg 385 390 395 400 Ile Asp Lys Gin Arg Asn Asp Gly Ile Ile Tyr Arg Ile Ser Val Val 405 410 415 Ile Gin Asn Ile Leu Arg His Pro Giu Vai Lys Vai Gin Ser Lys Val 420 425 430 Ala Glu Trp Leu Asn Ser Thi- Phe Gin Asn Trp Asn Tyr Thr Vai T[yr 435 440 445 Val Vai Asn Ile Ser Phe His Leu Ser Ala Gly Giu Asp Lys Ile Lys 450 455 460 Val Lys Arg Ser Leu Giu Asp Glu Pro Arg Leu Val Leu Ti-p Ala Leu 465 470 475 480 Leu Val Tyr Asn Ala Thr Asn Asn Thi- Asn Leu Giu Gly Lys Ile Ile 485 490 495 Gin Gin Lys Leu Leu Lys Asn Asn Giu Ser Leu Asp Glu.Gly Leu Arg 500 505 510 Leu His Thi- Vai Asn Val Arg Gin Leu Gly His Cys Leu Ala Met Giu 515 520 525 Giu Pro Lys Gly Tyr Tyr Trp Pro Ser Ile Gin Pro Ser Giu Tyr Val 530 535 540 Leu Pro Cys Pro Asp Lys Pro Gly Phe Ser Ala Ser Arg Ile Cys Phe 545 550 555 560 '[yr Asn Ala Thr Asn Pro Leu Val Thr T[yr Ti-p Gly Pro Val Asp Ile 565 570 575 Ser Asn Cys Leu Lys Giu Ala Asn Giu Vai Ala Asn Gin Ile Leu Asn 580 585 590 Leu Thi- Ala Asp Gly Gin Asn Leu Thr Ser Ala Asn Ilie Thr Asn Ile 595 600 605 Vai Giu Gin Val Lys Arg Ile Val Asn Lys Giu Giu Asn Ile Asp Ile 610 615 620 Thr Leu Giy Ser Thr Leu Met Asn Ilie Phe Ser Asn Ile Leu Ser Ser 625 630 635 640 Ser Asp Ser Asp Leu Leu Glu Ser Ser Ser Giu Ala Leu Lys Th- Ile 645 650 655 Asp Glu Leu Ala Phe Lys Ilie Asp Leu Asn Ser Thr Ser His Val Asn 660 665 670 Ilie Thr Thr Arg Asn Leu Ala Leu Ser Val Ser Ser Leu Leu Pro Gly 675 680 685 Thr Asn Ala Ile Ser Asn Phe Ser Ile Gly Leu Pro Ser Asn Asn Glu 690 695 700 Ser Tyr Phe Gin Val Met Ser Gin Ti-p Phe Leu Ser Phe 705 710 715 <210> <211> 3336 <212> DNA <213> homo sapiens 23 87 WO 01/18207 WO 0118207PCT/USOO/2459

I

<400> 15 atgt ttcgc t t tct tat ttg cgagtggttt ccaaacagcc acatt taacg gataatggag tcaagtgcga ttcaatgcca cagacatcag gctttcacac ttctcctact tactttctat aaagaagaca ggctctattg agtaaagtta tctctaaaag ctctccaacc aatatcccaa ccgctcccag gtaaactctc atcgataaac cttcgtcacc caaaattgga gacaagatta ctagtttaca ctaaaaaata ctgggtcatt tctgaatacg tacaatgcta aaagaagcaa acctcagcca.

aacat tgata tcagacagtg ttcaagatag agcgtatcat agcaataatg tc tgt aa tt t agaagagcac agaaaaactt ctgaaggatc atctgtgcct tgtgttgcac cactttggag aaagtcctca actctcctga atgaacctga acctccttca ctggcaacct gtatt taaca cctgccttag gaaa gt tatg tatgtgacct gtggtaatgg gaagtgttaa ggttttgcat ttcaattcat cagatcgaat ctttatatat tgtccaaccc aggcttgcat actttgacat agagccagac atgagatgca gctacatcag atgcttacca tctgctttga caaatgcatc ccatttctga tttttgcaga gtgtaaattt t tcc tgggaa gggacattta tcagctgtaa acctagctct cagcagaact ctagtactac aaaggaatga ctgaggtaaa actacacggt aagtcaagag atgctaccaa atgagtcctt gtcttgccat ttcttccttg ccaacccatt atgaagttgc atattaccaa taacacttgg acttgcttga acctaaatag ccctgttacc aatcgtattt tgcctccaaa agtttacttt tagtgagtta ctgttcaaat tctgggatct acagagattc ttctgatgga ctttcatcag catatgttgc gcacagccct atgtggatgg ttacctggat cttacattcg tggtgtcagt ggaaagaaaa gtgctgggta tgcagatctg ggaacc tgcg tctttgcctg tacaaggtaa gtggagc tgc catgtgtgtt ttctgggacc gtggacgctc tgaagaagct taaattttgt tgtgtccttt agttgccgtg ggtatctgtt agcaaccaaa ct tcacacaa ttcaaaatgt aagctttgaa caaaagaaac tgggaaattg taactttcga tgtgaaaggg gaaagctgaa ggccagc tgt accacccact tggaattatc agtacagagc ttatgtcgtt aagccttgag caatactaat ggatgaaggc ggaggaaccc tccagacaag ggtaacctac taaccagatt cattgtggaa ctcaactcta gtcatcttct cacatcacat agggacaaat ccagatggat cttacttgag cttcaacaaa tgtgatggcg aaaaatcaaa gaacaaaaac agatgcaagt ccttccaaga ctatattggg ttttgagaaa gctgttcctg actttgcatt ggggc tagaa ccgatacatt tgt tc tagcg aggtgatgaa ttttggagtc tgggaggaat cagtgtggtt gggaccctta gataaattgt cattggaaat cctcactcag tttacttctc cgagccccca cccaattgca ggagcaactg tcaagtgact tccttaagga gcaaaaagca gttggccatg ttgctcagtt ttgttgaata cagctctgcc tatgaaacag ttgttgggct ctttggaatt aatgtagtcg agcaacctaa gcagacctgg gtcaccacta tatagaatat aaggtggcag aatatcagtt gatgagccaa ttagaaggaa t tgaggctac aaaggctact cctggctttt tggggacctg ttaaatttaa caggtcaaaa atgaatatat gaagctttaa gtgaatatta gcaatttcaa t ttgagagtg aatttaagt-c ac tggact tt tgcagtattg catacaagaa aaaagttttg gagacagtct agtgcctcac tgtggaatat t tgcgaaggg aatctcctct gctgttgcag gcaattcaca c taaaattct agcagaaaca ttctgttgga atgttttttc ggcaagagaa agcttgacct aatatcccct acatga ggaagcccag tgtggggatg catgctaCCC ccggttatat tttatgactc ccaaaggc ct ttagcatcca atcaaaaggt tctctattCC aagacagtga t tggaaaggc atgcattacC ttgtttggaa ttccatgtga ccaatcaaaa ttaccatgaa ac tggcaaaa gc tgt gg ttc ggaccctctg acatgcctgt ccgtagtgat aa tggctcaa ttcacctgag gg ttgg tgc t aaatcattca atacagtgaa actggccatc ctgcttctcg ttgatatctC ctgctgatgg gaattgtgaa tttctaatat aaacaattga caactcggaa attttagcat gacaagtgga cagaagattC tccaggatgt gaaacattac ctcaggaagt gaggatggaa gcc tgtgtaa agttagatgc ctgctatttt attatccctc tcctcctaga tcctgttgca tgtacattgc gcatcattgg acaatgaagt ttcaagatcc tgaacattgc gcaaccggac ttctgttggg tcatgtacct tcctctcctg tgccaactgc taacgaC tac cattcagata attatccctt atcatttaac gaagaaagg t cattttaccc agagctcagt ttggacagct caagagtggC tgtcaaagaa taattctttg ttctaccatt tgaaattgtc tgc caaaa tc tgacttctgg c ta cctga tc tcaagctact tactaacaga tcagaacatc ttcaaccttc tgctggagag ttgggccctt gcagaagctc tgtgagacaa tatccaacct gatatgtttt caactgttta gcagaactta taaagaagaa cttaagcagt tgaattggcc cttggctctc tggtcttcca tccactggca tgtattagtt aggaczcccaa tatccagaat gcatcatccc cacgtcagga ccacttcaca aagaaacact t tcagcagca caaaatcttg tggctggatc tttcttcctt tctagttaaa ctggggtttg ctatggaaaa agtcatattt catgttcatt cctgagagaa catgacatgg cttctccatc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3336 <210> 16 <211> 1111 <212> PRT <213> homo sapiens 24 87 WO 01/18207 <400> 16 Met Phe 1 Ser ProI Ser Val Gly Thr Ala Cys Thr Phe Ser Leu Thr Ala Ser Phe 130 Tyr Ile 145 Gin Thr Pro Glu His Glu Thr Gln 210 Ile Ser 225 Lys Glu Asn Asn Thr Val Lys Leu 290 Asp Ile 305 Leu Ser Asn Asp Leu Ser Ser Cys 370 Ser Thr 385 Ile Asp Ile Gin Ala Giu Val Val 450 Val Lys 465 Leu Val His Ile Val Asp Gly 75 Pro Thr Ala Lys Gin 155 Al a Giu Tyr Ser Ala 235 Gin Phe Val Ile Thr 315 Asfl Leu Pro Ala Met 395 Tyr Lys Trp Giy Leu 475 Leu Lys Trp Cys Val Ser Asn Pro Asn Ile Ile Cys Ile Phe Cys 110 Giu Met 125 Phe Asn Val Ile Ser Ile Thr Lys 190 Asn Aia 205 Tyr Phe Pro Val Cys Leu Arg Asn 270 Pro Gly 285 Ser Leu Asn Aia Val Asp Ala Giu 350 Ala Giu 365 Val Asn Vai Thr Ile Ser Gin Ser 430 Tyr Thr 445 Asp Lys Leu Trp Gly Lys Lys Pro Pro Ser Gin Tyr Gly His Ala Leu Ser 175 Val Ser Leu Lys Val 255 Tyr Asn Lys Lys Trp 335 Ser Leu Ser Asfl Val 415 Lys Val Ile Ala Ile 495 PCTUSOOI2459 1 Pro His Ser Gin Ile Asp Ala Val1 Ser Pro 160 Ile Gly Phe Ser Glu 240 Trp Glu Gly Giy Ile 320 Gin Asn Ala Pro Arg 400 Val1 Val Tyr Lys Leu 480 Ile 87 WO 01/18207 PCTUSOO/2459 I Gin Gin Lys Leu Leu Lys Asn Asn Giu Ser LeU Asp Glu Gly Leu Arg 500 505 510 Leu His Thr Val Asn Val Arg Gin Leu Gly His Cys Leu Ala Met Giu 515 520 525 Giu Pro Lys Gly Tyr Tyr Trp Pro Ser Ile Gin Pro Ser Giu Tyr Val 530 535 540 Leu Pro Cys Pro Asp Lys Pro Giy Phe Ser Ala Ser Arg Ile Cys Phe 545 550 555 560 Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp Gly Pro Val Asp Ile 565 570 575 Ser Asn Cys Leu Lys Giu Ala Asn Giu Val Ala Asn Gin Ile Leu Asn 580 585 590 Leu Thr Ala Asp Giy Gin Asn Leu Thr Ser Ala Asn Ile Thr Asn Ile 595 600 605 Val Giu Gin Val Lys Arg Ile Val Asn Lys Glu Giu Asn Ile Asp Ile 610 615 620 Thr Leu Gly Ser Thr Leu Met Asn Ile Phe Ser Asn Ile Leu Ser Ser 625 630 635 640 Ser Asp Ser Asp Leu Leu Glu Ser Ser Ser Giu Ala Leu Lys Thr Ile 645 650 655 Asp Giu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr Ser His Vai Asn 660 665 670 Ile Thr Thr Arg Asn Leu Ala Leu Ser Val Ser Ser Leu Leu Pro Gly 675 680 685 Thr Asn Ala Ile Ser Asn Phe Ser Ile Giy Leu Pro Ser Asn Asn Giu 690 695 700 Ser Tyr Phe Gin Met Asp Phe Giu Ser Gly Gin Val Asp Pro Leu Ala 705 710 715 720 Ser Val Ile Leu Pro Pro Asn Leu Leu Giu Asn Leu Ser Pro Giu Asp 725 730 735 Ser Vai Leu Val Arg Arg Ala Gin Phe Thr Phe Phe Asn Lys Thr Giy 740 745 750 Leu Phe Gin Asp Val Gly Pro Gin Arg Lys Thr Leu Val Ser Tyr Val 755 760 765 Met Ala Cys Ser Ile Giy Asn Ile Thr Ile Gin Asn Leu Lys Asp Pro 770 775 780 Val Gin Ilie Lys Ilie Lys His Thr Arg Thr Gin Giu Vai His His Pro 785 790 795 800 Ile Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly Trp, 805 810 815 Asn Thr Ser Giy Cys Val Ala His Arg Asp Ser Asp Ala Ser Giu Thr 820 825 830 Val Cys Leu Cys Asn His Phe Thr His Phe Gly Val Leu met Asp Leu 835 840 845 Pro Arg Ser Ala Ser Gin Leu Asp Ala Arg Asn Thr Lys Val Leu Thr 850 855 860 Phe Ilie Ser Tyr Ilie Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala Ala 865 870 875 880 Thr Leu Leu Thr Tyr Val Ala Phe Giu Lys Leu Arg Arg Asp Tyr Pro 885 890 895 Ser Lys Ile Leu Met Asn Leu Ser Thr Aia Leu Leu Phe Leu Asn Leu 900 905 910 Leu Phe Leu Leu Asp Gly Trp Ilie Thr Ser Phe Asn Val Asp Gly Leu 915 920 925 Cys Ilie Ala Vai Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr Phe 930 935 940 Thr Trp Met Giy Leu Giu Ala Ilie His Met Tyr Ilie Ala Leu Val Lys 945 950 955 960 Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile Ile 965 970 975 Giy Trp, Gly Leu Pro Ala Leu Val Val Ser Val Val Leu Ala Ser Arg 980 985 990 Asn Asn Asn Giu Val Tyr Gly Lys Glu Ser Tyr Gly Lys Giu Lys Gly 26 87 WO 01/18207 WO 0118207PCTUSOO/24591 995 Asp Glu Phe 1010 Ala Gly Tyr Cys Tip Ile 1000 Gin Asp 1015 Met Phe Pro Val Ile 1005 Phe Tyr Val Thr Cys 1020 Ile Ala Met Phe Ile Phe Gly Val ?he Leu 1025 Vai Val 1030 Ile Cys Asn 1035 met Val Gin Thr Leu Arg Glu 1045 Giu Gly Arg Asn 1050 Arg Asn Leu i1y LYS Arg Ser Val Leu 1040 Asn Arg 1055 Thr Phe Leu 1075 Pro Leu Asn 1090 Gin Gly Lys 1105 1060 Leu Gly Met Thr 1065 Tip Gly Phe 1080 Tyr Leu Phe Arg Ser Val Val Ser Leu 1070 Ala Phe Phe Ala Tip, Gly 1085 Ser Ile Phe Asn Ser Leu 1100 Ile Pro Phe Ile Asn Cys 1110 4et 1095 ['hr <210> 17 <211> 3753 <212> DNA <213> homo sapiens <400> 17 atgatgtittc ctgttcttat tgccgagtgg tacccaaaca ataacatt ta.

cttgataatg aac tcaagtg ggtttcaatg ccccagacat agtgctttca gctttctcct ggctactttc gaaaaagaag ttgggctcta attagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc actgtaaact agaatcgata atccttcgtc ttccaaaatt gaggacaaga.

cttctagttt c tcctaaaaa.

caactgggtc ccttctgaat ttttacaatg t taaaagaag ttaacctcag gaaaacattg agttcagaca.

gccttcaaga c tcagcgtat c caagc aa ta gcatctgtaa.

g ttagaagag caaagaaaaa.

aatctgaagg cccatctgtg gctcagatcg itgctttata ttttgtccaa gccaggcttg acgactttga gagagagcca.

cgaatgagat ccagctacat cagatgctta cactctgctt ac tcaaatgc tatccatttc acat tt ttgc ttggtgtaaa ttattcctgg aaggggacat acctcagctg caaacctagc cagcagcaga ctcctagtac aacaaaggaa.

accc tgaggt ggaac tacac ttaaagtcaa acaatgctac ataatgagtc at tgtcttgc acgttcttcc ctaccaaccc caaatgaagt ccaatattac atataacact gtgacttgct tagacctaaa.

catccctgtt a tgaa tcgt a ttttgcctcc cacagtttac ctttagtgag atcctgttca ccttctggga aatgtggagc tatcatgtgt cccttctggg catgtggacg cat tgaagaa gactaaattt gca tgtg tcc cagagttgcc ccaggtatct tgaagcaacc atccttcaca tgattcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct actggccagc tacaccaccc tgatggaatt aaaagtacag ggtttatgtc gagaagcctt caacaatact cttggatgaa catggaggaa t tgtccagac attggtaacc tgctaaccag caacattgtg tggctcaact tgagtcatct tagcacatca accagggaca t t t caga tg aaacttactt tttcttcaac ttatgtgatg aataaaaatc tctgaacaaa tgccat tgga gttcctcact acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa.

gttgcaaaaa aaagt tggcc caat tgc tca tg tt tgt tga gaacagc tc t aactatgaaa.

ttgttgttgg cgactttgga.

gggaatgtag gaaagcaacc tgtgcagacc ac tgtcacca.

atctatagaa.

agcaaggtgg gttaatatca gaggatgagc aatttagaag ggcttgaggc cccaaaggct aagcctggct tactggggac attttaaatt gaacaggtca.

ctaatgaata tctgaagctt catg tgaata.

aatgcaattt gattttgaga gagaatttaa.

aaaactggac gcgtgcagta.

aaacatacaa.

aacaaaagtt aatggaagcc cagtgtgggg ctccatgcta ccaccggtta.

gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat tcgactggca taagctgtgg tggggaccct ctaacatgcc tatccgtagt cagaatggct gttttcacct caaggttggt gaaaaatcat tacatacagt actactggcc tttctgcttc ctgttgatat taactgctga aaagaattgt tat tttctaa taaaaacaat ttacaactcg caaattttag gtggacaagt gtccagaaga ttttccagga ttggaaacat gaactcagga ttggaggatg cagtcctctc atgtgccaac ccctaacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa.

ggtcatttta tccagagctc tgattggaca.

ggccaagagt acctgtcaaa.

gaataattct tgattCtacc aaa tgaaatt gaatgccaaa aaatgacttc ttcctacctg ctgtcaagct tgttactaac gattcagaac caattcaacc gagtgctgga gctttgggCC tcagcagaag gaatgtgaga.

atctatccaa.

tcggatatgt ctccaactgt tgggcagaac gaataaagaa tatcttaagc tgatgaattg gaacttggct cattggtctt ggatccactg ttctgtatta tgtaggaccc tac tatccag agtgcatcat gaacacgtca 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 27 87 WO 01/1,8207 WO 0118207PCTIJSOO/2459 1 ggatgtgttg acacact ttg actaaagtcc gcaac tc tcc ttgatgaacc atcacctcct cttctggcaa aaagtattta ttgcctgcct aaagaaagtt t t tta tgtga attgtggtaa gaagaagtgt tggggttttg atcttcaatt gttcagaaac gattggagta ttgtcttcaa LCtaccacct tcaaaactgg gataaggtca tcagacacct cacacagaga gagttCtgat tcactttcat tgacatatgt tgagcacagc tcaatgtgga cctttacctg acacttacat.

tagtggtgtc a tgggaaaga cctgtgctgg tggtgcagat.

taaggaacc t cattctttgc cattacaagg agtggcggcg agacagctac gctccattgg atttcaaaag cccatgctga agggttattg tcagccacag ttcagatgca ggaccttcca cagctatat t tgcttttgag cctgctgttc tggactttgc gatggggc ta tcgccgatac agttgttcta aaaaggtgat gtat tt tgga ctgtgggagg gcgcagtgtg ctggggaccc cttatttata gcatctctgc caatatcatc ttccaactca gaatagccac tggagatcaa caatgctcat cacaaagttt agtgagacag agaagtgcct gggtgtggaa aaattgcgaa ctgaatctcc attgctgttg gaagcaattc attctaaaat gcgagcagaa gaattctgtt.

gtcatgtttt aatggcaaga gttagcttga ttaaatatcc ttcatcttcc tgtggtagat aagaaaagtt acctatctta acagacagtg acatcaatca tcagacaact.

taa tctgcctgtg cacagttaga tatctgctat gggattatcc tcttcctcct cagtcctgtt acatgtacat tctgcatcat acaacaatga ggattcaaga ttctgaacat gaagcaaccg cctttctgtt ccttcatgta actgtgctat ttcggttagc ctgataatct catccaaatc cttccatgga tccctgtcca tctataaaaa taaccacttc tgcaagaaac t tt ttcagca ctccaaaatc aga tggc tgg gcatttcttc tgctctagtt tggctggggt agtctatgga tccagtcata tgccatgttc gac cc tgaga gggca tgaca cctcttctcc gaaggagaat agataactca aggaaaatct taaatccagc caagtccttg tcaggtcatt tattatcatg 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3753 <210> 18 <211> 1250 <212> PRT <213> homo sapiens <400> 18 Met Met Phe Arg Ser Asp Arg 1 5 Pro Ser Pro Leu Leu Phe Leu Met Trp Ser 10 Phe Ala Leu Asn Cys Arg Cys Tyr Val1 His Trp Lys Trp Lys Ile Met Cys Val Pro Val Leu Ser Asn Pro His Ser Val Ser Gly Thr Gin Ala Cx's Trp Gly Cys Ala Phe Thr Ser Pro 40 Cys Asp Tyr Tyr Pro Asn Pro Asn Ser Met Trp Arg Ala Ile Thr Phe Asn Asp Ile Glu Pro Thr Gly Glu Ala Pro Ser Gin Thr Tyr Ile Ile Asp Ser Leu Ala Thr Ala 115 Val Ser Phe Asp Asn Gly Asn Cys Lys Phe 110 Asn Glu Ile Tyr Cys Gly Met His Gly Leu Ser Phe Asn Ser Ser Ala 130 Ser Tyr Ile Ser Ser Asp Arg Val Ala Ile Gin Lys Gin Thr Ser Ala Tyr Ala Phe Ser Leu Arg Asn Gin Lys 155 Gin Val Ser Val Aia Lys 170 Thr Leu Cys Phe Giu Ala Phe Asn Aia Val Ile Leu 160 Ser Ile Ser 175 Thr Lys Val 190 Asn Ala Ser Tyr Phe Leu Ile Pro Glu Leu Gly His Glu 195 Phe Thr Gin Ser Asp Trp Thr 200 Phe Ser Tyr Leu Leu Ser Ser 225 Glu Ser Asp Ser Phe Gly Lys Ala Lys Ser 215 220 Cys Leu Leu Asn Asn Ala 235 Ala Glu Ser Phe Glu Gin Leu Pro Val Lys Giu Asp Trp Asn Asn Ser 260 Gly Ser Ile 250 Gly Val 265 Leu Cys Leu Val 255 Lys Arg Asn Tyr 270 Asn Phe 28 87 WO 01/18207 PCT/US00/24591 Glu Gly Gly 305 Ile Gin Asn Ala Pro 385 Arg Val Val Tyr Lys 465 Leu Ile Arg Glu Val 545 Phe Ile Asn Ile Ile 625 Ser Ile Asn Gly Glu 705 Ala Asp Gly Val Pro Cys Asp Ser Thr 280 Leu Leu Gly Ser Asn 295 Tyr Asn Phe Arg Leu 310 Asn Leu Ser Cys Asn 325 Phe Trp Asn Ile Pro 340 Cys Gly Ser Tyr Leu 360 Ala Asp Leu Gly Thr 375 Thr Pro Pro Thr Val 390 Lys Gin Arg Asn Asp 405 Asn Ile Leu Arg His 420 Trp Leu Asn Ser Thr 440 Asn Ile Ser Phe His 455 Arg Ser Leu Glu Asp 470 Tyr Asn Ala Thr Asn 485 Lys Leu Leu Lys Asn 500 Thr Val Asn Val Arg 520 Lys Gly Tyr Tyr Trp 535 Cys Pro Asp Lys Pro 550 Ala Thr Asn Pro Leu 565 Cys Leu Lys Glu Ala 580 Ala Asp Gly Gin Asn 600 Gin Val Lys Arg Ile 615 Gly Ser Thr Leu Met 630 Ser Asp Leu Leu Glu 645 Leu Ala Phe Lys Ile 660 Thr Arg Asn Leu Ala 680 Ala Ile Ser Asn Phe 695 Phe Gin Met Asp Phe 710 Ile Leu Pro Pro Asn 725 Leu Val Arg Arg Ala 740 Gin Asp Val Gly Pro 760 Cys Ser Ile Gly Asn Ile Ser Lys Val Ile Pro Gly Asn 285 29 87 WO 01/18207 WO 0118207PCTUSOO/2459 1 770 775 780 Pro Val Gin Ilie Lys Ile Lys His Thr Arg Thr Gin Giu Val His His 785 790 795 800 Pro Ilie Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly 805 810 815 Trp Asn Thr Ser Gly Cys Val Ala His Arg Asp Ser Asp Ala Ser Glu 820 825 830 Thr Val Cys Leu Cys Asn His Phe Thr His Phe Gly Val Leu Met Asp 835 840 845 Leu Pro Arg Ser Ala Ser Gin Leu Asp Ala Arg Asn Thr Lys Val Leu 850 855 860 Thr Phe Ile Ser Tyr Ile Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala 865 870 875 880 Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg Arg Asp Tyr 885 890 895 Pro Ser Lys Ile Leu Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn 900 905 910 Leu Leu Phe Leu Leu Asp Gly rrp Ilie Thr Ser Phe Asn Val Asp Gly 915 920 925 Leu Cys Ile Ala Val Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr 930 935 940 Phe Thr Trp Met Gly Lell Glu Ala Ile His Met Tyr Ile Ala Leu Val 945 950 955 960 Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile 965 970 975 Ile Gly Trp Gly Leu Pro Ala Leu Val Val Ser Val Val Leu Ala Ser 980 985 990 Arg Asn Asn Asn Giu Val Tyr Gly Lys Glu Ser Tyr Gly Lys Glu Lys 995 1000 1005 Gly Asp Glu Phe Cys Trp Ile Gin ASP Pro Vai Ile Phe Tyr Val Thr 1010 1015 1020 Cys Ala Gly Tyr Phe Gly Val Met Phe Phe Leu Asn Ile Ala Met Phe 1025 1030 1035 1040 Ilie Val Val Met Val Gin Ile Cys Gly Arg Asn Gly Lys Arg Ser Asn 1045 1050 1055 Arg Thr Leu Arg Glu Giu Val Leu Arg Asn Leu Arg Ser Val Val Ser 1060 1065 1070 Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp 1075 1080 1085 Gly Pro Leu Asn Ilie Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser 1090 1095 1100 Leu Gin Gly Leu Phe Ile Phe Ile Phe His Cys Ala Met Lys Giu Asn 1105 1110 1115 1120 Val Gln Lys Gin Trp, Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu 1125 1130 1135 Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys 1140 1145 1150 Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser Ilie Gly Ser 1155 1160 1165 Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr 1170 1175 1180 Phe Lys Arg Asn Ser His Thr Asp Ser Ala Ser Met Asp Lys Ser Leu 1185 1190 1195 1200 Ser Lys Leu Ala His Ala Asp Gly Asp Gin Thr Ser Ile Ile Pro Val 1205 1210 1215 His Gin Val Ile Asp Lys Val Lys Gly Tyr Cys Asn Ala His Ser Asp 1220 1225 1230 Asn Phe Tyr Lys Asn Ile Ile Met Ser Asp Thr Phe Ser His Ser Thr 1235 1240 1245 Lys Phe 1250 <210> 19 87 WO 01/18207 WO 0118207PCT/USOO/2459

I

<211> 3666 <212> DNA <213> homo sapiens <400> 19 atgatgtttc ctgttcttat tgccgagtgg tacccaaaca ataacattta cttgataatg aac tcaagtg ggtttcaatg ccccagacat agtgctttca gctttctcct ggctactttc gaaaaagaag ttgggctcta attagtaaag g tc tc tctaa atcctctcca tggaatatcc atcccgctcc actgtaaact agaatcgata atccttcgtc ttccaaaatt gaggacaaga ct tc tagtt t ctcctaaaaa caactgggtc ccttctgaat ttttacaatg ttaaaagaag t taacctcag gaaaacattg agttcagaca gccttcaaga ctcagcgtat ccaagcaata gcatctgtaa gttagaagag caaagaaaaa aatctgaagg cccatctgtg ggatgtgttg acacactttg actaaagtcc gcaactctcc ttgatgaacc atcacctcct cttctggcaa aaagtattta ttgcctgcct aaagaaagtt ttttatgtga attgtggtaa gaagaagtgt tggggttttg atcttcaatt gttcagaaac gattggagta gctcagatcg ttgctttata ttttgtccaa gccaggcttg acgactttga gagagagcca cgaatgagat ccagctacat cagatgctta cactctgctt actcaaatgc tatccatttc acatttttgc t tgg tg taaa ttattcctgg aaggggacat acctcagctg caaacctagc cagcagcaga ctcctagtac aacaaaggaa accctgaggt ggaactacac ttaaagtcaa acaatgctac ataatgagtc attgtcttgc acgttcttcc ctaccaacc caaatgaagt ccaatattac atataacact gtgacttgct tagacctaaa catccctgtt atgaatcgta ttttgcctcc cacagtt tac ctttagtgag atcctgttca ccttctggga cacacagaga gagttctgat tcactttcat tgacatatgt tgagcacagc tcaatgtgga cctttacctg acacttacat tagtggtgtc atgggaaaga cctgtgctgg tggtgcaga t taaggaacct cattctttgc cat tacaagg agtggCggcg agacagctac aatgtggagc tatcatgtgt ccc-ttctggg catgtggacg cattgaagaa gactaaattt gcatgtgtcc cagagttgcc ccaggtatct tgaagcaacc atccttcaca tga t tcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct actggccagc tacaccaccc tgatggaatt aaaagtacag ggtttatgtc gagaagcc tt caacaatact cttggatgaa catggaggaa ttgtccagac attggtaacc tgc taaccag caacattgtg tggctcaact tgagtcatct tagcacatca accagggaca tttccagatg aaacttactt tttcttcaac ttatgtgatg aataaaaatc tc tgaacaaa t tcagatgca ggacc ttc ca cagctatatt tgcttttgag cctgctgttc tggactttgc gatggggcta tcgccgatac agttgttcta aaaaggtgat gtattttgga c tg tgggagg gcgcagtgtg ctggggaccc cttatttata gcatctctgc caatatcatc tgccattgga gttcctcact acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagttggC caattgctca tgtttgttga gaacagc tct aactatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc ac bgtcacca atctatagaa agcaaggtgg gttaatatca gaggatgagc aatttagaag ggcttgaggc cccaaaggct aagcctggct tactggggac attttaaatt gaacaggtca ctaatgaata tctgaagctt catgtgaata aatgcaattt gattttgaga gagaatttaa aaaac tggac gcgtgcagta aaacatacaa aacaaaagtt agtgagacag agaagtgcct gggtgtggaa aaat tgcgaa ctgaatctcc attgctgttg gaagcaattc attctaaaat gcgagcagaa gaattctgtt gtcatgtttt aatggcaaga gttagcttga ttaaatatcc ttcatcttcc tgtggtagat aagaaaagtt aatggaagcc cagtgtgggg ctccatgcta ccaccggtta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gcc ttgt ttg cagttccatg gctccaatca attttaccat tcgactggca taagctgtgg tggggaccct c taacatgcc tatccgtagt cagaatggct gttttcacct caaggttggt gaaaaatcat tacatacagt actactggcc tttctgcttc ctgttgatat taactgctga aaagaattgt tattttctaa taaaaacaat ttacaactcg caaattttag gtggacaagt gtccagaaga ttttccagga t tggaaacat gaac tcagga ttggaggatg tctgcctgtg cacagttaga tatctgctat gggattatcc tcttcctcct cagtcctgtt acatgtacat tctgcatcat acaacaatga ggattcaaga ttctgaacat gaagcaaccg cctttctgtt ccttcatgta actgtgctat ttcggt tagc ctgataatct cagtcctctc atgtgccaac ccctaacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acctgtcaaa gaataattct tgattctacc aaatgaaat t gaatgccaaa aaatgacttc ttcctacctg ctgtcaagct tgttactaac gattcagaac caattcaacc gagtgctgga gctttgggcc tcagcagaag gaatgtgaga atctatccaa tcggatatgt ctccaactgt tgggcagaac gaataaagaa tatcttaagc tgatgaattg gaacttggct cattggtctt ggatccactg ttctgtatta tgtaggaccc tactatccag agtgcatcat gaacacgtca taaccacttc tgcaagaaac tttttcagca ctccaaaatc agatggc tgg gcatttCttC tgctctagtt tggctggggt agtctatgga tccagtcata tgccatgttc gaccctgaga gggcatgaca cctcttctcc gaaggagaa t agataactca aggaaaatct 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 31 87 WO 01/18207 PCT/US0012459 1 ttgtcttcaa gctccattgg ttccaactca acctatctta catccaaatc taaatccagc 3540 tctaccacct atttcaaaag gaatagccac acagataatg tctcctatga gcattccttc 3600 aacaaaagtg gatcactcag acagtgcttc catggacaag tccttgtcaa aactggccca 3660 tgctga 3666 <210> <211> 1221 <212> PRT <213> homo sapiens <400> Met Met Phe Arg Ser Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys 1 5 10 Pro Ser Pro Leu Leu Phe Leu Phe Ala Leu Tyr Ile Met Cys Val Pro 25 His Ser Val Trp Gly Cys Ala Asn Cys Arg Val Val Leu Ser Asn Pro 40 Ser Gly Thr Phe Thr Ser Pro Cys 'ryr Pro Asn Asp Tyr Pro Asn Ser 55 Gin Ala Cys Met Trp Thr Leu Arg Ala Pro Thr Gly Tyr Ile Ile Gin 70 75 Ile Thr Phe Asn Asp Phe Asp Ile Giu Giu Ala Pro Asn Cys Ile Tyr 90 Asp Ser Leu Ser Leu Asp Asn Gly Glu Ser Gin Thr Lys Phe Cys Gly 100 105 110 Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Ala Asn Glu Met His 115 120 125 Val Scr Phe Ser Ser Asp Phe Ser Ile Gin Lys Lys Gly Phe Asn Ala 130 135 140 Scr Tyr Ile Arg Val Ala Val 5cr Leu Arg Asn Gin Lys Val Ile Leu 145 150 155 160 Pro Gin Thr Ser Asp Ala Tyr Gin Val Ser Val Ala Lys Ser Ile Ser 165 170 175 Ilie Pro Giu Leu Ser Ala Phe Thr Leu Cys Phe Giu Ala Thr Lys Val 180 185 190 Gly His Glu Asp 5cr Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser 195 200 205 Phe Thr Gin Leu LOu 5cr Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu 210 215 220 cr Ile 5cr Asp 5cr Lys Cys Leu Leu Asn Asn Ala Leu Pro Val Lys 225 230 235 240 Giu Lys Glu Asp Ile Phe Ala Glu Ser Phe Giu Gin Leu Cys Lcu Val 245 250 255 Trp Asn Asn Ser Leu Gly 5cr Ile Gly Val Asn Phe Lys Arg Asn Tyr 260 265 270 Glu Thr Val Pro Cys Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn 275 280 285 Gly Lys Leu Leu Leu Gly Ser ASfl Gin Ann Glu Ile Val Ser Leu Lys 290 295 300 Gly Asp Ile Tyr Asn Phe Arg Lcu Trp Asn Phe Thr Met Asn Ala Lys 305 310 315 320 Ile Leu 5cr Asn Leu Ser Cys Asfl Val Lys Giy Asn Val Val Asp Trp, 325 330 335 Gin Asn Asp Phe Trp Asn Ilie Pro Asn Leu Ala Lcu Lys Ala Glu 340 345 350 Asfl Leu 5cr Cys Gly 5cr Tyr Leu Ile Pro Leu Pro Ala Ala Glu Leu 355 360 365 Ala 5cr Cys Ala Asp Leu Gly Thr Leu Cys Gin Ala Thr Val Asn Ser 370 375 380 Pro Ser Thr Thr Pro Pro Thr Val Thr Thr Asfl Met Pro Val Thr Asn 385 390 395 400 Arg Ile Asp Lys Gin Arg Asn Asp Gly Ile Ile Tyr Arg Ile Ser Val 405 410 415 32 87 WO 01/18207 Val Val Tyr Lys 465 Leu Ile Arg Giu Val 545 Phe Ile Asn Ile Ile 625 Ser Ile Asn Gly Giu 705 Ala Asp Giy Val1 Pro 785 Pro Trp Thr Leu Thr 865 Ala Pro Leu Gin Glu 435 Val1 Lys Val Gin His 515 Pro Pro Asn Asn Thr 595 Giu Leu Asp Giu Thr 675 Asn Tyr Val1 Val1 Phe 755 Ala Gin Cys Thr Cys 835 Arg Ile Leu Lys Phe Asn 420 Trp Asn Arg Tyr Lys 500 Thr Lys Cys Ala Cys 580 Ala Gin Giy Ser Leu 660 Thr Aia Phe Ile Leu 740 Gin Cys Ile Ala Ser 820 Leu Ser Ser Leu Ile 900 Leu Arg Ser Phe 455 Giu Thr Lys Val Tyr 535 Lys Pro Giu Gin Arg 615 Leu Leu Lys Leu Asn 695 Asp Pro Arg Giy Giy 775 Lys

ASP

Val His Gin 855 Giy Vai Asn Giy Pro 425 Phe Leu Giu Asn Asn 505 Gin Pro Giy Val Asn 585 Leu Val Asn Ser Asp 665 Leu Ser Giu Leu Gin 745 Gin Ile Thr Asn His 825 Thr Asp Gly Phe Scr 905 Ile Val Asn Ala Arg 475 Asn Ser Gly Ile Ser 555 Tyr Vali Ser Lys Phe 635 Ser Asn Val1 Gly Gly 715 Giu Thr Lys Ile Thr 795 Asn Asp Phe Arg Ser 875 Lys Ala Ser Vai Gin 430 Asn Tyr 445 Giu Asp Vai Leu Glu Gly ASP GiU 510 Cys Leu 525 Pro Ser Ser Arg Gly Pro Asn Gin 590 Asn Ile 605 Giu Asn Asn Ile Ala Leu Thr Ser 670 Ser Leu 685 Pro Ser Vai Asp Leu Ser Phe Asn 750 Leu Val 765 Asn Leu Giu Val Ser Phe Asp Ala 830 Val Leu 845 Thr Lys Ile Phe Arg Arg Leu Phe 910 Asn Val PCTUSOO/2459 I Ser Lys Thr Val Lys Ile Trp Aia 480 Lys Ile 495 Gly Leu Aia Met Glu Tyr le Cys 560 Val Asp 575 Ile Leu Thr Asn Ile Asp Leu Ser 640 Lys Thr 655 His Val Leu Pro Asn Asn Pro Leu 720 Pro Giu 735 Lys Thr Ser Tyr Lys Asp His His 800 Gly Giy 815 Ser Glu Met Asp Val Leu Ser Aia 880 Asp Tyr 895 Leu Asn Asp Gly 33 87 WO 01/18207 WO 0118207PCT[USOO/24591 Leu Cys 930 Phe Thr Ala Val Ala Val1 935 Glu Leu His Phe Phe Leu Ala Thr Trp Met Gly Ala Ile His Tyr Ile Ala Leu Val Phe Asn Ile Gly Trp Arg Asn Asn 995 Gly Asp Glu Leu Pro Giu Val Ile Arg Arg Ala Leu Val 985 Tyr Gly Lys 1000 Ile Gin Asp 1015 Val Met Phe Ile Cys Gly Leu Lys Phe Cys Ile 975 Ser Val Val Leu Ala Ser 990 Giu Ser TPyr Giy Lys Giu Lys 1005 Phe Cys Trp 1010 Cys Ala Pro Val Ile Phe Tyr 1020 Phe Leu Asn Ile Ala ;iy Tyr Phe 1025 Ile Val Val Met Gly 1030 Vai Gin 1045 1035 Arg Asn 1050 Val Thr Met Phe 1040 Ser Asn 1055 Gly Lys Arg Arg Thr Leu Leu Thr Phe 1075~ Gly Pro Leu 1090 Leu Gin Gly Arg Giu Giu Val Leu Arg Asn Leu Arg Ser Val Val Ser 1060 1065 1070 Leu Leu Gly Met Thr Trp, Gly Phe Ala Phe Phe Ala Trp 1080 1085 Asn Ile Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser 1095 1100 Leu Phe Ile Phe Ile Phe His Cys Ala Met Lys GlU Asn 1105 Val1Gin Lys Gin 1110 Trp Arg Arg His 1125 Asp Trp Ser Lys 1115 Leu Cys Cys Gly Arg 1130 Thr Ala Thr Asn Ile 1120 Phe Arg Leu 1135 Ilie Lys Lys 1150 Ala Asp Asn Ser 1140 1145 Ser Ser Asp Asn Leu Gly Lys Ser Leu 1155 1160 Asn Ser Thr Tyr LeU Thr Ser Lys Ser 1170 1175 Phe Lys Arg Asn Ser His Thr Asp Asn 1185 1190 Asn Lys Ser Gly Ser Leu Arg Gin Cys 1205 Lys Thr Gly Pro Cys 1220 Ser Ser Ser Ser Ilie Gly Ser 1165 Lys Ser Ser Ser Thr Thr Tyr 1180 Val Ser Tyr Glu His Ser Phe 1195 1200 Phe His Gly Gin Val Leu Val 1210 1215 <210> 21 <211> 2157 <212> DNA <213> homo sapiens <400> 21 atgatgtttc ctgttcttat tgccgagtgg tacccaaaca ataacatt ta cttgataatg aactcaagtg ggtttcaatg ccccagacat agtgc ttt ca gctttctcct ggctactttc gaaaaagaag ttgggctcta.

attagtaaag gtctctctaa atcctctcca gc tcagatcg ttgctttata.

ttttgtccaa gccaggcttg acgactttga gagagagcca cgaatgagat ccagctacat cagatgctta cactctgctt actcaaatgc tatccatttc acatttttgc ttggtgtaaa.

ttattcctgg aaggggacat acctcagctg aatgtggagc tatcatgtgt cccttctggg catgtggacg cat tgaagaa gactaaattt gcatgtgtcc cagagt tgcc ccaggtatct tgaagcaacc atccttcaca tgattcaaaa.

agaaagcttt t ttcaaaaga gaa tgggaaa ttataacttt taatgtgaaa tgccattgga gttcctcact acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagt tggcc caattgctca tgtttgttga gaacagctct aac tatgaaa ttgttgttgg cgactttgga gggaatgtag aatggaagcc cagtgtgggg ctccatgcta ccaccggtta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat tcgactggca cagtcctctc atgtgccaac ccctaacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa.

ggtcatttta tccagagctc tgat tggaca ggccaagagt acctgtcaaa gaataattct tgattctacc aaatgaaatt gaatgccaaa aaatgact tc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 34 87 WO 01/18207 WO 0118207PCT/USOO/2459 1 tggaatatcc atcccgctcc actgtaaact agaatcgata atccttcgtc ttccaaaat t gaggacaaga cttctagttt ctcc taaaaa caac tgggtc ccttctgaat ttttacaatg ttaaaagaag ttaacctcag gaaaacattg agttcagaca gccttcaaga ctcagcgtat ccaagcaata caaacctagc cagcagcaga ctcctagtac aacaaaggaa accctgaggt ggaactacac ttaaagtcaa acaatgctac ataatgagtc attgtcttgc acgt tc tt cc c taccaaCcc caaatgaagt ccaatattac atataacact gtgacttgct tagacc taaa catccctgtt atgaatcgta tctgaaagct ac tggccagc tacaccaccc tgatggaatt aaaagtacag ggtttatgtc gagaagcctt caacaatact cttggatgaa catggaggaa ttgtccagac attggtaacc tgctaaccag caacattgtg tggctcaact tgagtcatct tagcacatca accagggaca tttccaggta gaaagcaacc tgtgcagacc actgtcacca atctatagaa agcaaggtgg gt taa tat ca gaggatgagc aatttagaag ggcttgaggc cccaaaggct aagcctggct tactggggac attttaaatt gaacaggtca ctaatgaata tctgaagctt catgtgaata aatgcaattt atgagccagt taagctgtgg tggggaccc t ctaacatgcc tatccgtagt cagaatggct gttttcacct caaggttggt gaaaaatcat tacatacagt actactggcc tttctgcttc ctgttgatat taac tgc tga aaagaattgt tattttctaa taaaaacaat ttacaac tcg caaattttag gg tttctttC ttcctacctg ctgtcaagct tgttactaac g atic agaac caattcaacc gagtgctgga gctttgggcc tcagcagaag gaatgtgaga atctatccaa tcggaiatgt ctccaactgt tgggcagaac gaataaagaa tatcttaagc tgatgaattg gaacttggct cattggtcit atttta 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2157 <210> 22 <211> 718 <212> PRT <213> homo sapiens <400> 22 Met Met Phe Arg 1 Pro Ser Pro Leu His Ser Val Trp Ser Asp 5 Arg Met Trp Cys His Trp Lys Trp Lys Leu Phe Leu Phe Ala 25 Gly Cys Ala Asn Cys Leu Tyr Ile Met Arg Val Val Ser Gly Gin Ala Thr Phe Thr Ser Tyr Pro Asn T1yr Cys Met Trp Leu Arg Ala Pro Thr 75 .Cys Val Pro Ser Asn Pro -Pro Asn Ser Ile Ile Gin Cys Ile Tyr Phe Cys Gly 110 iGlu Met His r Phe Asn Ala Thr Phe Asn Asp Ile Giu Ala Pro Asr Asp Ser Leu Ala Thr Ala 115 Val Ser Phe Leu Asp Asn Gly Leu Ser Gly Glu 105 Phe Asn 120 Ser Ile Ser Gin Thr Lys Ser Ser Ala Ser Ser Asp Gin Lys Ile Arg Gin Thr Ser Ile Pro Giu Leu 180 Gly His Giu Asp 195 Phe Thr Gin Leu Vai Ala 150 Asp Ala 165 Ser Ala Ser Asp Leu Ser Tyr Gin Val Phe Thr Leu 185 Trp Thr Ala 200 Phe Gly Lys 215 Cys Leu Leu Ala Glu Ser Ser Val Ala 170 Cys Phe Glu Phe Ser Tyr Lys Ser Ile Ser 175 Ala Thr Lys Val 190 Ser Asn Ala Ser 205 Gly Tyr Phe Leu Ser Leu Arg Lys Val Ile 210 Ser Ile Ser Asp Ser Lys 230 Asp Ile Phe Ala Lys Asn Asn 235 Leu Pro Val Lys Glu Trp Asn Asn Ser Gly Ser Ile Gly 265 Ile Phe Giu Gin Leu 250 Val Asn Phe Lys Ser Lys Val Ile Cys Leu Val 255 Glu Thr Val 275 Gly Lys Leu Pro Cys Asp Ser Leu Leu Gly Ser 270 Pro Gly Asn Ser Leu Lys Gin Asn Glu Ile 285 Val 87 WO 01/18207 PCTIUSOO/24591 290 295 300 Giy Asp Ilie Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asn Ala Lys 305 310 315 320 Ile Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Asn Val Val Asp Trp 325 330 335 Gin Asn Asp Phe Trp Asn Ile Pro Asn Leu Ala Leu Lys Ala Giu Ser 340 345 350 Asn Leu Ser Cys Gly Ser Tyr Leu Ile Pro Leu Pro Ala Ala Giu Leu 355 360 365 Ala Ser Cys Ala Asp Leu Gly Thr Leu Cys Gin Ala Thr Vai Asn Ser 370 375 380 Pro Ser Thr Thr Pro Pro Thr Val Thr Thr Asn Met Pro Val Thr Asn 385 390 395 400 Arg Ilie Asp Lys Gin Arg Asn Asp Giy Ilie Ilie Tyr Arg Ile Ser Val 405 410 415 Vai Ile Gin Asn Ile Leu Arg His Pro Glu Val Lys Vai Gin Ser Lys 420 425 430 Val Ala Giu Trp Leu Asn Ser Thr Phe Gin Asn Trp Asn Tyr Thr Val 435 440 445 Tyr Val Val Asn Ilie Ser Phe His Leu Ser Ala Gly Giu Asp Lys Ile 450 455 460 Lys Val Lys Arg Ser Leu Glu Asp Giu Pro Arg Leu Val Leu Trp Ala 465 470 475 480 Leu Leu Val Tyr Asn Ala Thr Asn Asn Thr Asn Leu Giu Giy Lys Ile 485 490 495 Ile Gin Gin Lys Leu Leu Lys Asn Asn Giu Ser Leu Asp Giu Gly Leu 500 505 510 Arg Leu His Thr Val Asn Val Arg Gin Leu Gly His Cys Leu Ala Met 515 520 525 Glu Glu Pro Lys Gly Tyr Tyr Trp Pro Ser Ilie Gln Pro Ser Glu Tyr 530 535 540 Val Leu Pro Cys Pro Asp Lys Pro Giy Phe Ser Ala Ser Arg Ile Cys 545 550 555 560 Phe Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp, Gly Pro Val Asp 565 570 575 Ilie Ser Asn Cys Leu Lys Giu Ala Asn Glu Val Ala Asn Gin Ile Leu 580 585 590 Asn Leu Thr Ala Asp Giy Gln Asn Leu Thr Ser Ala Asn Ile Thr Asn 595 600 605 Ile Val Giu Gin Vai Lys Arg Ile Val Asn Lys Giu Giu Asn Ile Asp 610 615 620 Ile Thr Leu Gly Ser Thr Leu Met Asn Ile Phe Ser Asn Ile Leu Ser 625 630 635 640 Ser Ser Asp Ser Asp Leu Leu Glu Ser Ser Ser Giu Ala Leu Lys Thr 645 650 655 Ile Asp Giu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr Ser His Val 660 665 670 Asn Ile Thr Thr Arg Asn Leu Ala Leu Ser Val Ser Ser Leu Leu Pro 675 680 685 Gly Thr Asn Ala Ile Ser Asn Phe Ser Ile Gly Leu Pro Ser Asn Asn 690 695 700 Giu Ser Tyr Phe Gin Val Met Ser Gin Trp Phe Leu Ser Phe 705 710 715 <210> 23 <211> 3339 <212> DNA <213> homo sapiens <400> 23 atgatgtttc gctcagatcg aatgtggagc tgccattgga aatggaagcc cagtcctctc ctgttcttat ttgctttata tatcatgtgt gttcctcact cagtgtgggg atgtgccaac 120 tgccgagtgg ttttgtccaa cccttctggg acctttactt ctccatgcta ccctaacgac 180 36 87 WO 01/18207 WO 0118207PCTIUSOO/24591 tacccaaaca a taaca tt ta cttgataatg aactcaagtg ggtttcaatg ccccagacat agtgctttca gctttctcct ggctactttc gaaaaagaag ttgggctcta attagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc actgtaaact agaa tega ta atccttcgtc ttccaaaatt gaggacaaga cttctagttt ctcctaaaaa caactgggtc ccttctgaat ttttacaatg ttaaaagaag ttaacctcag gaaaacattg agttcagaca gcct tcaaga ctcagcgtat ccaagcaata gcatctgtaa gttagaagag caaagaaaaa aatctgaagg cccatctgtg ggatgtgttg acacactttg actaaagtcc gcaactctcc ttCga tgaac c atcacctcct cttctggcaa aaagtattta ttgcctgcct aaagaaagtt ttttatgtga attgtggtaa gaagaagtgt tggggtttCtg atcttcaatt gccaggcttg acgactttga gagagagcca cgaatgagat ccagctacat caga tgctta cactctgctt actcaaatgc tatccatttc acatttttgc ttggtgtaaa ttattcctgg aaggggacat acctcagctg caaacctagc cagcagcaga ctcctagtac aacaaaggaa accctgaggt ggaactacac t taaagtcaa acaatgctac ataatgagtc attgtcttgc acgttcttcc ctaccaaccc caaatgaagt ccaatattac atataacact gtgacttgct tagacctaaa catccctgtt atgaatcgta C C Ctgcc tcc cacagtttac c C Ctag tgag atcctgttca ccttctggga cacacagaga gagttctgat tcactttcat tgacatatgt tgagcacagc tcaatgtgga cctttacctg acacttacat tagtggtgtc atgggaaaga cctgtgCtgg tggtgcagat taaggaacc C cattctttgc cattacaagg catgtggacg cattgaagaa gactaaattt gcatgtgtcc cagagttgcc ccaggtatct tgaagcaacc atccttcaca tgattcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct actggccagc tacaccaccc tgatggaatt aaaagtacag ggtttatgtc gagaagcctt caacaatact cttggatgaa catggaggaa ttgtccagac attggtaacc tgc taaccag caacattgtg tggctcaact tgagtcatct tagcacatca accagggaca tttccagatg aaacttactt tttcttcaac ttatgtgatg aataaaaatc tctgaacaaa ttcagatgca ggaccttcca cagctatatt tgcttttgag cctgctgttc tggactttgc gatggggcta tcgccgatac agttgttcta aaaaggtgat gtattttgga ctgtgggagg gcgcagtgtg c tggggaccc taagataaat ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtcct taa gttgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aactatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tg tgcagacc ac tgtcacca atctatagaa agcaaggtgg gttaatatca gaggatgagc aatttagaag ggct Cgaggc cceaaaggct aagcctggct tactggggac at tttaaatt gaacaggtca ctaatgaata tctgaagctt ca tgtgaata aatgcaattt gattttgaga gagaaittaa aaaac tggac gcgtgcagta aaacatacaa aacaaaagtt agtgagacag agaagtgcct gggtgtggaa aaattgcgaa ctgaatctcc attgctgttg gaagcaat Cc attctaaaat gcgagcagaa gaat tctgtt gtcatgtttt aatggcaaga gttagcttga ttaaatatcc tgtacatga ccaccggtta gcatt ta tga c tgcc aaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat Ccgac tggca taagctgtgg tggggaccct ctaacatgcc tatccgtagt cagaatggct gttttcacct caaggttggt gaaaaatcat tacatacagt actactggcc tttctgcttc ctgttgatat Caactgctga aaagaattgt tattttctaa taaaaacaat ttacaactcg caaattttag gtggacaagt gtccagaaga C ttccagga C tggaaacat gaactcagga C tggaggatg tctgcctgtg cacagtCtaga tatctgctat gggattatcc tcttcctcct cagtcctgtt acatgtacat tctgcatcat acaacaatga ggattcaaga ttctgaacat gaagcaaccg cctttctgtt ccttcatgta tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta Cccagagctc Cgat tggaca ggccaagagt acc tgtcaaa gaataattct tgattctacc aaatgaaatt gaatgccaaa aaatgac ttcC Ctcctacctg ctgtcaagct tgttactaac gattcagaac caat tcaacc gagtgctgga gctttgggcc Ccagcagaag gaatgtgaga atctatccaa tcggatatgt ctccaactgt tgggcagaac gaataaagaa tatc ttaagc tgatgaattg gaacttggct cattggtcCC ggatccactg ttctgtatta tgtaggacc tactatccag agtgcatcat gaacacgtca taaccacttc tgcaagaaac tttttcagca ctccaaaatc agatggctgg gcatttcttc tgctctagtt tggc tggggt agtctatgga tccagtcata tgccatgttc gaccc tgaga gggcatgaca cctcttctcc 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3339 <210> 24 <211> 1112 <212> PRT <213> homo sapiens <400> 24 Met Met Phe Arg Ser Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys 1 5 10 Pro Ser Pro Leu Leu Phe Leu Phe Ala Leu Tyr Ile Met Cys Val Pro 37 87 WO 01/18207 Cys Tyr Ala Giu Giu 105 Asn Ile Leu Val1 Leu 185 Ala Lys Leu Ser Gly 265 Ile Gin Trp Vai Asn 345 Ile Leu Thr Gly Pro 425 Phe Leu Glu Asn Asn 505 Gin Leu Tyr Tyr Asn Lys Asn 125 Giy Lys Lys Ala Ser 205 Giy Leu Leu Lys Ile 285 Vai Met Val1 Lys Ala 365 Thr Pro Arg Val Asn 445 Giu Val1 Glu Asp Cys 525 PCTUSOO/24591 Pro Ser Gin Tyr Gly His Ala Leu 160 Ser Val Ser Leu

LYS

240 Val Tyr Asn Lys Lys 320 Trp Ser Leu Ser Asn 400 Val1 Lys Val1 Ile Ala 480 Ile Leu Met Arg Leu His Thr Val Asn Vai 515 38 87 WO 01/18207 WO 0118207PCT/USOO/2459 I Giu Glu Pro 530 Val Leu Pro 545 Phe Tyr Asn Ile Ser Asn Asn Leu Thr 595 Ilie Val Giu 610 Ile Thr Leu 625 Ser Ser Asp Ilie Asp Giu Asn Ilie Thr 675 Gly Thr Asn 690 Giu Ser Tyr 705 Ala Ser Val Asp Ser Val Gly Leu Phe 755 Val Met Ala 770 Pro Val Gin 785 Pro Ilie Cys Trp Asn Thr Thr Val Cys 835 Leu Pro Arg 850 Thr Phe Ilie 865 Ala Thr Leu Pro Ser Lys Leu Leu Phe 915 Leu Cys Ile 930 Phe Thr Trp 945 Lys Val Phe Ile Gly Trp Arg Asn Asn 995 Giy Asp Giu 1010 Cys Aia Gly Lys Cys Ala Cys 580 Ala Gin Gly Ser Leu 660 Thr Ala Phe Ile Leu 740 Gin Cys Ile Ala Ser 820 Leu Ser Ser Leu Ile 900 Leu Ala Met Asn Gly 980 Asn Phe Gly Tyr Pro Asp 550 Thr Asn 565 Leu Lys Asp Gly Vai Lys Ser Thr 630 Asp Leu 645 Ala Phe Arg Asn Ile Ser Gin Met 710 Leu Pro 725 Val Arg Asp Val Ser Ile Lys Ile 790 Phe Trp 805 Gly Cys Cys Asn Ala Ser Tyr Ile 870 Thr Tyr 885 Leu Met Leu Asp Val Ala Giy Leu 950 Thr Tyr 965 Leu Pro Glu Val Cys Trp Tyr 535 Lys Pro Giu Gin Arg 615 Leu Leu Lys Leu Asn 695 Asp Pro Arg Giy Gly 775 Lys Asp Val His Gin 855 Giy Val1 Asn Giy Val 935 Glu Ile Ala Tyr Ile 'rrp Pro Pro Gly Leu Val Aia Asn 585 Asn Leu 600 Ile Val Met Asn Giu Ser Ile Asp 665 Ala Leu 680 Phe Ser Phe Giu Asn Leu Ala Gin 745 Pro Gin 760 Asn Ile His Thr Leu Asn Ala His 825 Phe Thr 840 Leu Asp Cys Gly Ala Phe Leu Ser 905 Trp Ile 920 Leu Leu Ala Ilie Arg Arg Leu Val 985 Gly Lys 1000 Gin Asp Ser Phe Thr 570 Giu Thr Asn Ile S er 650 Leu Ser Ile Ser Leu 730 Phe Arg Thr Arg Lys 810 Arg His Ala Ile Glu 890 Thr Thr His His TIyr 970 Val1 Giu Pro Phe Gin 540 Ala Trp Ala Ala Giu 620 Ser Giu Ser Ser Leu 700 Gin Asn Phe Thr Gin 780 Gin Lys Ser Gly Asn 860 Ala Leu Leu Phe Phe 940 Tyr Leu Val Tyr Ile Pro Ser Ser Arg Gly Pro Asn Gin 590 Asn Ile 605 Giu Asn Asn Ile Ala Leu Thr Ser 670 Ser Leu 685 Pro Ser Val ASP Leu Ser Phe Asn 750 Leu Val 765 Asn Leu Giu Vai Ser Phe Asp Ala 830 Val Leu 845 Thr Lys Ile Phe Arg Arg Leu Phe 910 Asn Val 925 Leu Leu Ile Ala Lys Phe Val Leu 990 Gly Lys 1005 Phe Tyr Tyr Cys 560 Asp Leu Asn Asp Ser 640 Thr Val Pro Asn Leu 720 Glu Thr Tyr Asp His 800 Gly Giu Asp Leu Ala 880 Tyr Asn Gly Thr Val1 960 Ile Ser Lys Thr 1015 Tyr Phe Gly Val Met Phe 1020 Leu Asn Ile Ala Met Phe 39 87 WO 01/18207 WO 0118207PCT/USOO/2459

I

1025 Ile Val Val Met Vai 104~ Arg Thr Leu Arg Glu 1060 Leu Thr Phe Leu Leu 1075 Gly Pro Leu Asn Ile 1090 Leu Gin Gly Lys Ilie 1105 <210> <211> 1626 <212> DNA <213> homo sapiens 1030 1035 1040 Gin Ilie Cys Gly Arg Asn 5 1050 Giu Val Leu Arg Asn Leu 1065 Giy Met Thr Trp Gly Phe 1080 Pro Phe Met Tyr Leu Phe 1095 Asn Cys Thr 1110 Gly Lys Arg Ser Asn 1055 Arg Ser Val Val Ser 1070 Ala Phe Phe Ala Trp 1085 Ser Ile Phe Asn Ser 1100 <400> atggattttg cttgagaatt aacaaaactg atggcgtgca atcaaacata aaaaacaaaa gcaagtgaga ccaagaagtg attgggtgtg gagaaattgc ttcctgaatc tgcattgctg ctagaagcaa tacattctaa c tagcgagca gatgaattct ggagtcatgt aggaatggca gtggttagct cccttaaata atattcatct tgctgtggta atcaagaaaa tcaacctatc cacacagaca caaacatcaa cattcagaca ttttaa agagtggaca taagtccaga gacttttcca gtattggaaa caagaactca gttttggagg cagtctgcct cctcacagtt gaatatctgc gaagggatta tcCtcttcct ttgcagtcct ttcacatgta aattctgcat gaaacaacaa gttggattca tttttctgaa agagaagcaa tgacctttct tccccttcat tccactgtgc gatttcggtt gt tc tgataa t tacatccaa gtgcttccat tcatccctgt acttctataa agtggatcca agattctgta ggatgtagga cattactatc ggaagtgca t atggaacacg g tgtaaccac agatgcaaga tattttttca tccctccaaa.

cctagatggc gttgcatttc cattgctcta cattggctgg tgaagtctat agatccagtc cattgccatg ccggaccctg gttgggcatg gtacctcttc tatgaaggag agcagataac tc taggaaaa atctaaatcc ggacaagtcc ccatcaggtc aaatattatc ctggcatctg ttagttagaa ccccaaagaa cagaatctga catcccatct tcaggatgtg ttcacacact aacactaaag gcagcaactc atcttgatga tggatcacct ttccttctgg gttaaagtat ggtttgcctg ggaaaagaaa atattttatg ttcattgtgg agagaagaag acatggggt t tccatcttca aatgttcaga tcagattgga tctttgtctt agctctacca ttgtcaaaac attgataagg atgtcagaca taattttgcc gagcacagtt aaactttagt aggatcctgt gtgccttctg ttgcacacag ttggagttct tcctcacttt tcctgacata acctgagcac ccttcaatgt caacctttac ttaacactta ccttagtggt gttatgggaa tgacc tgtgc taatggtgca tgt taaggaa ttgcattctt attcattaca aacagtggcg gtaagacagc caagctccat cctatttcaa tggcccatgc tcaagggtta ccttcagcca tccaaactta tactttcttc gagttatgtg tcaaa taaaa ggatctgaac agattcagat gatggacctt catcagctat tgttgctttt agccctgctg ggatggactt ctggatgggg cat tcgccga gtcagttgtt agaaaaaggt tgggtatttt gatctgtggg cctgcgcagt tgcctgggga aggcttattt gcggcatctc taccaatatc tgg ttc caac aaggaatagc tgatggagat ttgcaatgct cagcacaaag 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 i1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1626 <210> 26 <211> 541 <212> PRT <213> homo sapiens <400> 26 Met Asp Phe Glu Ser 1 5 Pro Pro Asn Leu Leu Gly Gin Val Asp Pro Leu Ala Ser Val Ile Leu Phe Glu Asn Leu Thr Phe Phe Giu Asp Ser Arg Arg Ala Vai Giy Pro Ilie Gly Asn Lys Thr Gly Vai Leu Val Phe Gin Asp Ala Cys Ser Gin Arg Lys Val Ser Tyr Val Ile Thr Asn Leu Lys Asp Pro Val Gin Ile 87 WO 01/18207 PCT/US00/24591 Ile Lys His Thr Arg Thr Gin Glu Val His His Pro Ile Cys Ala Phe 90 Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly Trp Asn Thr Ser Gly 100 105 110 Cys Val Ala His Arg Asp Ser Asp Ala Ser Glu Thr Val Cys Leu Cys 115 120 125 Asn His Phe Thr His Phe Gly Val Leu Met Asp Leu Pro Arg Ser Ala 130 135 140 Ser Gin Leu Asp Ala Arg Asn Thr Lys Val Leu Thr Phe Ile Ser Tyr 145 150 155 160 Ile Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala Ala Thr Leu Leu Thr 165 170 175 Tyr Val Ala Phe Glu Lys Leu Arg Arg Asp Tyr Pro Ser Lys Ile Leu 180 185 190 Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn Leu Leu Phe Leu Leu 195 200 205 Asp Gly Trp Ile Thr Ser Phe Asn Val Asp Gly Leu Cys Ile Ala Val 210 215 220 Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr Phe Thr Trp Met Gly 225 230 235 240 Leu Glu Ala Ile His Met Tyr Ile Ala Leu Val Lys Val Phe Asn Thr 245 250 255 Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile Ile Gly Trp Gly Leu 260 265 270 Pro Ala Leu Val Val Ser Val Val Leu Ala Ser Arg Asn Asn Asn Glu 275 280 285 Val Tyr Gly Lys Glu Ser Tyr Gly Lys Glu Lys Gly Asp Glu Phe Cys 290 295 300 Trp Ile Gin Asp Pro Val Ile Phe Tyr Val Thr Cys Ala Gly Tyr Phe 305 310 315 320 Gly Val Met Phe Phe Leu Asn Ile Ala Met Phe Ile Val Val Met Val 325 330 335 Gin Ile Cys Gly Arg Asn Gly Lys Arg Ser Asn Arg Thr Leu Arg Glu 340 345 350 Glu Val Leu Arg Asn Leu Arg Ser Val Val Ser Leu Thr Phe Leu Leu 355 360 365 Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp Gly Pro Leu Asn Ile 370 375 380 Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser Leu Gin Gly Leu Phe 385 390 395 400 Ile Phe Ile Phe His Cys Ala Met Lys Glu Asn Val Gin Lys Gin Trp 405 410 415 Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu Ala Asp Asn Ser Asp 420 425 430 Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys Ser Ser Asp Asn Leu 435 440 445 Gly Lys Ser Leu Ser Ser Ser Ser Ile Gly Ser Asn Ser Thr Tyr Leu 450 455 460 Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr Phe Lys Arg Asn Ser 465 470 475 480 His Thr Asp Ser Ala Ser Met Asp Lys Ser Leu Ser Lys Leu Ala His 485 490 495 Ala Asp Gly Asp Gin Thr Ser Ile Ile Pro Val His Gin Val Ile Asp 500 505 510 Lys Val Lys Gly Tyr Cys Asn Ala His Ser Asp Asn Phe Tyr Lys Asn 515 520 525 Ile Ile Met Ser Asp Thr Phe Ser His Ser Thr Lys Phe 530 535 540 <210> 27 <211> 1539 <212> DNA <213> homo sapiens 41 87 WO 01/18207 PTUO/49 PCTIUSOO/24591 <400> 27 atggattttg cttgagaatt aacaaaactg atggcgtgca atcaaacata aaaaacaaaa gcaagtgaga ccaagaagtg attgggtgtg gagaaattgc ttcctgaatc tgcattgctg ctagaagcaa tacattctaa c tagcgagca gatgaattct ggagtcatgt aggaa tggca gtggttagct cccttaaata atattcatct tgc tgtggta atcaagaaaa tcaacctatc cacacagata ttccatggac agagtggaca taagtccaga gacttttcca gtattggaaa caagaactca gttttggagg cagtctgcct cctcacagtt gaatatctgc gaagggatta tcctcttcct ttgcagtcct.

ttcacatgta aattctgcat gaaacaacaa gttggattca tttttctgaa agagaagcaa tgacctttct tccccttcat tccactgtgc gatttcggtt gttctgataa ttacatccaa atgtctccta aagtccttgt agtggatcca agattctgta ggatgtagga cattactatc ggaagtgcat atggaacacg gtgtaaccac agatgcaaga tattttttca tccctccaaa cctagatggc gttgcatttc cattgctcta cattggctgg tgaagtctat agatccagtc cattgccatg ccggaccctg gttgggcatg gtacctcttc tatgaaggag agcagataac tc taggaaaa atctaaatcc tgagcattcc caaaactggc ctggcatctg ttagttagaa ccccaaagaa cagaatctga catcccatct tcaggatgtg ttcacacact.

aacactaaag gcagcaactc atcttgatga tggatcacct ttccttctgg gttaaagtat.

ggtttgcctg ggaaaagaaa atattttatg ttcattgtgg agagaagaag acatggggtt tccatcttca aatgttcaga tcagattgga tctttgtctt agctctacca ttcaacaaaa ccatgctga taattttgcc gagcacagtt aaactttagt aggatcctgt gtgccttctg t tgcacacag ttggagttct tcctcacttt tcctgacata acctgagcac ccttcaatgt caacctttac ttaacactta ccttagtggt gt tatgggaa tgacc tgtgc taatggtgca tgttaaggaa ttgcattctt attcattaca aacagtggcg gtaagacagc caagctccat cctatttcaa gtggatcact tccaaactta tactttcttc gagttatgtg tcaaataaaa ggatctgaac agattcagat gatggacctt catcagctat.

tgttgctttt agccctgctg ggatggactt ctggatgggg cattcgccga gtcagttgtt agaaaaaggt tgggtatttt gatctgtggg cctgcgcagt tgcctgggga aggc ttat tt gcggcatc tc taccaatatc tggttccaac aaggaa tagc cagacagtgc 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1539 <210> 28.

<211> 512 <212> PRT <213> homo sapiens <400> 28 Met Asp 1 Pro Pro The Giu Ser Gly Gin Val Asp Pro 10 Leu Ala Ser Val Ile Leu k.sn Leu Arg Arg Ala Gin Val Gly Pro Gin Gly Asn Ilie Lys His Thr Leu Glu Phe Thr Arg Lys 'Phr Ilie Arq Thr Asn Leu Ser Pro Glu Asp Ser Val Leu Val 25 Phe Phe Asn Lys Thr Gly Leu Phe Gin Asp 40 Thr Leu Val Ser Tyr Val Met Ala Cys Ser 55 Gin Asn Leu Lys Asp Pro Val Gin Ile Lys Gin Glu Val His His Gly Gly Pro Ile Trp Asn Trp Asp LeU Asn 100 Cys Val Ala His 115 Asn His Phe Thr 130 Ser Gin Leu Asp 145 Ile Gly Cys Gly Tyr Val Ala Phe 180 Met Asn Leu Ser Asn Lys Ser Cys Ala Phe Thr Ser Gly 110 Cys Leu Cys Arg Ser Ala Arg Asp Ser Ser Glu Thr His Phe Ala Arg 150 Leu Met Asp Leu Thr Lys Val Phe Ile Ser Ilie Ser Ala Ile Lys Leu Arg Phe Ser Ala Ala Thr Leu Leu Thr 170 175 Arg Asp Tyr Pro Ser Lys Ile Leu 185 190 Phe Leu Asn Leu Leu Phe Leu Leu Thr Ala Leu Asp Gly 210 Ala Val Ile Thr Ser Val Asp Gly Ile Ala Val Leu Leu His Phe Leu Leu Ala Thr Thr Trp Met Gly 42 87 WO 01/18207 WO 0118207PCT[USOO/24591 Ile His 245 Arg Tyr 260 Val Val Lys Giu Asp Pro Phe Phe 325 Gly Arg 340 Arg Asn Trrp Gly Tyr Leu Phe His 405 Leu Cys 420 Thr Ala Leu Ser Ser Lys Asn Val 485 230 Met Ile Ser Ser Val1 310 Leu Asn Leu Phe Phe 390 Cys Cys Thr Ser Ser 470 Ser Val Gly Asn 285 Asp Ala Val Thr Thr 365 Pro Gin Gin Asp Ser 445 Ser Lys Lys 240 Phe Asn Thr 255 Trp Gly Leu 270 Asn Asn Giu Giu Phe Cys Gly Tyr Phe 320 Val Met Val 335 LeU Arg Glu 350 Phe Leu Leu Leu Asn Ile Gly Leu Phe 400 Lys Gin Trp 415 Asn Ser Asp 430 Asp Asn Leu Thr Tyr Leu Arg Asn Ser 480 Ser GJly Ser 495 Giy Pro Cys 510 Leu Arg Gin Phe His Gly Gin Val Leu Val Lys Thr 505 <210> 29 <211> 27 <212> DNA <213> homo sapiens <400> 29 atgagccagt ggtttctttc attttaa <210> <211> 8 <212> PRT <213> horno sapiens <400> Met Ser Gin Trp Phe Leu Ser Phe 1 <210> 31 <211> 1212 <212> DNA <213> homo sapiens <400> 31 atggattttg agagtggaca agtggatcca ctggcatctg taattttgcc tccaaactta cttgagaatt taagtccaga agattctgta ttagttagaa gagcacagtt tactttcttc aacaaaactg gacttttcca ggatgtagga ccccaaagaa aaactttagt gagttatgtg atggcgtgca gtattggaaa cattactatc cagaatctga aggatcctgt tcaaataaaa 43 87 WO 01/18207 WO 0118207PCTIUSOO/24591 atcaaacata caagaaCtca aaaaacaaaa gttttggagg gcaagtgaga cagtctgcct ccaagaagtg cctcacagtt attgggtgtg gaatatctgc gagaaattgc gaagggatta ttcctgaatc tcctcttcct tgcattgctg ttgcagtcct ctagaagcaa ttcacatgta tacattctaa aattctgcat ctagcgagca gaaacaacaa gatgaattct gttggattca ggagtcatgt tttttctgaa aggaatggca agagaagcaa gtggttagct tgacctttct cccttaaata. tccccttcat aattgtacat ga <210> 32 <211> 403 <212> PRT <213> homo sapiens ggaagtgcat at ggaacacg gtgtaaccac agatgcaaga tattttttca tccctccaaa cctagatggc gttgcatttc cattgctcta cattggctgg tgaagtctat agatccag to cattgccatg ccggaccctg gttgggcatg gtacctcttc catcccatct tcaggatgtg ttcacacact aacactaaag gcagcaactc atcttgatga tggatcacct ttccttctgg gttaaagtat ggtttgcctg ggaaaagaaa atattttatg ttcattgtgg agagaagaag acatggggtt tccatcttca gtgccttctg ttgcacacag ttggagttct tcctcacttt tcctgacata acctgagcac ccttcaatgt caacctttac ttaacactta ccttagtggt gt tatgggaa tgacctgtgc taatggtgca tgttaaggaa ttgcattctt attcattaca.

ggatc tgaac agattcagat gatggacctt catcagctat tgttgctttt agccctgctg ggatggactt ctggatgggg cattcgccga gtcagttgtt agaaaaaggt tgggtatttt gatctgtggg cctgcgcagt tgcctgggga aggtaagata 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1212 <400> 32 Met Asp 1 Phe 0Th Ser Gly Gin Val Asp Leu Ala Ser Val Ile Leu 5 Leu Pro Pro Asn Arg Arg Ala Val Gly Pro Ile Gly Asn Leu Gin GlU Asn Leu Glu Asp Ser Val Leu Val Phe Gin Asp Phe Thr Phe Phe Lys Thr Gly Leu Gin Arg Lys Leu Val Ser Asn Leu Lys Tyr Val Aso Pro Met Ala Cys Ser Ile Thr Ile Thr Val Gin Ile Lys His Thr Arg Trp Asp Leu Asn Lys 100 Cys Vai Ala His Arg Gin Glu Val Pro Ile Cys Asn Lys Ser Gly Gly Trp Asn Asp Ser Ser Giu Thr Ile Lys Ala Phe Ser Giy Leu Cys Ser Ala Ser Tyr 160 Leu Thr 175 Ile Leu Asn His 130 Ser Gin Thr His Phe Val Leu Met Asp Thr Lys Val Leu Pro Arg Phe Ile Leu Asp Aia Ile Giy Cys Gly Ile 165 Tyr Val Aia Phe Giu 180 Met Asn Leu Ser Thr Ser Ala Ile Phe Ala Thr Leu Lys Leu Arg Tyr Pro Ser Lys Ala Leu Leu Asn Leu Phe Leu Leu Ile Ala Vai Asp Gly Trp Ile 210 Ala Vai Leu Leu 225 Leu Glu Ala Ile Thr Ser Phe 215 Asn Val Asp Gly His Phe Phe Leu Leu Aia Tyr Ile Ala Leu Thr Trp Met Lys Val Phe Asn Thr 255 Tyr Ilie Arg Pro Ala Leu 275 Val Tyr Giy Ilie Leu Lys Ile Ile Val Ser Val Aia Ser Arg Giy Trp Gly Leu 270 Asn Asn Asn Giu 285 Asp Glu Phe Cys Aia Giy Tyr Phe 290 Trp Ilie Gin Lys Glu Ser Asp Pro Val Lys Glu Lys Phe Tyr Val Thr 44 87 WO 01/18207 WO 0118207PCTLJSOO/24591 Gly Val Met Phe Gin Ile Cys Gly 340 Giu Val Leu Arca Asn Ile Ala Ile Val Val 320 Met Val 335 Asn Gly Lys Ser Asn Arg Thr Leu Arg Giu 350 Val Ser Leu Thr Phe Leu Leu Asn Leu Arg Gly Met Thr Trp Giy Phe 370 Pro Phe Met Tyr Leu Phe 385 390 Asn Cys Thr Phe Ala Trp Leu Asn Ile Ile Phe Asn Gin Giy Lys <210> 33 <211> 3669 <212> DNA <213> homo sapiens <400> 33 a tgt ttcgc t ttcttatttg tgccgagtgg tacccaaaca ataacattta cttgataatg aactcaagtg ggtttcaatg ccccagacat agtgctttca gctttCtcct ggctactttc gaaaaagaag t tgggc tc ta attagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc ggaattatct gtacagagca tatgtcgtta agccttgagg aatactaatt gatgaaggct gaggaaccca ccagacaagc gtaacctact aaccagattt at tgtggaac tcaactctaa tcatcttctg acatcacatg gggacaaatg cagatggatt ttacttgaga ttcaacaaaa gtgatggcgt aaaatcaaac aacaaaaaca gatgcaagtg ct tccaagaa tatat tgggt cagatcgaat ctttatatat ttttgtccaa gccaggcttg acgactttga gagagagcca cgaatgagat ccagctacat cagatgctta cactctgctt actcaaatgc tatccatttc aca tt t ttgc ttggtgtaaa t tat tcc tgg aaggggacat.

acctcagctg caaacctagc c agcagcaga atagaatatc aggtggcaga atatcagttt atgagccaag tagaaggaaa.

tgaggc taca.

aaggctacta ctggcttttc ggggacctgt taaatttaac aggtcaaaag tgaatatatt aagctttaaa tgaatattac caatttcaaa ttgagagtgg atttaagtcc ctggactttt gcagtattgg atacaagaac aaagttttgg agacagtctg gtgcctcaca g tggaatatc gtggagctgc catgtgtgtt cccttctggg catgtggacg cattgaagaa gactaaattt gcatgtgtcc cagagt tgcc ccaggtatct tgaagcaacc atccttcaca tgat tcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct ac tggccagc cgtagtgatt atggctcaat tcacctgagt gttggtgctt aa tcat tcag tacagtgaat ctggccatct tgcttctcgg tgatatctcc tgctgatggg aattgtgaat ttctaatatc aacaattgat aactcggaac ttttagcatt acaagtggat agaagattct ccaggatgta aaacattact tcaggaagtg agga tggaac cctgtgtaac gt tagatgca tgctattttt cattggaaat cctcactcag acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aac tatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc cagaacatcc tcaacc ttcc gctggagagg tgggcccttc cagaagctcc gtgagacaac atccaacctt atatgttttt aactgtttaa cagaac ttaa aaagaagaaa t taagcagtt gaattggcct ttggctctca ggtcttccaa ccac tggcat gtattagtta ggaccccaaa atccagaatc catcatccca acgtcaggat cact tcacac agaaacacta tcagcagcaa ggaagcccag cagtgtgggg ctccatgcta ccaccggtta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat tcgac bggca taagctgtgg tggggaccc t ttcgtcaccc aaaat tggaa acaagat taa tagtttacaa taaaaaataa tgggtcattg ctgaatacgt acaatgctac aagaagcaaa cctcagccaa acattgatat cagacagtga tcaagataga gcgtatcatc gcaataatga ctgtaatttt gaagagcaca gaaaaacttt tgaaggatcc tctgtgcctt gtgttgcaca actttggagt aagtcctcac ctctcctgac tcctctcctg atgtgccaac ccc taacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acctgtcaaa gaataattct tgattctacc aaatgaaatt gaatgccaaa aaatgacttc ttcctacctg ctgtcaagat tgaggtaaaa ctacacggtt agtcaagaga tgctaccaac tgagtccttg tcttgccatg tcttccttgt caacc cat tg tgaagttgct tattaccac aacacttggc ct tgc ttgag cctaaatagc cctgttacca atcgtatttc gcc tccaaac gtttactttc agtgagttat tgttcaaata ctgggatctg cagagattca tctgatggac tttcatcagc atatgttgct 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 87 WO 01/18207 WO 0118207PCT/USOO/2459

I

tttgagaaat ctgttcctga ctttgcattg gggctagaag cgatacattc gttctagcga ggtgatgaat tttggagtca gggaggaa tg agtgtggtta ggaccct taa tttatattca ctctgctgtg atcatcaaga aactcaacct agccacacag gatcaaacat gctcattcag aagttttaa tgcgaaggga atctcctctt c tgttgcagt caattcacat taaaat tctg gcagaaacaa tc tgt tggat tgttttttct gcaagagaag gcttgacctt atatcccctt tcttccactg gtagatttcg aaagttctga atcttacatc acagtgcttc caatcatccc acaacttcta ttatccctcc cc tCCtagat cctgttgcat gtacattgct catcattggc caatgaagtc tcaagatcca gaacattgcc caaccggacc tctgttgggc catgtacctc tgctatgaag gttagcagat taatc tagga caaatctaaa catggacaag tgtccatcag aaaatcttga ggctggatca ttcttccttc ctagttaaag tggggtttgc tatggaaaag gtcatatttt atgttcattg c tgagagaag atgacatggg ttctccatct gagaatgttc aactcagatt aaatctttgt tccagctcta tccttgtcaa gtcattgata tgaacctgag cctccttcaa tggcaacctt tatttaacac ctgccttagt aaagttatgg atgtgacctg tggtaatggt aagtgttaag gttttgcatt tcaattcatt agaaacagtg ggagtaagac cttcaagctc ccacctattt aactggccca aggtcaaggg acaccttcag cacagccctg tgtggatgga tacctggatg ttacattcgc ggtgtcagtt gaaagaaaaa tgctgggtat gcagatctgt gaacctgcgc ctttgcctgg acaaggctta gcggcggcat agc taccaat cattggttcc caaaaggaat tgctgatgga t tattgcaat ccacagcaca 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3669 taaaaatatt atcatgtcag <210> 34 <211> 1222 <212> PRT <213> homo sapiens <400> 34 Met Phe Arg Ser Asp 1 5 Ser Pro Leu Leu Phe Arg Met Trp Ser Leu Phe Ala Leu Cys 10 Tyr Arg His Trp, Lys Trp Lys Pro Ser Ala Val Trp, 25 Cys Ile Met Cys Val Val Leu Val Pro His Ser Asn Pro Gly Cys Ala Ser Gly Thr Phe Gin Ala Cys Met Ilie Thr Phe Asn Thr Ser Pro Cys Tyr Pro Asn Tyr Pro Asn Ser Trp Thr 70 Asp Phe Leu Asp Leu Arg Ala Pro Tyr Ile Asn Cys Asp Ilie Giu Glu Ala Pro 90 Ile Gin Ile Tyr Cys Gi)? Met His Asp Ser Leu Ala Thr Ala Ser Asn Gly Ser Ser Gly Leu Ser Gin Thr Lys Phe 110 Ser Ala Asn Giu 125 Lys Lys Gly Phe Vai Ser 130 Ser Tyr Ser Ser Asp Phe Ile Gin Asn Ala Ile Arg Val Ser Leu Arg Lys Val Ile 145 Pro Gin Thr Ser Tyr Gin Val Ala Lys Giu Ala Ile Pro Giu Gly His Giu 195 Phe Thr Gin Ala Phe Thr Leu Cys Phe 185 Ser Ile Ser 175 Thr Lys Vai 190 Asn Ala Ser Tyr Phe Leu Ser Asp Trp Ala Lys Leu Leu Ser Phe Ser T[yr Ser 205 Ala Lys Ser Gly 220 Asn Asn Ala Leu Ser 225 Glu Ser Asp Ser Leu Leu Pro Val Lys Glu Asp Ala Giu Ser Trp Asn Asn Giu Thr Val 275 Gly Lys Leu Ser 260 Pro Gly Ser Ile Phe 250 Val1 Ser Asn Giu Gin Cys Asp Ser Leu Cys Leu Val 255 Thr Ile 280 Asn Gin Asn Phe Lys Arg Asn Tyr 270 Lys Vai Ile Pro Gly Asn 285 Giu Ile Val Ser Leu Lys Leu Leu Giy Ser 46 87 WO 01/18207 300 Thr Asn Leu Pro Asp 380 His Thr His Asp Asn 460 Asn Arg Trp Pro Leu 540 Ala Asn Ile Met Glu 620 Ile Ala Phe Phe Asn 700 Ala Pro Asn His Leu 780 Ala Asn Val Ala 350 Ala Ile Glu Gin Ser 430 Pro Thr Glu Leu Ser 510 Phe Thr Giu Thr Asn 590 Ile Ser Leu Ser Ile 670 Ser Leu Phe Arg Thr 750 Arg Lys Arg PCTfUSOO/2459 1 Lys 320 Trp, Ser Leu Tyr Lys 400 Trp Gly Leu Leu Leu 480 His Gin Ala Trp, Ala 560 Ala Glu Ser Glu Ser 640 Ser Leu Gin Asn Phe 720 Thr Gin Gin Lys Ser 800 47 87 WO 01/18207 WO 0118207PCT/USOO/2459 1 Asp Ala Ser Glu Thr Val Cys Leu Cys Asn His Phe Thr His Phe Gly 805 810 815 Val Leu Met Asp Leu Pro Arg Ser Ala Ser Gin Leu Asp Ala Arg Asn 820 825 830 Thr LYS Val Leu Thr Phe Ile Ser Tyr Ile Gly Cys Gly Ilie Ser Ala 835 840 845 Ile Phe Ser Ala Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu 850 855 860 Arg Arg Asp Tyr Pro Ser Lys Ile Leu Met Asn Leu Ser Thr Ala Leu 865 870 875 880 Leu Phe Leu Asn Leu Leu Phe Leu Leu Asp Gly Trp, Ile Thr Ser Phe 885 890 895 Asn Val Asp Gly Leu Cys Ile Ala Val Ala Val Leu Leu His Phe Phe 900 905 910 Leu Leu Ala Thr Phe Thr Trp, Met Gly Leu Giu Ala Ile His Met Tyr 915 920 925 Ile Ala Leu Val Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu 930 935 940 Lys Phe Cys Ile Ilie Gly Trp Giy Leu Pro Ala Leu Val Val Ser Val 945 950 955 960 Val Leu Ala Ser Arg Asn Asn Asn Glu Val Tyr Gly Lys Glu Ser Tyr 965 970 975 Gly Lys Glu Lys Gly Asp Glu Phe Cys Trp Ile Gin Asp Pro Val Ile 980 985 990 Phe Tyr Val Thr Cys Ala Giy Tyr Phe Giy Val Met Phe Phe Leu Asn 995 1000 1005 Ile Ala Met Phe Ile Val Val Met Val Gin Ile Cys Gly Arg Asn Gly 1010 1015 1020 Lys Arg Ser Asn Arg Thr Leu Arg Glu Glu Val Leu Arg Asn Leu Arg 1025 1030 1035 1040 Ser Val Val Ser Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala 1045 1050 1055 Phe Phe Ala Trp Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser 1060 1065 1070 Ilie Phe Asn Ser tLeu Gin Gly Leu Phe Ile Phe Ile Phe His Cys Ala 1075 1080 1085 Met Lys Glu Asn Val Gin Lys Gin Trp Arg Arg His Leu Cys Cys Gly 1090 1095 1100 Arg Phe Arg Leu Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn 1105 1110 1115 1120 Ilie Ile Lys Lys Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser 1125 1130 1135 Ser Ilie Gly Ser Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser 1140 1145 1150 Ser Thr Thr Tyr Phe Lys Arg Asn Ser His Thr Asp Ser Ala Ser Met 1155 1160 1165 Asp Lys Ser Leu Scr Lys Leu Ala His Ala Asp Gly Asp Gin Thr Ser 1170 1175 1180 Ile Ile Pro Val His Gln Vai Ile Asp Lys Val Lys Gly Tyr Cys Asn 1185 1190 1195 1200 Ala His Ser Asp Asri Phe Tyr Lys Asn Ile Ile Met Ser Asp Thr Phe 1205 1210 1215 Ser His Ser Thr Lys Phe 1220 <210> <211> 3582 <212> DNA <213> homo sapiens <400> atgtttcgct cagatcgaat gtggagctgc cattggaaat ggaagcccag tcctctcctg ttcttatttg ctttatatat catgtgtgtt cctcactcag cagtgtgggg atgtgccaac 120 48 87 WO 01/18207 WO 0118207PCTUSOO/24591 tgccgagtgg tttgtccaa tacccaaaca gccaggcttg ataacattta acgactttga cttgataatg gagagagcca aactcaagtg cgaatgagat ggtttcaatg ccagctacat ccccagacat cagatgctta agtgctttca cactctgctt gctttctcct actcaaatgc ggctactttc tatccatttc gaaaaagaag acatttttgc ttgggctcta ttggtgtaaa attagtaaag ttattcctgg gtctctctaa aaggggacat atcctctcca acctcagctg tggaatatcc caaacctagc atcccgctcc cagcagcaga ggaattatct atagaatatc gtacagagca aggtggcaga tatgtcgtta atatcagttt agccttgagg atgagccaag aatactaatt tagaaggaaa gatgaaggct tgaggctaca gaggaaccca aaggctacta ccagacaagc ctggcttttc gtaacctact ggggacctgt aaccagattt taaatttaac attgtggaac aggtcaaaag tcaactctaa tgaatatatt tcatcttctg aagctttaaa acatcacatg tgaatattac gggacaaatg caatttcaaa cagatggatt ttgagagtgg ttacttgaga atttaagtcc ctcaacaaaa ctggactttt gtgatggcgt gcagtattgg aaaatcaaac atacaagaac aacaaaaaca aaagttttgg gatgcaagtg agacagtctg cttccaagaa gtgcctcaca tatattgggt gtggaatatc tttgagaaat tgcgaaggga ctgttcctga atctcctctt ctttgcattg ctgttgcagt gggctagaag caattcacat cgatacattc taaaattctg gttctagcga gcagaaacaa ggtgatgaat tctgttggat tttggagtca tgttttttct gggaggaatg gcaagagaag agtgtggtta gcttgacctt ggacccttaa atatcccctt tttatattca tcttccactg ctctgctgtg gtagatttcg atcatcaaga aaagttctga aactcaacct atcttacatc agccacacag ataatgtctc tgcttccatg gacaagtcct <210> 36 <211> 1193 <212> PRT <213> homo sapiens Cccttctggg catgtggacg cattgaagaa gactaaattt gcatgtgtcc cagagt tgcc ccaggtatct tgaagcaacc atccttcaca tgattcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct actggccagc cgtagtgatt atggctcaat tcacctgagt gttggtgctt aatcattcag tacagtgaat ctggccatct tgcttctcgg tgatatctcc tgctgatggg aattgtgaat ttctaatatc aacaattgat aactcggaac ttttagcatt acaagtggat agaagattct ccaggatgta aaacattact tcaggaagtg aggatggaac cctgtgtaac gttagaigca tgctattttt ttatccctcc cctcctagat cctgttgcat gtacattgct catcattggc caatgaagtc tcaagatcca gaacattgcc caaccggacc tctgttgggc catgtacctc tgctatgaag gttagcagat taatctagga caaatctaaa ctatgagcat tgtcaaaact acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagt tggcc caattgctca tgtttgttga gaacagctct aac tatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc cagaacatcc tcaaccttcc gctggagagg tgggcccttc cagaagc tcc gtgagacaac atccaacctt atatgttttt aactgtttaa cagaacttaa aaagaagaaa ttaagcagtt gaattggcc t ttggctctca ggtcttccaa ccactggcat gtattagtta ggaccccaaa atccagaatc catcatccca acgtcaggat cacttcacac agaaacacta tcagcagcaa aaaatcttga ggctggatca ttcttccttc ctagttaaag tggggtt tgc tatggaaaag gtcatatttt atgttcattg ctgagagaag atgacatggg ttctccatct gagaatgt tc aactcagatt aaatctttgt tccagctcta tccttcaaca ggcccatgct ctccatgcta ccaccggtta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat tcgactggca taagctgtgg tggggaccct ttcgtcaccc aaaat tggaa acaagattaa tagtttacaa taaaaaataa tgggtcattg ctgaatacgt acaatgc tac aagaagcaaa cctcagccaa acattgatat cagacagtga tcaagataga gcgtatcatc gcaataatga ctgtaatttt gaagagcaca gaaaaacttt tgaaggatcc tctgtgcctt gtgttgcaca actttggagt aagtcctcac ctctcctgac tgaacctgag cctccttcaa tggcaacctt tatttaacac ctgccttagt aaagttatgg atg tgacc tg tggtaatggt aagtgt taag gttttgcatt tcaattcatt agaaacagtg ggagtaagac cttcaagctc ccacctattt aaagtggatc ga ccctaacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acctgtcaaa gaataattct tgattctacc aaatgaaatt gaatgccaaa aaatgacttc ttcctacctg c tgtcaagat tgagg taaaa ctacacggtt agtcaagaga tgc taccaac tgagtccttg tcttgccatg tcttccitgt caacccattg tgaagttgct tattaccaac aacact tggc cttgcttgag cctaaatagc cctgttacca atcgtatttc gcctccaaac gtttactttc agtgagttat tgttcaaata ctgggatctg cagagattca tctgatggac tttcatcagc atatgttgct cacagccctg tgtgga tgga tacc tggatg ttacattcgc ggtgtcagtt gaaagaaaaa tgctgggtat gcagatctgt gaacctgcgc ctttgcctgg acaaggctta gcggcggca t agctaccaat cattggttcc caaaaggaat actcagacag 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3582 49 87 WO 01/18207 PTUOI49 PCTIUSOO/24591 <400> 36 Met Phe 1 Ser Pro I Ser AlaI Ser Gly Gin Ala Ile ThrI Asp SerI Ala Thr Val Ser 1 130 Ser Tyr 145 Pro Gin Ile ProC Giy His Phe Thr 210 Ser Ile 225 Giu Lys Trp AsnJ Giu Thr I Gly Lys 1 290 Gly Asp 305 Ile Leu Gin Asn 2 Asn Leu Ala Ser 370 Arg Ile 385 Vai Gin Asn Tyr Giu Asp I Val Leu 450 Giu Giy 1 465 Asp Giu( 87 WO 01/18207 Cys Pro Ser Gly 545 Asn Asn Glu Asn Ala 625 Thr Ser Pro Val Leu 705 Phe Leu Asn Glu Ser 785 Asp Val Thr Ile Arg 865 Leu Asn Leu Ile Lys 945 Val Gly Phe Ala Giu 515 Ile Val Ile Thr Ile 595 Leu Lys His Leu Asn 675 Pro Pro Lys Ser Lys 755 His Gly Ser Met Val1 835 Ser Asp Leu Asp Ala .915 Leu Cys Ala Giu Val1 Giu Pro Leu Pro Tyr Asn 535 Ser Asn 550 Leu Thr Val Glu Thr Leu Ser Asp 615 Asp Giu 630 Ile Thr Thr Asn Ser Tyr Ser Val 695 Ser Val 710 Leu Phe Met Ala Vai Gin Ile Cys 775 Asn Thr 790 Val Cys Pro Arg Phe Ile Thr Leu 855 Ser Lys 870 Leu Phe Cys Ile Thr Trp Val Phe 935 Gly Trp 950 Asn Asn Asp Giu Ala Gly PCTIUSOO/24591 Gin Ala Trp Ala 560 Ala Giu Ser Glu Ser 640 Ser Leu Gin Asn Phe 720 Thr Gin Gin Lys Ser 800 Gly Asn Ala Leu Leu 880 Phe Phe Tyr Leu Val 960 Tyr Ile Asn 51 87 WO 01/18207 WO 0118207PCT/USOO/2459 I 995 1000 1005 Ile Ala Met Phe Ilie Val Val Met Val Gin Ile Cys Gly Arg Asn Gly 1010 1015 1020 LYS Arg 1025 Ser Asn Arg Ser Phe Ile Val Val Ser Leu 1045 Phe Ala Trp Gly 1060 Phe Asn Ser Leu rhr Leu 1030 Thr Phe Pro Leu Arg Giu Giu Val 1035 Leu Leu Gly Met 1050 Asn Ile Pro Phe Leu Thr Trp Gly Phe Ala 1055 Met Tyr Leu Phe Ser 1070 Ile Phe His CyS Ala 1085 Arg Asn Leu Arg 1040 1075 Glin Gly Leu 1080 1065 Phe Ilie Phe Met Lys Giu Asn Val Gin Lys Gin Trp Arg Arg His Leu Cys Cys Gly 1090 1095 1100 Arg Phe Arg Leu Ala Asp Asn Ser Asp Trp, Ser Lys Thr Ala Thr Asn 1105 1110 ill5 1120 Ile Ile Lys Ser Ile Gly Lys Ser 1125~ Ser Asn 1140 Ser Thr Thr Tyr Phe 1155 Glu His Ser Phe Asn 1170 Gin Vai Leu Val Lys 1185 <210> 37 <211> 2073 <212> DNA <213> homo sapiens Ser Asp Asn Leu Gly 1130 Ser Thr Tyr Leu Thr 1145 Lys Arg Asn Ser His 1160 Lys Ser Gly Ser Leu 1175 Thr Gly Pro Cys 1190 Lys Ser Leu Ser Ser Ser 1135 Ser Lys Ser Lys Ser Ser 1150 Thr Asp Asn Val Ser Tyr 1165 Arg Gin Cys Phe His Gly 1180 <400> 37 atgtttcgct ttcttatttg tgccgagtgg tacccaaaca ataacattta cttgataatg aactcaagtg ggtttcaatg ccccagacat.

agtgctttca gctttctcct ggctac tt tc gaaaaagaag ttgggctcta at tagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc ggaattatct gtacagagca tatgtcgtta agccttgagg aatactaatt gatgaaggct gaggaaccca ccagacaagc gtaacctact.

aaccagattt at tgtggaac tcaactctaa cagatcgaat ctttatatat ttttgtccaa gccaggcttg acgactttga gagagagcca cgaatgagat ccagctacat cagatgctta cactctgctt actcaaatgc tatccatttc acatttttgc ttggtgtaaa ttattcctgg aaggggacat acc tcagctg caaacctagc cagcagcaga atagaatatc aggtggcaga atatcagttt atgagccaag tagaaggaaa tgaggctaca aaggctacta ctggcttttc ggggacctgt taaatttaac aggtcaaaag tgaatatatt gtggagctgc catgtgtgtt.

ccct tctggg ca tgtggacg cattgaagaa gactaaabttt gc atgtgt cc cagagttgc ccaggtatc t tgaagcaacc atccttcaca tgat tcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct ac tggccagc cgtagtgat t atggctcaat tcacctgagt gttggtgctt aatcattcag tacagtgaat ctggccatct tgcttctcgg tgatatctcc tgctgatggg aattgtgaat ttctaatatc cattggaaat cc tcac tcag acctttactt ctccgagcce gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gt tgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aactatgaaa t tgt tg ttgg cgact ttgga gggaatgtag gaaagcaacc tgtgcagacc cagaacatcc tcaaccttcc gc tggagagg tgggcccttc cagaagctcc gtgagacaac atccaacctt atatgtt tt t aactgtttaa cagaacttaa aaagaagaaa ttaagcagtt ggaagcccag cagtgtgggg ctccatgctA ccaccggtta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat tcgactggca taagctgtgg tggggaccct ttcgtcaccc aaaattggaa acaagattaa tagtttacaa taaaaaa taa tgggtcattg ctgaatacgt acaatgctac aagaagcaaa cctcagccaa acattgatat.

cagacagtga tcctctcctg atgtgccaac ccctaacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acctgtcaaa gaatiaattct tgattctacc aaatgaaatt gaatgccaaa aaatgacttc ttcctacctg ctgtcaagat tgaggtaaaa ctacacggtt agtcaagaga tgctaccaac tgagtccttg tcttgccatg tcttccttgt caacccattg tgaagttgct tattaccaac aacacttggc cttgcttgag 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 52 87 WO 01/18207 PCTUSOO/24591 tcatcttctg aagctttaaa aacaattgat gaattggcct tcaagataga cctaaatagc 1920 acatcacatg tgaatattac aactcggaac ttggctctca gcgtatcatc cctgttacca 1980 gggacaaatg caatttcaaa ttttagcatt ggtcttccaa gcaataatga atcgtatttc 2040 caggtaatga gccagtggtt tctttcattt taa 2073 <210> 38 <211> 690 <212> PRT <213> homo sapiens <400> 38 Met Phe Arg Ser Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys Pro 1 5 10 Ser Pro Leu Leu Phe Leu Phe Ala Leu Tyr Ile met Cys Val Pro His 25 Ser Ala Val Trp Gly Cys Ala Asn Cys Arg Val Val Leu Ser Asn Pro 40 Ser Gly Thr Phe Thr Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Ser 55 Gin Ala Cys Met Trp Thr Leu Arg Ala Pro Thr Gly Tyr Ilie Ile Gin 70 75 Ile Thr Phe Asn Asp Phe Asp Ile Giu Glu Ala Pro Asn Cys Ile Tyr 90 Asp Ser Leu Ser Leu Asp Asn Gly Glu Ser Gin Thr Lys Phe Cys Gly 100 105 110 Ala Thr Aia Lys Gly Leu Ser Phe Asn Ser Ser Ala Asn Giu Met His 115 120 125 Val Ser Phe Ser Ser Asp Phe Ser Ile Gin Lys Lys Gly Phe Asn Ala 130 135 140 Ser Tyr Ilie Arg Val Ala Val Ser Leu Arg Asn Gin Lys Val Ile Leu 145 150 155 160 Pro Gin Thr Ser Asp Ala Tyr Gin Val Ser Vai Ala Lys Ser Ile Ser 165 170 175 Ile Pro Glu Leu Ser Ala Phe Thr Leu Cys Phe Giu Ala Thr Lys Val 180 185 190 Gly His Glu Asp Ser Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser 195 200 205 Phe Thr Gin Leu Leu Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu 210 215 220 Ser Ile Ser Asp Ser Lys Cys Leu Leu Asn Asn Ala Leu Pro Vai Lys 225 230 235 240 Giu Lys Giu Asp Ile Phe Ala Glu Ser Phe Glu Gin Leu Cys Leu Val 245 250 255 Trp Asn Asn Ser Leu Gly Ser Ile Gly Val Asn Phe Lys Arg Asn Tyr 260 265 270 Glu Thr Val Pro Cys Asp Ser Thr Ilie Ser Lys Val Ilie Pro Gly Asn 275 -280 285 Gly Lys Leu Leu Leu Gly Ser Asn Gin Asn Giu Ile Val Ser Leu Lys 290 295 300 Gly Asp Ile Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asn Aia Lys 305 310 315 320 Ile Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Asn Val Val Asp Trp 325 330 335 Gin Asn Asp Phe Trp Asn Ilie Pro Asn Leu Aia Leu Lys Ala Giu Ser 340 345 350 Asn Leu Ser Cys Giy Ser Tyr Leu Ile Pro Leu Pro Ala Ala Giu Leu 355 360 365 Ala Ser Cys Ala Asp Leu Gly Thr Leu Cys Gin Asp Gly Ile Ilie Tyr 370 375 380 Arg Ile Ser Val Vai Ile Gin Asn Ile Leu Arg His Pro Glu Val Lys 385 390 395 400 Val Gin Ser Lys Val Ala Giu Trp Leu Asn Ser Thr Phe Gin Asn Trp 405 410 415 53 87 WO 01/18207 WO 0118207PCTIUSOO/2459

I

Asn Tyr Thr Giu Asp Lys 435 Val Leu Trp Tyr Vai Val Asn Lys Val Lys Arg 440 Leu Leu Val Tyr Ser Phe His Leu Leu Giu Asp Glu Ser Ala Gly 430 Pro Arg Leu Thr Asn Leu Ala Asn Ala Thr Giu 465 Asp Giy Lys Ile Glu Giy Leu Ile Gin Lys Leu Leu Lys 475 Val Asn Glu Ser Leu 480 Giy His 495 Cys LeU Ala Met 500 Pro Ser Giu Tyr 515 Ser Arg Ile Cys Arg Leu His 485 Giu Giu Pro Val Lieu Pro Phe Tyr Asn 535 Ile Ser Asn 550 Asn Leu Thr Thr Vai Lys Giy 505 Cys Pro 520 Ala Thr Arg Gin Leu Tyr Trp, Pro Asp Lys Pro Ser Ilie Gin 510 Phe Ser Ala Thr Tyr Trp Asn Pro 530 Giv Pro Val Asp Gin Ile Leu Asn Ile Thr Asn Val Glu Cys Led Lys Ala Asp Gly 570 Gin Val Lys 585 Gly Ser Thr Gin Asn Leu Arg Ile Val Thr Ser Ala 575 Asn Lys Giu 590 Ilie Phe Ser Ser Ser Giu Asn Giu Val Glu Asn Ile 595 Asn Ile Leu ASP Ilie Thr Leu Leu Met Ser Ser 610 Ala Leu Lys Thr Ile Ser His Ser Leu Leu Pro Ser Asn 675 Ser Phe 690 Val Asn 645 Pro Gly 660 Asn Giu Ser Asp Ser 615 Asp Giu Leu 630 Ile Thr Thr Thr Asn Aia Ser Tyr Phe 680 Ala Plie Arg Asn 650 Ile Ser 665 Gin Val Leu Ala Leu Asn Phe Ser Asp Leu Asn Ser Vai Ser 655 Ile Gly Leu 670 Trp, Phe Leu Asp Leu Leu Met Ser <210> 39 <211> 3255 <212> DNA <213> homo sapiens <400> 39 atgtttcgct ttcttatttg tgccgagtgg tacccaaaca ataacattta cttgataatg aactcaagtg ggtttcaatg ccccagaca t agtgctttca gctttctcct ggctactttc gaaaaagaag ttgggctcta at tagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc ggaattatct cagatcgaat ctttatatat ttttgtccaa gccaggc t g acgactttga gagagagcca cgaatgagat ccagctacat cagatgct ta cactctgctt actcaaatgc tatccatttc acatttttgc ttggtgtaaa ttattcctgg aaggggacat acc tcagc tg caaacctagc cagcagcaga atagaatatc gtggagctgc catgtgtgtt cccttctggg catgtggacg cattgaagaa gactaaattt gcatgtgtcc cagagttgcc ccaggtatct tgaagcaacc atccttcaca tgattcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct actggccagc cgtagtgatt cattggaaat cctcactcag acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aactatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc cagaacatcc ggaagcccag cagtgtgggg ctccatgcta ccaccggtta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gc tccaatca attttaccat tcgactggca taagctgtgg tggggaccct ttcgtcaccc tcctctcctg atgtgccaac ccctaacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acctgtcaaa gaataattct tgattctacc aaatgaaat t gaatgccaaa aaatgacttc ttcctacctg ctgtcaagat tgaggtaaaa 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 54 87 WO 01/18207 WO 0118207PCT/USOO/2459 1 gtacagagca tatgtcgtta agcc ttgagg aatactaatt gatgaaggct gaggaaccca ccagacaagc gtaacctact aaccagattt attgtggaac tcaactctaa tcatcttctg acatcacatg gggacaaatg cagatggatt ttacttgaga ttcaacaaaa gtga tggcgt aaaatcaaac aacaaaaaca gatgcaagtg cttccaagaa tatattgggt tttgagaaat ctgttcctga ctttgcattg gggctagaag cgatacattc gttctagcga ggtgatgaat tttggagtca gggaggaatg agtgtggtta ggacccttaa aggtggcaga atatcagttt atgagccaag tagaaggaaa tgaggctaca aaggc tac ta ctggcttttc ggggacctgt taaatttaac aggtcaaaag tgaatatatt aagctttaaa tgaatattac caatttcaaa t tgagagtgg atttaagtcc ctggactttt gcagtattgg atacaagaac aaagttttgg agacagtctg gtgcctcaca gtggaatatc tgcgaaggga atctcctctt ctgttgcagt caat tcacat taaaattctg gcagaaacaa tctgttggat tgttttttct gcaagagaag gc ttgacct t atatcccctt atggctcaat tcacctgagt gttggtgctt aatcattcag tacagtgaat ctggccatct tgcttCtcgg tgatatctcc tgctgatggg aattgtgaat ttctaatatc aacaat tgat aactcggaac ttttagcatt acaagtggat agaagattct ccaggatgta aaacattact.

tcaggaagtg aggatggaac cctgtgtaac gttagatgca tgctattttt ttatccctcc cctcctagat cctgttgcat gtacattgct catcattggc caatgaagtc tcaagatcca gaacattgcc caaccggacc tctgttgggc catgtacctc tcaaccttcc gc tggagagg tgggcccttc cagaagctcc gtgagacaac atccaacctt atatgttttt aactgtttaa cagaacttaa aaagaagaaa ttaagcagtt gaattggcct ttggctctca ggtcttccaa ccactggcat gtattagtta ggaccccaaa atccagaatc catcatccca acgtcaggat cacttcacac agaaacacta tcagcagc aa aaaatcttga ggctggatca ttcttccttc ctagttaaag tggggtttgc tatggaaaag gtcatatttt atgttcattg c tgagagaag atgacatggg ttctccatct aaaattggaa acaagattaa tagtttacaa* taaaaaataa tgggtcattg ctgaatacgt acaatgctac aagaagcaaa ccticagccaa acattgatat cagacagtga tcaagataga gcgtatcatc gc aa taa tga ctgtaatttt gaagagcaca gaaaaacttt tgaagga tc c tctgtgcctt gtgttgcaca actttggagt aagtcctcac ct c tcc tgac tgaacctgag cctccttcaa tggcaacctt tatttaacac ctgccttagt aaagttatgg atgtgacctg tggtaatggt aagtgttaag gttttgcatt tcaattcatt ctacacggtt ag tcaagaga tgctaccaac tgagtccttg tcttgccatg tcttccttgt caacccattg tgaagttgc t tattaccaac aacacttggc cttgcttgag cctaaatagc cctgttacca atcgtatttc gcctccaaac gtttactttc agtgagttat tgttcaaata ctgggatctg cagagat tca tctgatggac tttcatcagc atatgttgct cacagccctg tgtggatgga tacctggatg ttacattcgc ggtgtcagtt gaaagaaaaa tgctgggtat gcagatctgt gaacctgcgc ctttgcctgg acaaggtaag 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3255 ataaattgta catga <210> <211> 1084 <212> PRT <213> horno sapiens <400> Met Phe Arg Ser Asp Arg Met Trp Ser His Trp Lys Trp Lys Pro Pro Leu Leu Ala Val Trp Phe Leu Phe Ala Gly Cys Ala Asn Ile Met Cys Val Pro His Ser Asn Pro Ser Arg Val Val Ser Gly Thr Phe Thr Ser Cys Tyr Pro Asn Tyr Pro Asn Ser Gin Ala Cys Met Trp Leu Arg Ala Pro Gly Tyr Ile Ile Thr Phe Asn Asp Phe Asp Ile Giu Glu Ala Pro Asn Asp Ser Leu Ala Thr Ala 115 Val Ser Phe Leu Asp Asn Gly Ser Gin Thr Lys Cys Ile Tyr Phe Cys Gly 110 Glu Met His Phe Asn Ala Gly Leu Ser Ser Ser Ala Asn 125 Gly Ser Ser Asp Ile Gin Lys 130 Ser Tyr Ilie Arg Val Ser Leu Arg Asn Lys Val Ile Gin Thr Ser Asp Tyr Gin Val Ser Ala Lys Ser Ile 87 WO 01/18207 PCTIUSOO/2459 1 165 170 175 Ile Pro Giu Leu Ser Ala Phe Thr Let' Cys Phe Git' Ala Thr Lys Val 180 185 190 Gly His Giu Asp Ser Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser 195 200 205 Phe Thr Gin Let' Leu Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu 210 215 220 Ser Ile Ser Asp Ser Lys Cys Leu Let' Asn Asn Ala Leu Pro Val Lys 225 230 235 240 Giu Lys Git' Asp Ile Phe Ala Giu Ser Phe Glu Gin Let' Cys Leu Val 245 250 255 Trp, Asn Asn Ser Let' Gly Ser Ile Gly Val Asn Phe Lys Arg Asn Tyr 260 265 270 Ciii Thr Val Pro Cys Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn 275 280 285 Gly Lys Leu Let' Leu Gly Ser Asn Gin Asn Gi' Ile Val Ser Leu Lys 290 295 300 Gly Asp Ilie Tyr Asn Phe Arg Let' Trp Asn Phe Thr Met Asn Ala Lys 305 310 315 320 Ile Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Asn Val Val Asp Trp, 325 330 335 Gin Asn Asp Phe Trp Asn Ile Pro Asn Let' Ala Let' Lys Ala Git' Ser 340 345 350 Asn Let' Ser Cys Gly Ser Tyr Let' Ilie Pro Let' Pro Ala Ala Git' Leu 355 360 365 Ala Ser Cys Ala Asp Let' Gly Thr Let' Cys Gin Asp Gly Ile Ile Tyr 370 375 380 Arg Ilie Ser Val Val Ilie Gin Asn Ilie Leu Arg His Pro Giu Val Lys 385 390 395 400 Val Gin Ser Lys Val Ala Ciii Trp Let' Asn Ser Thr Phe Gin Asn Trp 405 410 415 Asn Tyr Thr Vai Tyr Val Val Asn Ile Ser Phe His Leu Ser Ala Gly 420 425 430 Cit' Asp Lys Ile Lys Val Lys Arg Ser Let' Cli Asp Giu Pro Arg Let' 435 440 445 Vai Leu Trp, Ala Let' Leu Val Tryr Asn Ala Thr Asn Asn Thr Asn Leu 450 455' 460 Giu Cly Lys Ile Ilie Gin Gin Lys Leu Leu Lys Asn Asn Cit' Ser Let' 465 470 475 480 Asp Cit' Gly Let' Arg Leu 1-is Thr Val Asn Val Arg Gin Leu Giy His 485 490 495 Cys Let' Ala Met Giu Clu Pro Lys Cly Tyr Tyr Trp, Pro Ser Ile Gin 500 505 510 Pro Ser Git' Tyr Vai Leu Pro Cys Pro Asp Lys Pro Cly Phe Ser Ala 515 520 525 Ser Arg Ilie Cys Phe Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp 530 535 540 Gly Pro Vai Asp Ilie Ser Asn Cys Let' Lys Clu Ala Asn Git' Vai Aia 545 550 555 560 Asn Gin Ile Let' Asn Let' Thr Ala Asp Gly Gin Asn Let' Thr Ser Ala 565 570 575 Asn Ilie Thr Asn Ilie Val Cit' Gin Vai Lys Arg Ile Val Asn Lys Clii 580 585 590 Git' Asn Ilie Asp Ile Thr Let' Gly Ser Thr Leu Met Asn Ile Phe Ser 595 600 605 Asn Ile Leu Ser Ser Ser Asp Ser Asp Let' Let' Git' Ser Ser Ser Ciu 610 615 620 Ala Let' Lys Thr Ile Asp Ciu Let' Ala Phe Lys Ile Asp Let' Asn Ser 625 630 635 640 Thr Ser His Val Asn Ile Thr Thr Arg Asn Let' Ala Let' Ser Val Ser 645 650 655 Ser Leu Leu Pro Gly Thr Asn Ala Ilie Ser Asn Phe Ser Ile Gly Let' 660 665 670 56 87 WO 01/18207 Pro Ser Asn i 675 Val Asp Pro 1 690 Leu Ser ProC 705 Phe Asn Lys Leu Val Ser Asn Leu Lys 1 755 Giu Val His 770 Ser Phe GJly 785 Asp Ala Ser( Val Leu Met I Thr Lys Val 1 835 Ile Phe Ser 2 850 Arg Arg Asp 865 Leu Phe Lea 2 Asn Val Asp Leu Leu Ala 915 Ile Ala Lea 1 930 Lys Phe Cys 945 Val Leu Ala Gly Lys Giu I Phe Tyr Val 995 Ile Ala Met I 1010 Lys Arg Ser 2 1025 Ser Val Val Phe Phe Ala Ile Phe Asn 1075 PCT[USOOI2459 1 Giu Ser Tryr Phe Gin 680 Ala Ser Val Ile Leu 695 ASP Ser Val Leu Val 710 Gly Lea Phe Gin Asp 725 Val Met Ala Cys Ser 745 Pro Val Gin Ile Lys 760 Pro Ile Cys Ala Phe 775 Trp Asn Thr Ser Gly 790 Thr Val Cys Leu Cys 805 Leu Pro Arg Ser Ala 825 Thr Phe Ile Ser Tyr 840 Ala Thr Leu Leu Thr 855 Pro Ser Lys Ile Leu 870 Leu Leu Phe Leu Leu 885 Leu Cys Ile Ala Val 905 Phe Thr Trp Met Gly 920 Lys Val Phe Asn Thr 935 Ilie Gly Trp, Gly Leu 950 Arg Asn Asn Asn Glu 965 Gly Asp Glu Phe Cys 985 Cys Ala Gly Tyr Phe 1000 Ile Val Val Met Val 1015 Arg Thr Leu Arg Giu 1030 Leu Thr Phe Leu Leu 1045 Gly Pro Leu Asn Ile Met Asp Phe Giu Ser 685 Pro Pro Asn Leu Leu 700 Arg Arg Ala Gin Phe 715 Val Gly Pro Gin Arg 730 Ile Gly Asn Ile Thr 750 Ile Lys His Thr Arg 765 Trp Asp Leu Asn Lys 780 Cys Vai Ala His Arg 795 Asn His Phe Thr His 810 Ser Gln Leu Asp Ala 830 Ile Gly Cys Giy Ile 845 Tyr Val Ala Phe Giu 860 Met Asn Leu Ser Thr 875 Asp Gly Trp Ilie Thr 890 Ala Vai Leu Leu His 910 Leu Giu Ala Ile His 925 Tyr Ile Arg Arg Tyr 940 Pro Ala Leu Val Vai 955 Val Tyr Gly Lys Giu 970 Trp Ile Gln Asp Pro 990 Gly Val Met Phe Phe 1005 Gin Ile Cys Giy Arg 1020 Glu Val Leu Arg Asn 1035 Gly Met Thr Trp Gly 1050 Pro Phe Met Tyr Leu Gly Gin Glu Asn Thr Phe 720 Lys Thr 735 Ile Gin Thr Gin Asn Lys Asp Ser 800 Phe Gly 815 Arg Asn Ser Aia Lys Leu Ala Leu 880 Ser Phe 895 Phe Phe Met Tyr Ile Leu Ser Val 960 Ser TPyr 975 Val Ile Leu Asn Asn Gly Leu Arg 1040 Phe Ala 1055 Phe Ser 1'rp 1060 Ser Leu Gln Gly 1065 Lys Ile Asn Cys Thr 1080 1070 <210> 41 <211> 3666 <212> DNA <213> homo sapiens <400> 41 atgtttcgct cagatcgaat gtggagctgc cattggaaat ggaagcccag tcctctcctg ttcttatttg ctttatatat catgtgtgtt cctcactcag tgtggggatg tgcCaactgC cgagtggttt tgtccaaccc ttctgggacc tttacttctc catgctaccc taacgactac ccaaacagcc aggcttgcat gtggacgctc cgagccccca ccggttatat cattcagata 57 87 WO 01/18207 WO 0118207PCTIUSOO/2459 I acatttaacg gataatggag tcaagtgcga ttcaatgcca cagacatcag gcttcacac ttctcctact tacttctat aaagaagaca ggctctattg agtaaagtta tctctaaaag ctciccaacc aatatcccaa ccgctcccag attatctata cagagca agg gtcgt taata cttgaggatg actaatttag gaaggc t ga gaacccaaag gacaagcctg acctactggg cagaitiaa gtggaacagg actctaatga tcttctgaag tcacatgtga acaaatgcaa atggattttg ci igagaatt aacaaaactg atggcgtgca atcaaacata aaaaacaaaa gcaagtgaga ccaagaagtg attgggtgtg gagaaattgc ttccigaatc tgcaitgctg ctagaagcaa tacattctaa ctagcgagca gatgaattct ggagtcatgt aggaatggca gtggt tagct cccttaaata atattcaict tgctgtggta atcaagaaaa tcaacctatc cacacagaca caaacatcaa cattcagaca ttttaa actgacat agagccagac atgagatgca gctacatcag atgcttacca tctgcttga caaatgcatc ccaticga tt i igcaga gtgtaaattt ttcctgggaa gggacattta icagctgiaa acctagctct cagcagaac t gaatatccgt tggcagaatg tcagttttca agccaaggt t aaggaaaaat ggctacatac gciactactg gcttttctgc gacctgtiga atttaactgc tcaaaagaat aiatattttc ctttaaaaac aiattacaac tttcaaattt agagtggaca taagtccaga gactttcca gtattggaaa caagaactca gttttggagg cagtctgcct cctcacagtt gaaiatctgc gaagggatta.

icctcticct ttgcagicct ttcacatgia aattctgcat gaaacaacaa gttggattca ii ii c tgaa agagaagcaa tgacctttci iccccticat iccactgtgc gatitcggtt gttctgataa Ltacatccaa gtgciiccai icaiccctgt acttctataa igaagaagct taaattttgt tgig icc iii agttgccgtg ggtatctgit agcaaccaaa cticacacaa ticaaaatgi aagcttigaa caaaagaaac tgggaaatig taacticga igigaaaggg gaaagcigaa ggccagctgt agigattcag gcicaattca cctgagtgct ggtgctttgg caiicagcag agtgaaigtg gccatctatc ttctcggata taiciccaac tgaigggcag igtgaaiaaa taatatctta aattgatgaa icggaacttg tagcattggt agiggaicca agattcigia ggatgtagga cattactaic ggaagigcat atggaacacg gigiaaccac agaigcaaga tatttica tccciccaaa cc tagatggc giigcaiitc cattgctcia caitggctgg igaagtctat agatccagtc caiigccaig ccggaccctg gtigggcatg giacctctic taigaaggag agcagataac tctaggaaaa aiciaaatcc ggacaag icc ccatcaggic aaatattatc cccaaitgca ggagcaacig tcaagtgact tccttaagga gcaaaaagca gttggccatg ttgcicagt iigitgaaia cagctcigcc tatgaaacag iigtigggct cttiggaatt aatgiagicg agcaacctaa gcagacctgg aacatccttc accticcaaa ggagaggaca gcccttctag aagctcciaa agacaacigg caaccttctg igtttaca igtiiaaaag aacitaacci gaagaaaaca agcagt icag ttggcctica gcictcagcg cttccaagca ctggcatctg t tagiiagaa ccccaaagaa cagaaiciga catcccaic t tcaggaigig ttcacacact aacactaaag gcagcaactc atcttgaiga.

iggatcacci ttccttctgg gtiaaagiat ggittgcctg ggaaaagaaa atatttatg ttcattgtgg agagaagaag acaiggggtt tccatcttca aatgttcaga icagatigga ictgicit agctciacca itgicaaaac aiigaiaagg atgtcagaca ii tatgac ic ccaaaggcci ttagcaicca atcaaaaggi tctctattcc aagacagtga ttggaaaggc atgcattacc ttgtitggaa ticcatgtga ccaatcaaaa ttaccaigaa aciggcaaaa gctgiggtic ggaccctcig gtcaccc iga atiggaacta aga ttaaagi ttiacaaigc aaaataatga gicattgici aatacgtici atgctaccaa aagcaaatga cagccaaiai ttgataiaac acagigacti agatagacc t tatcatccct ataaigaatc taatttigcc gagcacagti aaactiagi aggatccigi gigcctictg iigcacacag itggagtict iccicactt icctgacata accigagcac ccttcaatgt caaccittac tiaacactta cct tagiggi gttatgggaa igaccigigc taatggtgca tgiiaaggaa ttgcattcti attcattaca aacagiggcg gtaagacagc caagctccat cctatiicaa iggcccaigc icaagggita ccttcagcca attatcccii atcaittaac gaagaaaggt caiiiiaccc agagcicagt ttggacagci caagagtggc tgtcaaagaa iaaiicttig iictaccaii tgaaattgtC igccaaaaic igacitctgg ctaccigaic tcaagatgga gg taaaagia cacggtai caagagaagc taccaacaat gtcci iggat igccatggag tccttgtcca cccai iggia agttgctaac taccaacatt acttggcica gct igagica aaatagcaca gitaccaggg giatttccag iccaaactta tacticttc gagttatgtg icaaataaaa ggaictgaac agaticagai gatggaccit caicagctat tgttgcitti agccctgctg ggaiggactt ciggatgggg caticgccga gicagtigtt agaaaaaggi igggtatt ii gaictgtggg cctgcgcagt tgccigggga aggciiattt gcggcatctc taccaatatc iggiiccaac aaggaatagc tgaiggagat t igcaatgct cagcacaaag 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3666 <210> 42 <211> 1221 <212> PRT <213> homo sapiens 58 87 WO 01/18207 4400> 42 met Phe Arg .1 Ser Pro LeuI Ser Val Trp Gly Thr Phe Ala Cys Met Thr Phe Asn Ser Leu Ser Thr Ala Lys 115 Ser Phe Ser 130 Tyr Ile Arg 145 Gin Thr Ser Pro Glu Leu His Glu Asp 195 Thr Gin Leu 1 210 Ile Ser Asp 225 Lys Glu Asp Asn Asn Ser I Thr Val Pro 275 Lys Leu Leu 1 290 Asp Ile Tyr3 305 Leu Ser Asn I Asn ASP Phe Leu Ser CysC 355 Ser Cys Ala 1 370 Ile Ser Val 385 Gin Ser LYS I Tyr Thr Val J Asp Lys Ile I 435 Leu Trp Ala I 450 Gly Lys Ile 465 Glu Gly Leu I Asp 5 Phe Cys Ser Thr Phe

ASP

Leu Asp Ala Al a 165 Ala

ASP

Ser Lys Phe 245 Gly Asp Gly Phe Ser 325 Asn Ser Leu Ile Ala 405 Val Val Leu Gin Leu 485 Met Phe Asn Cys Arg Ile Giy Phe Ser 135 Ser Gin Thr Thr Gly 215 Leu Glu Ile Thr Asn 295 Leu Asn Pro Leu Thr 375 Asn Trp Asn Arg Tyr 455 Lys Thr Cys 10 Tyr Val Asn Thr Ala 90 Gin Ser Lys Asn Val2 170 Phe Ser Lys Asn Glu 250 Asn Lys Giu Phe Gly 330 Ala Leu Gin Arg Ser 410 Phe Giu Thr Lys Val 490 Lys Pro Pro Ser Gin Tyr Gly His Ala Leu Ser 175 Val Ser Leu Lys Val 255 Tyr Asn Lys Lys Trp 335 Ser Leu Tyr Lys Trp 415 Gly Leu Leu Leu His 495 PCT/USOO/24591 Pro His Ser Gin Ile Asp Ala Val Ser Pro 160 Ile Gly Phe Ser Glu 240 Trp Giu Gly Gly Ile 320 Gin Asn Ala Arg Val 400 Asn Giu Val1 Giu Asp 480 Cys 59 87 WO 01/18207 Leu Ser Arg Pro 545 Gin Ile Asn Ile Leu 625 Ser Leu Ser Asp Ser 705 Asn Val1 Leu Val Phe 785 Ala Leu Lys Phe Arg 865 Phe Vai Leu Ala Phe 945 Leu Lys Tyr Lys Cys Aia 535 Cys Aia Gin Giy Ser 615 Leu Thr Aia Phe Ile 695 Leu Gin Cys Ile Ala 775 Ser Leu Ser Ser Leu 855 Ile Leu Ala Met Asn 935 Giy Asn Phe Tyr Tyr 505 Asp Asn Lys Gly Lys 585 Thr Leu Phe Asn Ser 665 Met Pro Arg Val1 Ile 745 Ile Trp, Cys Asn Ser 825 Ile Tyr Met Asp Aia 905 Leu Tyr Pro Val Trp 985 Giy Trp, Pro Leu Aia 555 Asn Ile Met Giu Ile 635 Ala Phe Phe Asn Ala 715 Pro Asn His Leu Al a 795 Phe Leu Cys Ala Leu 875 Trp Leu Ala Arg Leu 955 Gly Gin Met PCTIUSOO/24591 Pro Ser Giy Asn 560 Asn Glu Asn Ala Thr 640 Ser Pro Val Leu Phe 720 Leu Asn Giu Ser Asp 800 Val Thr Ile Arg Leu 880 Asn Leu Ile Lys Val 960 Gly Phe Ile 87 WO 01/18207 WO 0118207PCT/USOO/2459 I 995 1000 1005 Ala Met Phe Ile Val Val Met Val Gin Ile Cys Gly Arg Asn Gly Lys 1010 1015 1020 Arg Ser Asn Arg Thr Leu Arg Giu Glu Val Leu Arg Asn Leu Arg Ser 1025 1030 1035 1040 Val Val Ser Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe 1045 1050 1055 Phe Ala Trp Gly Pro Leu Asn Ilie Pro Phe Met Tyr Leu Phe Ser Ile 1060 1065 1070 Phe Asn Ser Leu Gin Gly Leu Phe Ile Phe Ile Phe Hius Cys Ala Met 1075 Lys Giu Asn 1090 Phe Arg Leu Val Gin Lys Ala Asp Asn ill( Ser Ser Asp 1125 Asn Ser Thr 1080 1085 Gin Trp Arg Arg His Leu Cys Cys Giy Arg 1095 1100 Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile 1115 1120 Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser 1130 1135 Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser 1105 Ile ys Lys lie Clv Ser 114 Thr Thr Tyr Phe 1155 Lys Ser Leu Ser 0 1145 Ile 1185 His 1170 Pro Val His Lys Arg Asn Lys Leu Ala 1175 Gin Val Ile 1190 Phe Tyr Lys 1205 Phe His Ala Asp Gly Asp Gin Thr 1180 Asp Lys Val Lys Gly Tyr Cys 1195 Asn Ile Ilie Met Ser Asp Thr 1210 Ser Ile Asn Ala 1200 Phe Ser 1215 3er His 1160 Thr Asp Ser 1150 Ala Ser Met Asp 1165 Ser Asp Asn His Ser Thr Lys 1220 <210> 43 <211> 3579 <212> DNA <213> homo sapiens <400> 43 atgtttcgct tt ct tat ttg cgagtggttt ccaaacagcc acatttaacg gataatggag tcaagtgcga t tcaatgcca cagacatcag gctttcacac ttctcctact tactttctat aaagaagaca ggctctattg agtaaagtta tctctaaaag ctctccaacc aatatcccaa ccgctcccag attatctata cagagcaagg gtcgttaat-a cttgaggatg actaatttag gaaggcttga gaacccaaag gacaagcctg cagatcgaat ctttatatat tgtccaaccc aggcttgcat actttgacat agagccagac atgagatgca gctacatcag atgcttacca tctgctttga caaa tgcat c ccatttctga tttttgcaga gtgtaaattt ttcctgggaa gggacattta tcagctgtaa acctagctct cagcagaact ga ata t ccg t tggcagaatg tcag tt ttca agccaaggtt aaggaaaaa t ggc taca tac gctactactg gcttttctgc gtggagctgc catgtgtgtt ttctgggacc gtggacgc tc tgaagaagct taaattttgt tgtgtccttt agttgccgtg ggtatctgtt agcaaccaaa cttcacacaa ttcaaaatgt aagct ttgaa caaaagaaac tgggaaattg taactttcga tgtgaaaggg gaaagctgaa ggccagctgt agtgat tcag gctcaattca cctgagtgct ggtgctttgg cattcagcag agtgaatgtg gccatctatc ttctcggata cattggaaat cctcactcag tttacttctc cgagccccca cccaattgca ggagcaactg tcaagtgact tccttaagga gcaaaaagca gttggccatg ttgctcagtt ttgttgaata cagctctgcc tatgaaacag ttgttgggct ctttggaatt aatgtagtcg agcaacc taa gcagacctgg aacatccttc accttccaaa ggagaggaca gcccttctag aagctcctaa agacaactgg caaccttctg tgtttttaca ggaagcccag tgtggggatg catgctaccc ccggttatat tttatgactc c caaaggc ct ttagcatcca atcaaaaggt tctctattcc aagacag tga t tggaaaggc atgcattac ttgtttggaa ttccatgtga ccaatcaaaa t taccatgaa actggcaaaa gctgtggttc ggaccctctg gtcacc ctga attggaacta agattaaagt t ttacaatgc aaaataatga gtcattgtct aatacgttct atgctaccaa tcCtctcctg tgccaactgc taac gac tac cattcagata at tatccct t atcatttaac gaagaaaggt cattttaccc agagctcagt ttggacagct caagagtggc tgtcaaagaa taattctttg ttctaccatt tgaaattgtc tgccaaaatc tgacttctgg ctacctgatc tcaagatgga ggtaaaagta cacggtttat caagagaagc taccaacaat gtccttggat tgccatggag tccttgtcca cccattggta 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 61 87 WO 01/18207 WO 0118207PCT/USOO/24591 acc tac tggg cagattttaa gtggaacagg actctaatga tcttctgaag tcacatgtga acaaatgcaa atggattttg cttgagaatt aacaaaactg atggcgtgca atcaaacata aaaaacaaaa gcaag tgaga ccaagaagtg attgggtgtg gagaaattgc ttcctgaatc tgcattgctg ctagaagcaa tacattctaa c tagcgagca gatgaattct ggagtcatgt aggaatggca gtggttagct cccttaaata atattcatct tgctgtggta atcaagaaaa tcaacctatc cacacagata t tccatggac gacctgttga at ttaactgc tcaaaagaat atatattttc ctttaaaaac atattacaac tttcaaattt agagtggaca taagtccaga gacttttcca gtat tggaaa caagaactca gttttggagg cagtctgcct cctcacagtt gaatatctgc gaagggatta tcCtcttcCt ttgcagtcct ttcacatgta aattctgcat gaaacaacaa gttggattca tttttctgaa agagaagcaa tgacctttct tccccttcaL tccactgtgc gatttcggtt gttctgataa ttacatccaa atgtctccta aagtccttgt tatctccaac tgatgggcag tgtgaataaa taatatctta aat tgatgaa tcggaacttg tagcattggt agtggatcca agattctgta ggatgtagga cattactatc ggaagtgca t atggaacacg gtgtaaccac agatgcaaga tattttttca tccctccaaa cctagatggc gttgcatttc cattgctcta cattggctgg tgaagtctat agatccagtc cattgccatg ccggaccctg gttgggcatg gtacctcttc tatgaaggag agcagataac tctaggaaaa atctaaatcc tgagcattcc caaaactggc tgtt taaaag aacttaacct gaagaaaaca agcagttcag ttggccttca gctctcagcg cttccaagca ctggcatctg ttagttagaa ccccaaagaa cagaatctga catcccatct tcaggatgtg ttcacacact aacactaaag gcagcaactc atct tgatga tggatcacct ttccttctgg gttaaagtat ggtttgcctg ggaaaagaaa atattttatg ttcattgtgg agagaagaag acatggggtt tccatcttca aatgttcaga tcagattgga tctttgtctt agctctacca ttcaacaaaa ccatgctga aagcaaatga cagccaatat ttgatataac acagtgactt agatagacct tatcatccct ataatgaatc taattttgcc gagcacagtt aaactttagt aggatcctgt gtgccttctg ttgcacacag ttggagttct tcctcacttt tcctgacata acctgagcac ccttcaatgt caacctttac ttaacactta ccttagtggt gt tatgggaa tgacc tgtgc taatggtgca tgttaaggaa ttgcattctt attcattaca aacagtggcg gtaagacagc caagc tccat cctatttcaa gtggatcact agttgctaac taccaacatt acttggctca gcttgagtca aaatagcaca gttaccaggg gtatttccag tccaaactta tactttcttc gagttatgtg tcaaataaaa ggatc tgaac agattcagat gatggacctt catcagctat tgttgctttt agc ctgc tg ggatggactt ctggatgggg cattcgccga gtcagttgtt agaaaaaggt tgggtatttt gatctgtggg cctgcgcagt tgcc tgggga aggcttattt gcggcatctc taccaatatc tggt tccaac aaggaatagc cagacagtgc 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3579 <210> 44 <211> 1192 <212> PRT <213> homo sapiens <400> 44 Met Phe Arg Ser ASP Arg Met Trp Ser His Trp Lys Trp Lys Pro Pro Leu Leu Val Trp Gly Leu Phe Ala Ile Met Cys Ser Cys Ala Asn Arg Val Val Leu Ser Val Pro His Asn Pro Ser Asn Ser Gin Pro Gly Thr Ala Cys Phe Thr Ser Pro Met Trp Thr Arg Ala Pro Asn Asp Tyr Pro Thr Gly Tyr Glu Ala Pro Asn Ile Ile Gin Thr Phe Asn Asp Phe ASP Ile Giu Cys Ilie Ser Leu Ser Thr Ala Lys 115 Ser Phe Ser 130 Tyr Ie Arci Leu 100 Gly Asp Asn Gly Giu Thr Lys Phe Leu Ser Phe Asn Ser Ser 120 Ala Asn Cys Gly Ala 110 Met His Val Asn Ala Ser Ser Asp Phe Ile Leu Val Ala Gin Lys Lys Gly 140 Arg Asn Gin Lys 155 Ser Val Ala Lys Val Ilie Leu 145 Gin Thr Ser Asp Gin Val Ser Ile Ser Ilie 175 Val Gly Pro Giu Leu Ser Phe Thr Leu Cys Giu Ala Thr Lys 62 87 WO 01/18207 WO 0118207PCTIUS00124591 Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser Phe Lys Leu Ser Gly Ile 280 Gin Trp Val Asn Ile 360 Lcu Ile Leu Ile Ser 440 Asn Leu Vai Giy Pro 520 Thr Leu Asp Val1 Ser 600 Asp Ala Arg Ile Gin 680 205 Tyr Phe Leu Ser Pro Val Lys Giu 240 Cys Leu Vai Trp 255 Arg Asn Tyr Giu 270 Pro Giy Asn Giy 285 Ser Leu Lys Gly Asn Aia Lys Ile 320 Val Asp Trp Gin 335 Aia Giu Ser Asn 350 Aia Giu Leu Ala 365 Ile Ile Tyr Arg Glu Vai Lys Val 400 Gin Asn Trp Asn 415 Ser Ala Gly Giu 430 Pro Arg Leu Val 445 Thr Asn Leu Giu Giu Ser Leu Asp 480 Leu Gly His Cys 495 Ser Ile Gin Pro 510 Phe Ser Ala Ser 525 Thr Tyr Trp Giy Giu Val Ala Asn 560 Thr Ser Ala Asn 575 Asn Lys Giu Giu 590 Ile Phe Ser Asn 605 Ser Ser Giu Ala Leu Asn Ser Thr 640 Ser Val Ser Ser 655 Ile Gly Leu Pro 670 Ser Gly Gin Val 685 63 87 WO 01/18207 WO 0118207PCTUSOO/2459 1 Asp Pro Leu Ala Ser Val Ilie Leu Pro Pro Asn Leu Leu Giu Asn Leu 690 695 700 Ser Pro GiU ASP Ser Val Leu Vai Arg Arg Ala Gin Phe Thr Phe Phe 705 710 715 720 Asn Lys Thr Gly Leu Phe Gin Asp Val Giy Pro Gin Arg Lys Thr Leu 725 730 735 Val Ser Tyr Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gin Asn 740 745 750 Leu Lys Asp Pro Val Gin Ilie Lys Ile Lys His Thr Arg Thr Gin Glu 755 760 765 Val His His Pro Ilie Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser 770 775 780 Phe Gly Gly Trp Asn Thr Ser Gly Cys Val Ala His Arg Asp Ser Asp 785 790 795 800 Ala Ser Giu Thr Val Cys Leu Cys Asn His Phe Thr His Phe Gly Val 805 810 815 Leu Met Asp Leu Pro Arg Ser Ala Ser Gin Leu Asp Ala Arg Asn Thr 820 825 830 Lys Val Leu Thr Phe Ile Ser Tyr Ilie Gly Cys Gly Ile Ser Ala Ile 835 840 845 Phe Ser Ala Ala Thr Leu Leu Thr Tyr Val Ala Phe Giu Lys Leu Arg 850 855 860 Arg Asp Tyr Pro Ser Lys Ile Leu Met Asn Leu Ser Thr Ala Leu Leu 865 870 875 880 Phe Leu Asn Leu Leu Phe Leu Leu Asp Gly Trp Ile Thr Ser Phe Asn 885 890 895 Val Asp Gly Leu Cys Ile Ala Val Aia Val Leu Leu His Phe Phe Leu 900 905 910 Leu Ala Thr Phe Thr Trp Met Gly Leu Giu Ala Ile His Met Tyr Ile 915 920 925 Ala Leu Val Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ilie Leu Lys 930 935 940 Phe Cys Ilie Ilie Gly Trp Gly Leu Pro Ala Leu Val Val Ser Val Val.

945 950 955 960 Leu Ala Ser Arg Asn Asn Asn Giu Val Tyr Gly Lys Glu Ser Tyr Giy 965 970 975 Lys Glu Lys Gly Asp Giu Phe Cys Trp Ile Gin Asp Pro Val Ile Phe 980 985 990 Tyr Val Thr Cys Ala Giy Tyr Phe Gly Val Met Phe Phe Leu ASf l Te 995 1000 1005 Ala Met Phe Ile Val Val met Vai Gin Ile Cys Gly Arg Asn Gly Lys 1010 10i5 1020 Arg Ser Asn Arg Thr Leu Arg Giu Giu Val Leu Arg Asn Leu Arg Ser 1025 1030 1035 1040 Val Vai Ser Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe 1045 1050 1055 Phe Ala Trp Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser Ile 1060 1065 1070 Phe Asn Ser Leu Gin Gly Leu Phe Ilie Phe Ile Phe His Cys Ala Met 1075 1080 1085 Lys Giu Asn Val Gin Lys Gin Trp Arg Arg His Leu Cys Cys Gly Arg 1090 1095 1100 Phe Arg Leu Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile 1105 lila i1i5 1120 Ile Lys Lys Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser 1125 1130 1135 Ile Gly Ser Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser 1140 1145 1150 Thr Thr Tyr Phe Lys Arg Asn Ser His Thr Asp Asn Val Ser Tyr Glu 1155 1160 1165 His Ser Phe Asn Lys Ser Gly Ser Leu Arg Gin Cys Phe His Gly Gin 1170 1175 1180 Val Leu Val Lys Thr Gly Pro Cys 64 87 WO 01/18207 WO 0118207PCT/USOO/2459 1 1185 1190 <210> <211> 2070 <212> DNA <213> homo sapiens <400> atgtttcgct ttcttatttg cgagtggt tt ccaaacagcc acatttaacg gataatggag tcaagtgcga ttcaatgcca cagacatcag gctttcacac ttctcctact tactttctat aaagaagaca ggctctattg agtaaagtta tctctaaaag ctctccaacc aatatcccaa ccgctcccag attatctata cagagcaagg gtcgttaata cttgaggatg actaatttag gaaggcttga gaacccaaag gacaagcctg acctactggg cagattttaa gtggaacagg actctaatga tcttctgaag tcacatgtga acaaatgcaa gtaatgagcc cagatcgaat ctttatatat tgtccaaccc aggcttgcat actttgacat agagccagac atgagatgca gctacatcag a tgc ttacca tctgctttga caaatgcatc ccatttctga tttttgcaga gtgtaaattt ttcctgggaa gggacattta tcagctgtaa acctagctct cagcagaac t gaata tc cg t tggcagaatg tcagttttca agccaaggtt aaggaaaaat ggctacatac gctactactg gcttttctgc gacctgt iga atttaactgc tcaaaagaat atatattttc ct ttaaaaac atattacaac tttcaaattt agtggtt tc t gtggagctgc catgtgtgit ttctgggacc gtggacgctc tgaagaagc t t aaat t ttgt tgtgtcct tt agttgccgtg ggtatctgtt agcaaccaaa cttcacacaa t tcaaaatgt aagctttgaa caaaagaaac tgggaaat tg taactttcga tgtgaaaggg gaaagc tgaa ggccagctgt agtgat tcag gctcaattca cctgagtgct ggtgctttgg cattcagcag agtgaatgtg gccatetatc t ictcggata tatc tccaac tgatgggcag tgtgaataaa taatatctta aattgatgaa tcggaacttg tagcattggt ttcattttaa cattggaaat cctcactcag tttacttctc cgagccccca cccaattgca ggagcaactg tcaagtgac t tccttaagga gcaaaaagca gttggccatg ttgctcagtt ttgttgaata cagctctgcc tatgaaacag ttgttgggct ctttggaatt aatgtagtcg agcaacc taa gcagacc tgg aacatccttc accttccaaa ggagaggaca gcccttctag aagctcctaa agacaac tgg caaccttctg tgtttttaca tgtttaaaag aacttaacct gaagaaaaca agcagt tcag t tggcct ica gctctcagcg cttccaagca ggaagcccag tgtggggatg catgctaccc ccggttatat tttatgactc ccaaaggcct ttagcatcca atcaaaaggt tctctattcc aagacagtga t iggaaaggc atgcattacc t tgt ttggaa ttccatgtga ccaatcaaaa ttaccatgaa actggcaaaa gctgtggttc ggaccc ic g gtcaccctga attggaacta aga ttaaagt tttacaatgc aaaataatga gtcattgtct aatacgttct atgctaccaa aagcaaatga cagccaatat ttgatataac acagtgactt agatagacct tatcatccct ataatgaatc tcCtctcctg tgccaactgc taacgactac cattcagata attatccctt atcatttaac gaagaaaggt cattttaccc agagctcagt t tggacagc t caagagtggc tgtcaaagaa taattctttg ttctaccatt tgaaattgtc tgccaaaatc tgacttctgg ctacctgatc tcaagatgga ggtaaaagta cacggtttat caagagaagc taccaacaat gtccttggat tgccatggag tccttgtcca cccattggta agttgctaac taccaacatt acttggcica gcttgagtca aaatagcaca gt taccaggg gtatttccag 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2070 <210> 46 <211> 689 <212> PRT <213> homo sapiens <400> 46 Met Phe Arg Ser Asp Arg Met Trp Ser 1 Ser Pro Leu Cys His Trp Lys Trp 10 Tyr Ile Met Cys Val Lys Pro Pro His Leu Phe Ala Ser Val Trp Gly Cys Gly Thr Phe Thr Ser Ala Cys Met Trp Thr Thr Phe Asn Asp Phe Ala Asn Pro Cys Leu Arg 70 Val Val Leu Asn Pro Ser Asn Ser Gin Pro Asn Asp Tyr Pro Thr Gly 75 Tyr Ile Ile ASP Ile Glu Glu Pro Asn Cys Ile Thr Lys Phe Cys Gin Ile Tyr Asp Gly Ala Ser Leu Ser Leu Asp Asn Gly Glu Ser 87 WO 01/18207 Thr Ser Tyr 145 Gin Pro His Thr Ile 225 Lys Asn Thr Lys Asp 305 Leu Asn Leu Ser Ile 385 Gin Tyr Asp Leu Gly 465 Giu Leu Ser Arg Pro 545 Gin Ile Asn Lys 115 Ser Arg Ser Leu Asp 195 Leu Asp Asp Ser Pro 275 Leu Tyr Asn Phe Cys 355 Aia Val1 Lys Val1 Ile 435 Ala Ile Leu Met Tyr 515 Cys Asp Leu Asn Asp 595 His Ala Leu Ser 175 Val1 Ser Leu Lys Val1 255 Tyr Asn

LYS

Lys Trp 335 Ser Leu Tyr Lys Trp, 415 Gly Leu Leu Leu His 495 Gin Ala Trp Ala Ala 575 Glu Ser PCT/USOO/2459 I Val Ser Pro 160 Ile Giy Phe Ser Giu 240 Trp Glu Gly Gly Ile 320 Gin Asn Ala Arg Val 400 Asn Glu Val Giu Asp 480 Cys Pro Ser Gly Asn 560 Asn Glu Asn 66 87 WO 01/18207 WO 0118207PCTIUSO/2459 I Ile Leu 610 Leu Lys Ser Ser Ser Asp Asp Leu Leu Giu Thr Ile Asp Leu Ala Phe Lys Ser 620 Asp Leu 625 Ser His Val Asn Thr Arg Asn Ser Ser Giu Ala Leu Asn Ser Thr 640 Ser Val Ser Ser 655 Ile Gly Leu Pro 670 Trp Phe Leu Ser Leu Leu Pro Ser Asn Asn 675 Phe Gly 660 Giu Thr Asn Ala Ile Ser Tyr Phe Gin 680 Phe Ser Met Ser Gin 47 <211> 3252 <212> DNA <213> homo sapiens <400> 47 atgtttcgct ttcttatttg cgagtggttt ccaaacagcc acatttaacg gataatggag tcaagtgcga ttcaatgcca cagacatcag gctttcacac ttctcctact tactttctat aaagaagaca ggctctattg agtaaagtta tctctaaaag ctctccaacc aatatcccaa ccgctcccag attatctata cagagcaagg gtcgt taata cttgaggatg actaatttag gaaggcttga gaacccaaag gacaagcctg acctactggg cagattttaa gtggaacagg actctaatga tcttctgaag tcaca tgtga acaaa tgcaa atggattttg cttgagaatt aacaaaactg atggcgtgca atcaaacata aaaaacaaaa gcaagtgaga ccaagaagtg attgggtgtg gagaaattgc cagatcgaat ctttatatat tgtccaaccc aggcttgcat actttgacat agagccagac atgagatgca gctacatcag atgcttacca tctgctttga caaatgcatc ccatttctga tttttgcaga gtgtaaattt ttcctgggaa gggacattta tcagctgtaa acctagctct cagcagaact gaatatccgt tggcagaatg tcagttttca agccaaggt aaggaaaaat ggctacatac gctactactg gcttttctgc gacctgttga atttaactgc tcaaaagaat atatattttc ctttaaaaac atat tacaac tttcaaattt agagtggaca taagtccaga gacttttcca gtattggaaa caagaactca gttttggagg cagtctgcct cctcacagtt gaatatctgc gaagggat ta gtggagc tgc catgtgtgtt ttctgggacc gtggacgctc tgaagaagc t taaattttgt tgtgtccttt agttgccgtg ggta tc tgt t agcaaccaaa cttcaCaCaa ttcaaaatgt aagctttgaa caaaagaaac tgggaaattg taactttcga tgtgaaaggg gaaagc tgaa ggccagctgt agtgattcag gctcaattca cctgagtgct ggtgctt tgg cattcagcag agtgaatgtg gcc atc tat c ttctcggata tatctccaac tgatgggcag tgtgaataaa taatatctta aattgatgaa tcggaac ttg tagcattggt agtggatcca agattctgta ggatgtagga cattactatc ggaagtgcat atggaacacg gtgtaaccac agatgcaaga tattttttca tccctccaaa cattggaaat cctcactcag tttacttctc cgagccccca cccaattgca ggagcaactg tcaagtgact tccttaagga gcaaaaagca gttggccatg ttgctcagtt ttgttgaata cagctctgcc tatgaaacag ttgttgggct ctttggaatt aatgtagtcg agcaacctaa gcagacctgg aacatccttc accttccaaa ggagaggaca gcccttctag aagc tcctaa agacaactgg caaccttctg tgtttttaca tgtt taaaag aact taacct gaagaaaaca agcagt tcag ttggccttca gctctcagcg cttccaagca ctggcatctg t tagttagaa ccccaaagaa cagaatctga catcccatct tcaggatg tg t tcacacact aacactaaag gcagcaactc atcttgatga ggaagcccag tgtggggatg catgctaccc ccggttatat tttatgactc ccaaaggcct t tagc atcc a atcaaaaggt tctctattcc aagacag bga ttggaaaggc atgcattacc ttgtttggaa ttccatgtga ccaatcaaaa ttaccatgaa actggcaaaa gctgtggttc ggaccctctg gtcaccctga at tggaacta agattaaagt tttacaatgc aaaataatga gtcattgtct aatacgttct atgctaccaa aagcaaatga cagccaatat ttgatataac acagtgactt agatagacct tatcatccct ataatgaatc taattttgcc gagcacagtt aaactttagt aggatcctgt gtgccttctg ttgcacacag ttggagttct tcctcacttt tcctgacata acctgagcac tcCtctcctg tgccaac tgc taacgactac cattcagata attatccctt atcatttaac gaagaaaggt cattttaccc agagctcagt ttggacagct caagagtggc tgtcaaagaa taattctttg ttctaccatt tgaaattgtc tgccaaaatc tgacttctgg ctacctgatc tcaagatgga ggtaaaagta cacggtttat caagagaagc taccaacaat gtccttggat tgccatggag tccttgtcca cccattggta agttgctaac taccaacatt acttggctca gct tgagtca aaatagcaca gttaccaggg gtatttccag tccaaact ta tactttcttc gagttatgtg tcaaataaaa ggatctgaac aga ttcagat gatggacctt catcagctat tgttgctttt agccctgctg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 67 87 WO 01/18207 WO 0118207PCTIUSOO/24591 ttcctgaatc tcctcttcct cctagatggc tggatcacct tgcattgctg ttgcagtcct gttgcatttc ttccttctgg ctagaagcaa ttcacatgta cattgctcta gttaaagtat tacattctaa aattctgcat cattggctgg ggtttgcctg ctagcgagca gaaacaacaa tgaagtctat ggaaaagaaa gatgaattct gttggattca agatccagtc atattttatg ggagtcatgt tttttctgaa cattgccatg ttcattgtgg aggaatggca agagaagcaa ccggaccctg agagaagaag gtggttagct tgacctttct gttgggcatg acatggggtt cccttaaata tccccttcat gtacctcttc tccatcttca aattgtacat ga <210> 48 <211> 1083 <212> PRT <213> homo sapiens ccttcaatgt ggatggactt caacctttac ctggatgggg ttaacactta cattcgccga ccttagtggt gtcagttgtt gttatgggaa agaaaaaggt tgacctgtgc tgggtatttt taatggtgca gatctgtggg tgttaaggaa cctgcgcagt ttgcattctt tgcctgggga attcattaca aggtaagata 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3252 <400> 48 Met Phe Arg 1 Ser Pro Leu Ser Val Trp Gly Thr Phe Ala Cys Met Thr Phe Asn Ser Leu Ser Thr Ala Lys 115 Ser Phe Ser 130 Tyr Ile Arg 145 Gin Thr Ser Pro Glu Leu His Glu Asp 195 Thr Gin Leu 210 Ile Ser Asp 225 Lys Glu Asp Asn Asn Ser Thr Val Pro 275 Lys Leu Leu 290 Asp Ile Tyr 305 Leu Ser Asn Asn Asp Phe Leu Ser Cys Ser Leu Gly Thr Trp Asp Leu 100 G ly Ser Val Asp Ser 180 Ser Leu Ser Ile Leu 260 Cys Leu Asn Leu Trp 340 Gly Met Phe Asn Cys Arg Ile Gly Phe Ser 135 Ser Gin Thr Thr Gly 215 Leu Giu Ile Thr Asn 295 Leu Asn Pro Leu 68 87 WO 01/18207 Ser Cys 370 Ile Ser 385 Gin Ser Tyr Thr Asp Lys Leu Trp, 450 Gly Lys 465 Glu Gly Leu Ala Ser Giu Arg Ile 530 Pro Vai 545 Gin Ile Ile Thr Asn Ile Ile L-eu 610 Leu Lys 625 Ser His Leu Leu Ser Asn Asp Pro 690 Ser Pro 705 Asn Lys Vai Ser Leu Lys Val His 770 Phe Gly 785 Ala Ser Leu Met Lys Val Phe Ser 850 355 Ala Vali Lys Val Ile 435 Ala Ile Leu Met Tyr 515 Cys Asp Leu Asn

ASP

595 Ser Thr Vai Pro Asn 675 Leu Giu Thr Tyr Asp 755 his Gly Giu Asp Leu 835 Ala 365 Ile Giu Gin Ser Pro 445 Thr Giu Leu Ser Phe 525 Thr Giu Thr Asn Ile 605 Ser Leu Ser Ile Ser 685 Leu Phe Arg Thr Arg 765 Lys Arg His Ala Ile 845 Glu PCT/USOO/24591 Arg Val 400 Asn Giu Val Glu Asp 480 Cys Pro Ser Giy Asn 560 Asn Giu Asn Aia Thr 640 Ser Pro ValI Leu Phe 720 Leu Asn Giu Ser Asp 800 Vali Thr Ile Arg Aia Thr Leu Leu Thr 855 69 87 WO 01/18207 WO 0118207PCTIUSOO/24591 Asp Tyr Pro Ser Ile Leu Met Asn Ser Thr Ala Leu Phe Leu Asn Leu Val Asp Gly Leu 900 Leu Ala Thr Phe 915 Ala Leu Val Lys Leu Leu Asp Trp Ilie Thr Ser Phe Asn 895 Ile Ala Val Leu Leu His Thr Trp, Met Glu Ala Ile Phe Phe Leu 910 Met Tyr Ile Ile Leu Lys Val Phe Tyr Ile Arg 930 Phe Cys 945 Leu Ala Ile le Gly Ser Arg Asn 965 Lys Giy Asp 980 Thr Cys Ala Leu Pro Ala Val Ser Val Asn Glu Val Lys Glu Ser Tyr Gly 975 Glu Val Met 1010 Giu Phe Cys Gin Asp Pro Gly Tyr 995 Phe Ile Val Val Met Phe Gly 1000 Val Gin Val Met Phe Ile Cys Gly 1020 Val Leu Arg Phe 1005 Arg Val Ile Phe 990 Leu Asn Ile Asn Gly Lys Arg Ser 1025 Val Val Asn Arg Thr Leu 1030 1015 A.rg Glu Glu Asn Leu Arg Ser Leu Thr Phe 1045 Leu Leu Gly 1035 Met Thr 1050 Phe Met Trp, Gly Phe Tyr Leu Phe 1070 Ser 1040 Ala Phe 1055 Ser Ile Phe Ala Trp Phe Asn Ser 1075 Gly Pro Leu Asn 1060 Ueu Gin Gly Lys Ile Pro 1065 Ile Asn Cys Thr 1080 <210> 49 <211> 3669 <212> DNA <213> homo sapiens <400> 49 atgatgtttc ctgttcttat tgccgagtgg tacccaaaca ataacattta cttgataatg aac tcaagtg ggtttcaatg ccc cagaca t agtgctttca gctttctcct ggctactttc gaaaaagaag ttgggctcta attagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc ggaattatct gtacagagca tatgtcgtta agcc ttgagg aatactaatt gatgaaggct gaggaaccca ccagacaagc gtaacctact gctcagatcg ttgctttata ttttgtccaa gccaggcttg acgact ttga gagagagcca cgaatgagat ccagctacat cagatgctta cactctgctt actcaaatgc tatccatttc acatttttgc ttggtgtaaa ttattcctgg aaggggacat acctcagctg caaacctagc cagcagcaga atagaatatc aggtggcaga atatcagttt atgagccaag tagaaggaaa tgaggctaca aaggctacta ctggcttttc ggggacctgt aatgtggagc tatcatgtgt cccttctggg catgtggacg cattgaagaa gactaaattt gcatgtgtcc cagagttgcc ccaggtatct tgaagcaacc atccttcaca tgattcaaaa agaaagcttt t ttcaaaaga gaatgggaaa ttataacttt taa tg tgaaa tctgaaagct actggccagc cgtagtgatt atggctcaat tcacctgagt g ttggtgct t aatcattcag tacagtgaat ctggccatct tgcttctcgg tgatatctcc tgccattgga gttcctcact acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aactatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc cagaacatcc tcaaccttcc gctggagagg tgggcccttc cagaagctcc gtgagacaac atccaacctt atatgttttt aactgtttaa aatggaagcc cagtgtgggg ctccatgcta ccaccggtta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat t cgact ggca taagctgtgg tggggaccct ttcgtcaccc aaaattggaa acaagattaa tagtttacaa taaaaaataa tgggtcattg ctgaatacgt acaatgctac aagaagcaaa cagtcctctc atgtgccaac ccctaacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgat tggaca ggccaagagt acctgtcaaa gaataattct tgattctacc aaatgaaatt gaatgccaaa aaatgacttc ttcctacctg ctgtcaagat tgaggtaaaa ctacacggtt agtcaagaga tgctaccaac tgagtccttg tcttgccatg tcttccttgt caacccattg tgaagttgct 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 87 WO 01/18207 WO 0118207PCTUSOO/24591 aaccagattt attgtggaac tcaactctaa tcatcttctg acatcacatg gggacaaatg cagatggatt ttacttgaga ttcaacaaaa gtgatggcgt aaaatcaaac aacaaaaaca gatgcaagtg ct tccaagaa tatattgggt tttgagaaat ctgttcctga ctttgcattg gggctagaag cgatacattc gttctagcga ggtgatgaat tt tggagtca gggaggaatg agtgtggtta ggaccct taa tttatattca ctctgctgtg atcatcaaga aactcaacct agccacacag gatcaaacat gctcattcag aagttttaa taaatttaac aggtcaaaag tgaatatatt aagctttaaa tgaatattac caatttcaaa ttgagagtgg atttaagtcc C tggaCt t tt gcagtattgg atacaagaaC aaagt tttgg agacagtctg gtgcctCaca gtggaatatc tgcgaaggga atctcctctt ctgttgcagt caattcacat taaaattctg gcagaaacaa tctgttggat tgttttttct gcaagagaag gcttgaCctt atatcccctt tcttccactg gtagatttcg aaagttctga atcttaca tc acagtgcttc caatcatccc acaacttcta tgc tgatggg aat tgtgaat ttctaatatc aacaattgat aactcggaac ttttagcatt acaagtggat agaagattct ccaggatgta aaacattact tcaggaag tg aggatggaac cctgtgtaac gttagatgca tgc tat tttt t tatccctcc cctcctagat cctgttgcat gtacattgct catcat tggc caatgaagtc tcaagatcca gaacattgcc caaccggaCC tctgttgggc catgtacCtc tgctatgaag gttagcagat taatctagga caaatctaaa catggacaag tgtcca tcag taaaaatatt cagaacttaa aaagaagaaa ttaagcagtt gaattggcct ttggctctca ggtcttccaa ccactggcat gtattagtta ggaccccaaa atccagaatc catcatccca acgtcaggat cacttcacac agaaacacta tcagcagcaa aaaatcttga ggctggatca ttcttccttc ctagttaaag tggggtttgc tatggaaaag gtcatatttt atgttcattg ctgagagaag atgacatggg ttctccatct gagaatgttc aactcagatt aaatctttgt tccagctcta tccttgtcaa gtcattgata atcatgtcag cctcagccaa acattgatat.

cagacagtga tcaagataga gCgtatCatc gcaataatga ctgtaatttt gaagagcaca gaaaaacttt tgaaggatcC tctgtgcctt gtgt tgcaca actttggagt aagtCctcaC ctctcctgac tgaacc tgag cctccttcaa tggcaacct t tatttaacac ctgcct tag t aaagttatgg atgtgacctg tggtaatggt aagtgttaag gttttgcatt tcaattcatt agaaacagtg ggagtaagaC cttcaagctc ccacctattt aactggceCa aggtcaaggg acaccttcag tattaCCaac aacacttggc c ,ttgcttgag cctaaatagC cctgttacca atcgtatttc gcctcCaaaC gtttactttc agtgagttat tgttcaaata ctgggatctg cagagattca tctgatggaC tttcatcagc atatgttgct cacagccctg tgtggatgga tacctggatg ttacattcgc ggtgtcagtt gaaagaaaaa tgctgggtat gcagatctgt gaacctgcgc ctttgcctgg acaaggctta gcggcggcat agctaccaat cattggttcc caaaaggaat tgctgatgga ttattgcaat ccacagcaca 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3669 <210> <211> 1222 <212> PRT <213> homo sapiens <400> Met Met Phe 1 Pro Ser Pro His Ser Val.

Ser Gly Thr Arg Ser Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys Leu Leu Phe Leu Phe Tyr Ile Met Trp Gly Cys Ala Phe Thr Ser Pro Arg Val Val Tyr Pro Gin Ala Cys Met Trp Leu Arg Ala Pro Asn ASP Thr Gly Ala Pro Thr Phe Asn Asp Phe ASP Ile Glu Cys Val Pro Ser Asn Pro Pro Asn Ser Ile Ile Gin Cys Ile Tyr Phe Cys Giy 110 Giu Met His Phe Asn Ala Val Ile Leu 160 Ser Ile Ser Ser Leu Ser 100 Thr Ala Lys 115 Ser Phe Ser Leu Asp Asn Gly Gly Leu Ser Phe Gin Thr Lys Ser Ser Val Ser Asp Ile Gin Lys 130 Ser Tyr Aia Asn 125 Lys Gly 140 Gin Lys Ala Lys Ile Arg Vai Ser Leu Arg Asn Gin Thr Ser Asp 165 Tyr Gin Val 71 87 WO 01/18207 PCT/USOO/2459 1 Ile Pro Giu Leu Ser Ala Phe Thr Leu Cys Phe Glu Ala Thr Lys Val 180 185 190 Gly His Giu Asp Ser Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser 195 200 205 Phe Thr Gin Leu Leu Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu 210 215 220 Ser Ilie Ser Asp Ser Lys Cys Leu Leu Ann Asn Ala Leu Pro Val Lys 225 230 235 240 Glu Lys Giu Asp Ile Phe Ala Giu Ser Phe Giu Gin Leu Cys Leu Vai 245 250 255 Trp Asn Asn Ser Leu Gly Ser Ilie Gly Val Asn Phe Lys Arg Asn Tyr 260 265 270 Giu Thr Vai Pro Cys Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn 275 280 285 Gly Lys Leu Leu Leu Gly Ser Asn Gin Ann Giu Ile Val Ser Leu Lys 290 295 300 Gly Asp Ile Tyr Asn Phe Arg Leu Trp, Asn Phe Thr Met Asn Ala Lys 305 310 315 320 Ilie Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Asn Val Vai Asp Trp 325 330 335 Gin Ann Asp Phe Trp Asn Ilie Pro Asn Leu Aia Leu Lys Aia Glu Ser 340 345 350 Ann Leu Ser Cys Giy Ser Tyr Leu Ile Pro Leu Pro Ala Ala Glu Leu 355 360 365 Ala Ser Cys Ala Asp Leu Gly Thr Leu Cys Gin Asp Gly Ile Ile Tyr 370 375 380 Arg Ile Ser Val Val Ile Gin Asn Ilie Leu Arg His Pro Giu Val Lys 385 390 395 400 Val Gin Ser Lys Val Ala Giu Trp, Leu Asn Ser Thr Phe Gin Asn Trp, 405 410 415 Asn Tyr Thr Val Tyr Val Val Asn Ile Ser Phe His Leu Ser Ala Giy 420 425 430 Giu Asp Lys Ile Lys Vai Lys Arg Ser Leu Giu Asp Giu Pro Arg Leu 435 440 445 Val Leu Trp Ala Leu Leu Val Tyr Asn Ala Thr Asn Asn Thr Asn Leu 450 455 460 Giu Gly Lys Ile Ilie Gin Gln Lys Leu Leu Lys Ann Ann Giu Ser Leu 465 470 475 480 Asp Giu Giy Leu Arg Leu His Thr Val Asn Val Arg Gin Leu Gly His 485 490 495 Cys Leu Ala Met Glu Giu Pro Lys Gly Tyr Tyr Trp Pro Ser Ile Gin 500 505 510 Pro Ser Giu Tyr Val Leu Pro Cys Pro Asp Lys Pro Giy Phe Ser Ala 515 520 525 Ser Arg Ile Cys Phe Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp, 530 535 540 Gly Pro Val Asp Ile Ser Asn Cys Leu Lys Giu Ala Asn Giu Val Ala 545 550 555 560 Asn Gin Ile Leu Asn Leu Thr Aia Asp Giy Gin Asn Leu Thr Ser Ala 565 570 575 Asn Ilie Thr Asn Ile Val Giu Gin Vai Lys Arg Ile Val Asn Lys Giu 580 585 590 Giu Asn Ile Asp Ile Thr Leu Giy Ser Thr Leu Met Asn Ilie Phe Ser 595 600 605 Asn Ilie Leu Ser Ser Ser Asp Ser Asp Leu Leu Giu Ser Ser Ser Giu 610 615 620 Ala Leu Lys Thr Ile Asp Giu Leu Ala Phe Lys Ile Asp Leu Asn Ser 625 630 635 640 Thr Ser His Val Asn Ile Thr Thr Arg Ann Leu Ala Leu Ser Val Ser 645 650 655 Ser Leu Leu Pro Gly Thr Asn Ala Ile Ser Asn Phe Ser Ilie Gly Leu 660 665 670 Pro Ser Ann Asn Giu Ser Tyr Phe Gin Met Asp Phe Giu Ser Giy Gin 72 87 WO 01/18207 WO 0118207PCT/USOO/2459 I 675 680 685 Val Asp Pro Leu Ala Ser Val Ile Leu Pro Pro Asn Leu Leu Giu Asn 690 695 700 Leu Ser Pro Giu Asp Ser Val Leu Vai Arg Arg Ala Gin Phe Thr Phe 705 710 715 720 Phe Asn Lys Thr Gly Leu Phe Gin Asp Val Gly Pro Gin Arg Lys Thr 725 730 735 Leu Val Ser Tyr Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gin 740 745 750 Asn Leu Lys Asp Pro Val Gin Ile Lys Ile Lys His Thr Arg Thr Gin 755 760 765 Glu Val His His Pro Ilie Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys 770 775 780 Ser Phe Gly Gly Trp Asn Thr Ser Gly Cys Val Ala His Arg Asp Ser 785 790 795 800 Asp Ala Ser Glu Thr Val Cys Leu Cys Asn His Phe Thr His Phe Giy 805 810 815 Val Leu Met Asp Leu Pro Arg Ser Ala Ser Gin Leu Asp Ala Arg Asn 820 825 830 Thr Lys Val Leu Thr Phe Ile Ser Tyr Ile Gly Cys Gly Ile Ser Ala 835 840 845 Ile Phe Ser Ala Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu 850 855 860 Arg Arg Asp Tyr Pro Ser Lys Ile Leu Met Asn Leu Ser Thr Ala Leu 865 870 875 880 Leu Phe Leu Asn Leu Leu Phe Leu Leu Asp Gly Trp Ilie Thr Ser Phe 885 890 895 Asn Vai Asp Giy Leu Cys Ile Ala Val Ala Val Leu Leu His Phe Phe 900 905 910 Leu Leu Ala Thr Phe Thr Trp, Met Giy Leu Giu Ala Ile His Met Tyr 915 920 925 Ile Ala Leu Val Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu 930 935 940 Lys Phe Cys Ile Ile Gly Trp Giy Leu Pro Ala Leu Val Val Ser Val 945 950 955 960 Val Leu Ala Ser Arg Asn Asn Asn Giu Vai Tyr Giy Lys Giu Ser Tyr 965 970 975 Gly Lys Glu Lys Gly Asp Giu Phe Cys Trp Ile Gin Asp Pro Val Ile 980 985 990 Phe Tyr Val Thr Cys Ala Gly Tyr Phe Gly Val Met Phe Phe Leu Asn 995 1000 1005 Ile Ala Met Phe Ilie Vai Val Met Val Gin Ile Cys Gly Arg Asn Gly 1010 1015 1020 Lys Arg Ser Asn Arg Thr Leu Arg Glu Giu Val Leu Arg Asn Leu Arg 1025 1030 1035 1040 Ser Val Val Ser Leu Thr Phe Leu Leu Gly Met Thr Trp, Giy Phe Ala 1045 1050 1055 Phe Phe Ala Trp Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser 1060 1065 1070 Ile Phe Asn Ser Leu Gin Gly Leu Phe Ilie Phe Ilie Phe His Cys Ala 1075 1080 1085 Met Lys Glu Asn Val Gin Lys Gin Trp Arg Arg His Leu Cys Cys Gly 1090 1095 1100 Arg Phe Arg Leu Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn 1105 1110 1115 1120 Ile Ilie Lys Lys Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser 1125 1130 1135 Ser Ile Gly Ser Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser 1140 1145 1150 Ser Thr Thr Tyr Phe Lys Arg Asn Ser His Thr Asp Ser Ala Ser Met 1155 1160 1165 Asp Lys Ser Leu Ser Lys Leu Ala His Ala Asp Gly Asp Gin Thr Ser 1170 1175 1180 73 87 WO 01/18207 WO 0118207PCTIUSOO/24591 Ile Ilie Pro Val His Gin Val Ile Asp Lys Val Lys Gly Tyr Cys Asn 1185 1190 1195 1200 Ala His Ser Asp Asn Phe Tyr Lys Asn Ile Ile Met Ser Asp Thr Phe 1205 1210 1215 Ser His Ser Thr LYS Phe 1220 <210> 51 <211> 3582 <212> DNA <213> homo sapiens <400> 51 atgatgtttc ctgttcttat tgccgagtgg tacccaaaca ataacattta cttgataatg aac tcaagtg ggtttcaatg ccccagacat agtgctttca gctttctcct ggctactttc gaaaaagaag t tgggctc ta attagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc ggaattatct gtacagagca tatgtcgtta agccttgagg aatactaatt gatgaaggct gaggaaccca ccagacaagc gtaacctact aaccagat tt attgtggaac tcaactctaa tcatcttctg acatcacatg gggacaaatg cagatggatt ttacttgaga ttcaacaaaa gtgatggcgt aaaatcaaac aacaaaaaca gatgcaagtg cttccaagaa tatattgggt tttgagaaat ctgttcctga ctttgcattg gggctagaag cgatacattc gttc tagcga ggtgatgaat gctcagatcg aatgtggagc ttgctttata tatcatgtgt ttttgtccaa cccttctggg gccaggcttg catgtggacg acgactttga cattgaagaa gagagagcca gactaaattt cgaatgagat gcatgtgtcc ccagctacat cagagttgcc cagatgctta ccaggtatct cactctgctt tgaagcaacc actcaaatgc atccttcaca tatccatttc tgattcaaaa acatttttgc agaaagcttt ttggtgtaaa tttcaaaaga ttattcctgg gaatgggaaa aaggggacat ttataacttt acctcagctg taatgtgaaa caaacctagc tctgaaagct cagcagcaga actggccagc atagaatatc cgtagtgatt aggtggcaga atggctcaat atatcagttt tcacctgagt atgagccaag gttggtgctt tagaaggaaa aatcattcag tgaggctaca tacagtgaat aaggctacta ctggccatct ctggcttttc tgcttctcgg ggggacctgt tgatatctcc taaatttaac tgctgatggg aggtcaaaag aattgtgaat tgaatatatt ttctaatatc aagctttaaa aacaattgat tgaatattac aactcggaac caatttcaaa ttttagcatt ttgagagtgg acaagtggat atttaagtcc agaagattct ctggactttt ccaggatgta gcagtattgg aaacattact atacaagaac tcaggaagtg aaagttttgg aggatggaac agacagtctg cctgtgtaac gtgcctcaca gttagatgca gtggaatatc tgctattttt tgcgaaggga ttatccctcc atctcctctt cctcctagat ctgttgcagt cctgttgcat caattcacat gtacattgct taaaattctg catcattggc gcagaaacaa caatgaagtc tctgttggat tcaagatcca tgccattgga gttcctcact acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aactatgaaa ttgt tgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc cagaacatcc tcaaccttcc gctggagagg tgggcccttc cagaagctcc gtgagacaac atccaacctt atatgttttt aactgtttaa cagaacttaa aaagaagaaa ttaagcagtt gaattggcct ttggctctca ggtcttccaa ccactggcat gtattagtta ggaccccaaa atccagaatc catcatccca acgtcaggat cacttcacac agaaacac ta tcagcagcaa aaaatcttga ggctggatca ttcttccttc ctagttaaag tggggtttgc ta tggaaaag gtcatatttt aatggaagcc cagtgtgggg ctccatgcta ccaccggtta gcatttatga ctgccaaagg act ttagca t ggaatcaaaa gcatc tc tat atgaagacag gtt ttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat tcgactggca taagctgtgg tggggaccct ttcgtcaccc aaaattggaa acaagattaa tagtttacaa taaaaaataa tgggtcattg ctgaatacgt acaatgctac aagaagcaaa cctcagccaa acattgatat cagacagtga tcaagataga gcgtatcatc gcaataatga ctgtaatttt gaagagcaca gaaaaacttt tgaaggatcc tctgtgcctt gtgt tgcaca act ttggagt aagtcctcac ctctcctgac tgaacctgag cctccttcaa tggcaacct t tatttaacac ctgccttagt aaagttatgg atgtgacctg cagtcctctc atgtgccaac ccctaacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acctgtcaaa gaataattct tgat tc tacc aaa tgaaat t gaatgccaaa aaatgacttc ttcctacctg ct gt caaga t tgaggtaaaa c tacacggtt agtcaagaga tgctaccaac tgagtccttg tcttgccatg tcttccttgt caacccattg tgaagt tgc t tattaccaac aacact tggc cttgcttgag cctaaatagc cctgttacca atcgtatttc gcctccaaac gtttactttc agtgagttat tgttcaaata ctggga tctg cagagat tca tctgatggac tttcatcagc atatgttgct cacagccctg tgtggatgga tacctggatg ttacattcgc ggtgtcagtt gaaagaaaaa tgctgggtat 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 74 87 WO 01/18207 WO 0118207PCT/USOO/2459 1 tttggagtca gggaggaa tg agtgtggt ta ggacccttaa tttatattca ctctgctgtg atcatcaaga aactcaacct agccacacag tgcttccatg tgttttttct gaacattgcc atgttcattg gcaagagaag caaccggacc ctgagagaag gcttgacctt tctgttgggc atgacatggg atatcccctt catgtacctc ttctccatct tcttccactg tgctatgaag gagaatgttc gtagatttcg gttagcagat aactcagatt aaagttctga taatctagga aaatctttgt atcttacatc caaatctaaa tccagctcta ataatgtctc ctatgagcat tccttcaaca gacaagtcct tgtcaaaact ggcccatgct tggtaatggt gcagatctgt aagtgttaag gaacctgcgc gttttgcatt ctttgcCtgg tcaattcatt acaaggctta agaaacagtg gcggcggcat ggagtaagac agctaccaat cttcaagctc cattggttcc ccacctattt caaaaggaat aaagtggatc actcagacag ga 3060 3120 3180 3240 3300 3360 3420 3480 3540 3582 <210> 52 <211> 1193 <212> PRT <213> homo sapiens <400> 52 Met Met Phe Arg Ser 1 5 Pro Ser Pro Leu Leu His Ser Val Trp Gly Ser Gly Thr Phe Thr Gin Ala Cys Met Trp Ilie Thr Phe Asn Asp Asp Ser Leu Ser Leu 100 Ala Thr Ala Lys dly 115 Val Ser Phe Ser Ser 130 Ser Tyr Ilie Arg Val 145 Pro Gin Thr Ser Asp 165 Ilie Pro Giu Leu Ser 180 Gly His Glu Asp Ser 195 Phe Thr Gin Leu Leu 210 Ser Ile Ser Asp Ser 225 Glu Lys Giu Asp Ile 245 Trp Asn Asn Ser Leu 260 Giu Thr Val Pro Cys 275 Gly Lys Leu Leu Leu 290 Gly Asp Ile Tyr Asn 305 Ile Leu Ser Asn Leu 325 Gin Asn Asp Phe Trp 340 Asn Leu Ser Cys Gly 355 Arg Met Leu Phe Ala Asn 40 Pro Cys 55 Leu Arg Asp Ilie Asn Giy Ser Phe 120 Phe Ser 135 Val Ser Tyr Gin Phe Thr Trp, Thr 200 Phe Gly 215 Cys Leu Ala Glu Ser Ile Scr Thr 280 Ser Asn 295 Arg Leu Cys Asn Ile Pro Tyr Leu 360 Ser Cys Leu Tyr Arg Val Pro Asn Pro Thr Giu Ala Ser Gin Ser Ser Gin Lys Arg Asn 155 Ser Val 170 Cys Phe Phe Ser Ala Lys Asn Asn 235 Phe Giu 250 Vai Asn Ser Lys Asn Giu Asn Phe 315 Lys Gly 330 Leu Ala Pro Leu His Trp Ile Met Vai Leu Asp Tyr Gly Tyr Pro Asn Thr Lys Ala Asn 125 Lys Gly 140 Gin Lys Ala Lys Glu Ala Tyr Scr 205 Ser Gly 220 Ala Leu Gln Leu Phe Lys Val Ile 285 Ile Val 300 Thr Met Asn Val Leu Lys Pro Ala 365 Lys Cys Ser Pro Ile Cys Phe 110 Giu Phe Val Ser Thr 190 Asn Tyr Pro Cys Arg 270 Pro Ser Asn Val Ala 350 Ala 87 WO 01/18207 WO 0118207PCTIUSOO/24591 Ala Arg 385 Val1 Asn Giu Val1 Giu 465 Asp Cys Pro Ser Gly 545 Asn Asn Giu Asn Ala 625 Thr Ser Pro Val Leu 705 Phe Leu Asn Giu Ser 785 Asp Val Thr Ile Arg Ser 370 Ilie Gin Tyr

ASP

Leu 450 Gly Glu Leu Ser Arg 530 Pro Gin Ile Asn Ilie 610 Leu Ser Leu Ser Asp 690 Ser Asn Val Leu Val 770 Phe Ala Leu Lys Phe 850 Arg Ala Asp Leu Gly 375 Vai Val Ile Gin 390 Lys Vai Ala Giu 405 Val Tyr Val Val 420 Ile Lys Val Lys Ala Leu Leu Val 455 Ile Ile Gin Gin 470 Leu Arg Leu His 485 Met Giu Glu Pro 500 Tyr Val Leu Pro Cys Phe Tyr Asn 535 Asp Ile Ser Asn 550 Leu Asn LeU Thr 565 Asn Ile Val Giu 580 Asp Ile Thr Leu Ser Ser Ser Asp 615 Thr Ile Asp Giu 630 Val Asn Ilie Thr 645 Pro Gly Thr Asn 660 Asn Giu Ser Tyr Leu Ala Ser Val 695 Giu Asp Ser Vai 710 Thr Gly Leu Phe 725 Tyr Val Met Ala 740 Asp Pro Vai Gin His Pro Ile Cys 775 Gly Trp, Asn Thr 790 Giu Thr Val Cys 805 Asp Leu Pro Arg 820 Leu Thr Phe Ile Ala Ala Thr Leu 855 Tyr Pro Ser Lys Thr Leu Cys Gin Asp Gly Ile Ile Tyr 380 Leu Asn 410 Ser Leu Al a Leu Asn 490 Tyr Asp Asn Lys Giy 570 Lys Thr Leu Phe Asn 650 Ser Met Pro Arg Val 730 Ile Ile Trp Cys Asn 810 Ser Ile Tyr Met His Thr His

ASP

Asn 460 Asn Arg Trp Pro Leu 540 Ala Asn Ile Met Giu 620 Ile Ala Phe Phe Asn 700 Ala Pro Asn His Leu 780 Ala Phe Leu Cys Ala 860 Leu 76 87 WO 01/18207 WO 0118207PCT/USOO/2459 I Leu Phe Leu Asn Leu Leu Phe Leu Leu 885 Asn Val Asp Gly Len Cys Ile Ala Val 900 905 Leu Leu Ala Thr Phe Thr Trp Met Gly 915 920 Ile Ala Leu Val Lys Val Phe Asn Thr Trp Ile Thr 880 Ser Phe 895 Val Leu Leu Leu Giu Ala Ile His Phe Phe 910 His Met Tyr Tyr Ile Leu Tyr Ile 935 Cys Ile Ile Gly Trp,Gly Leu Pro Ala 955 Val Val Ser Leu Ala Ser Gly Lys Giu Phe Tyr Val 995 Ile Ala Met 1010 Lys Arg Ser Lys Gly Asp 980 Thr Cys Ala Phe Ilie Val Asn Asn Giu Glu Phe Cys 985 Gly Tyr Phe 1000 Val Met Val 1015 Val1 Tyr Gly Lys Giu Ser Tyr 975 Ile Gin Asp Pro Val Ile 990 Gly Val Met Gin Ile Cys 1020 ?he Phe Leu Asn 1005 ;ly Arg ASn Giy Asn Arg 1025 Ser Val Val Ser Len 1045 Thr Leu Arg Giu Giu Val Leu Arg Asn Leu Arg 1030 1035 1044 Thr Phe Len Leu Gly Met Thr Trp Gly Phe Ala 1050 1055 Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser 1065 1070 Gin Gly Leu Phe Ile Phe Ile Phe His Cys Ala 1080 1085 0 Phe Phe Ala Ilie Phe Asn 1075 Trp Gly 1060 Ser Leu Met Lys 1090 Arg Phe 1105 Ile Giu Asn Val Gin Lys Gin Trp Arg Arg His Len Cys Cys Gly 1095 1100 Arg Leu Ala Asp Asn Ser Asp Trp, Ser Lys Thr Ala Thr Asn 1110 1115 1120 Lys Lys Ser Ser Asp Asn Leu Gly Lys Ser Len Ser Ser Ser 1125 1130 1135 Gly Ser Asn Scr Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ile Ser Ile 1140 Tyr Phe Ser Thr Thr 1145 Lys Arg Asn Ser 1160 Lys Ser Gly Ser 1155 His Thr Asp Leu Arg Gin 1180 1150 Asn Val 1165 Cys Phe Ser Tyr His Gly Giu His Ser 1170 Gin Val Leu 1185 Phe Asn Val Lys Thr 1190 1175 Gly Pro Cys <210> 53 <211> 2073 <212> DNA <213> homo sapiens <400> 53 atgatgtt tc ctgttcttat tgccgagtgg tacccaaaca ataacattta cttgataatg aactcaagtg ggtttcaatg ccccagacat agtgctt tca gctttctcct ggctactttc gaaaaagaag ttgggctcta attagtaaag gctcagatcg ttgctttata ttttgtccaa gccaggct tg acgactttga gagagagcca cgaatgagat ccagctacat cagatgctta cactctgctt actcaaatgc tatccatttc acatttttgc t tggtgtaaa ttattcctgg aatgtggagc tatcatgtgt cccttctggg catgtggacg cat tgaagaa gactaaattt gCatgtgtcc cagagttgcc ccaggtatct tgaagcaacc atccttcaca tgattcaaaa agaaagcttt tttcaaaaga gaatgggaaa tgccattgga gttcctcact acctttactt ctccgagccc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gttgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aactatgaaa t tgt tg ttgg aatggaagcc cagtgtgggg ctccatgcta ccacc gg tta gcatttatga ctgccaaagg actttagcat ggaatcaaaa gca tctc tat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gc tccaatca cagtcctctc atgtgccaac ccc taacgac tatcattcag ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acctgtcaaa gaataattct tgattctacc aaatgaaatt 77 87 WO 01/18207 WO 0118207PCTUSOO/2459 I gtctctctaa atcctctcca.

tggaatatcc atcccgctcc ggaattatct gtacagagca tatgtcgtta agccttgagg aatactaatt gatgaaggct gaggaaccca ccagacaagc gtaacctact aaccagattt attgtggaac tcaactctaa tcatcttctg acatcacatg gggacaaatg caggtaatga aaggggaca t acctcagctg caaacctagc cagcagcaga atagaatatc aggtggcaga atatcagttt at gagccaag tagaaggaaa tgaggctaca aaggctacta.

ctggcttttc ggggacctgt taaatttaac aggtcaaaag tgaatatatt aagctttaaa.

tgaatattac caatttcaaa gccagtggt t ttataac ttt taatgtgaaa.

tctgaaagct ac tggccagc cgtagtgatt atggctcaat tcacc tgagt gttggtgctt aatcattcag tacagtgaat ctggccatct tgctt Ct cgg tgatatctcc tgctgatggg aattgtgaat ttctaatatc aacaattgat aactcggaac ttttagcatt tctttcattt cgactttgga gggaatgtag gaaagcaacc tgtgcagacc cagaacatcc t caa cc ttc c gctggagagg tgggccc ttc cagaagc tcc gtgagacaac atccaacctt atatgttttt aactgtttaa cagaacttaa aaagaagaaa ttaagcagtt gaattggcct ttggctctca.

ggtcttccaa taa.

attttaccat tcgactggca taagc tgtgg tggggaccct ttcgtcaccc aaaat tggaa acaagat taa tagtttacaa taaaaaataa tgggtcattg ctgaatacgt acaatgc tac aagaagcaaa.

cctcagccaa.

acattgatat cagacagtga tcaagataga.

gcgtatcatc gcaataatga gaatgccaaa aaatgacttc ttcctacctg ctgtcaagat tgaggt~aaaa ctacacggtt agtcaagaga tgc tac caac tgagtccttg tcttgccatg tcttccttgt caacccattg tgaagttgct tattaccaac aacacttggc cttgcttgag cctaaatagc cctgttacca atcgtatttc 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2073 <210> 54 <211> 690 <212> PRT <213> homo sapiens <400> 54 Met Met Phe Arg Ser Asp Arg Met Pro Ser Pro Leu Leu Phe Leu Phe His Ser Val Trp Gly Cys Ala Asn Ser GlY Thr Phe Thr Ser Pro Cys Trp Ser Cys His Trp Lys Trp Lys 10 Ala Leu Tyr Ile Met Cys Val Pro 25 Cys Arg Val Val Leu Ser Asn Pro Tyr Pro Asn Pro Asn Ser Gin Ala Cys Met Trp Thr Ile Thr Phe Asn Asp Phe Akrg Ala Pro Tyr Ile Ile Asp Ilie Giu Ala Pro Asn Asp Ser Leu Ala Thr Ala 115 Val Ser Phe Asp Asn Gly Giu Ser Gin Thr Lys Cys Ile Tyr Phe Cys Gly 110 Glu Met His Phe Asn Ala Gly Leu Ser Ser Asp Phe Ser Ser Ala Asn 130 Ser Tyr 145 Pro Gin Ilie Pro Ile Arg Val Thr Ser Asp 165 Giu Leu Ser Val Tyr Ser Ile Gin Lys Ser Leu Arg Asn 155 Gin Val Ser Val 170 Thr Leu Cys Phe Lys Vai Ile Ala Lys Giu Ala Ala Phe Ser Asp Trp Thr Ser Ile Ser 175 Thr Lys Val 190 Asn Ala Ser Tyr Phe Leu Gly His Glu 195 Phe Thr Gin Phe Ser Tyr Leu Leu Ser Lys Ala Lys Ser 225 Giu Ser Asp Ser Leu Leu Asn Asn 235 Glu Leu Pro Val Lys Glu Asp Ala Giu Ser Gin Leu Trp Asn Asn Giu Thr Val 275 Leu Gly Ser Ile Asn Phe Lys Cys Leu Val 255 Arg Asn Tyr 270 Pro Gly Asn Cys Asp Ser Ser Lys Val 78 87 WO 01/18207 WO 0118207PCT[USOO/2459 I Gly Lys Leu Leu Leu Gly Ser Asn Gin Asn Giu Ile Val Ser Leu LYS 290 295 300 Gly Asp Ile Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asn Ala Lys 305 310 315 320 Ile Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Asn Val Val Asp Trp 325 330 335 Gin Asn Asp Phe Trp Asn Ilie Pro Asn Leu Ala Leu Lys Ala Giu Ser 340 345 350 Asn Leu Ser Cys Gly Ser Tryr Leu Ilie Pro Leu Pro Ala Ala Giu Leu 355 360 365 Ala Ser Cys Ala Asp Leu Giy Thr Leu Cys Gin Asp Gly Ile Ile Tyr 370 375 380 Arg Ilie Ser Val Vai Ile Gin Asn Ile Leu Arg His Pro Giu Val Lys 385 390 395 400 Val Gin Ser Lys Val Ala Giu Trp, Leu Asn Ser Thr Phe Gin Asn Trp, 405 410 415 Asn Tyr Thr Val Tyr Vai Vai Asn Ile Ser Phe His Leu Ser Aia Gly 420 425 430 Giu Asp Lys Ile Lys Val Lys Arg Ser Leu Giu Asp Giu Pro Arg Leu 435 440 445 Vai Leu Trp Aia Leu Leu Vai Tyr Asn Ala Thr Asn Asn Thr Asn Leu 450 455 460 Giu Gly Lys Ilie Ile Gin Gin Lys Leu Leu Lys Asn Asn Giu Ser Leu 465 470 475 480 Asp Giu Giy Leu Arg Leu His Thr Val Asn Vai Arg Gin Leu Giy His 485 490 495 Cys Leu Ala Met Giu Giu Pro Lys Gly Tyr Tyr 'Prp Pro Ser Ile Gin 500 505 510 Pro Ser Giu Tyr Val Leu Pro Cys Pro Asp Lys Pro Gly Phe Ser Ala 515 520 525 Ser Arg Ile Cys Phe Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp 530 535 540 Giy Pro Val Asp Ile Ser Asn Cys Leu Lys Giu Aia Asn Giu Val Ala 545 550 555 560 Asn Gin Ile Leu Asn Leu Thr Ala Asp Gly Gin Asn Leu Thr Ser Ala 565 570 575 Asn Ilie Thr Asn Ile Val Giu Gin Val Lys Arg Ile Vai Asn Lys Giu 580 585 590 Giu Asn Ilie Asp Ile Thr Leu Gly Ser Thr Leu Met Asn Ile Phe Ser 595 600 605 Asn Ile Leu Ser Ser Ser Asp Ser Asp Leu Leu Giu Ser Ser Ser Giu 610 615 620 Ala Leu Lys Thr Ilie Asp Giu LeU Ala Phe Lys Ile Asp Leu Asn Ser 625 630 635 640 Thr Ser His Val Asn Ile Thr Thr Arg Asn Leu Ala Leu Ser Vai Ser 645 650 655 Ser Leu Leu Pro Giy Thr Asn Ala Ile Ser Asn Phe Ser Ile Giy Leu 660 665 670 Pro Ser Asn Asn Giu Ser Tyr Phe Gin Val Met Ser Gin Trp, Phe Leu 675 680 685 Ser Phe 690 <210> <211> 3255 <212> DNA <213> homo sapiens <400> atgatgtttc gctcagatcg aatgtggagc tgCCattgga aatggaagcc cagtcctctc ctgttcttat ttgctttata tatCatgtgt gttcctcact cagtgtgggg atgtgccaac 120 tgacgagtgg ttttgtccaa cccttctggg acctttactt ctccatgcta ccctaacgac 180 tacccaaaca gccaggcttg catgtggacg ctccgagccc ccaccggtta tatcattcag 240 79 87 WO 01/18207 WO 0118207PCTIUSOO/2459 I ataacattta cttgataatg aactcaagtg ggtttcaatg ccccagacat agtgctttca gctttctcct ggctactttc gaaaaagaag ttgggctcta at tagtaaag gtctctctaa atcctctcca tggaatatcc atcccgctcc ggaattatct gtacagagca tatgtcgtta agcct tgagg aatactaatt gatgaaggct gaggaaccca ccagacaagc gtaacctact aaccagattt attgtggaac tcaactctaa tcatcttctg acatcacatg gggacaaatg cagatggatt ttacttgaga ttcaacaaaa gtgatggcgt aaaatcaaac aacaaaaaca gatgcaagtg cttccaagaa tatattgggt tttgagaaat ctgttcctga ctttgcattg gggctagaag cga taca ttc gttctagcga ggtgatgaat tttggagtca gggaggaatg agtgtggtta ggacccttaa ataaattgta acgactttga gagagagcca cgaatgagat ccagctacat cagatgctta cactctgctt actcaaatgc tatccatttc acatttttgc ttggtgtaaa ttattcctgg aaggggacat acctcagctg caaacctagc cagcagcaga atagaatatc aggtggcaga atatcagttt atgagccaag tagaaggaaa tgaggctaca aaggctacta ctggcttttc ggggacctgt taaatttaac aggtcaaaag tgaatatatt aagctttaaa tgaatattac caatttcaaa t tgagagtgg atttaagtcc ctggactttt gcagtattgg atacaagaac aaagttttgg agacagtctg gtgcctcaca gtggaatatc tgcgaaggga atctcctctt ctgttgcagt caattcacat taaaattctg gcagaaacaa tctgttggat tgttttttct gcaagagaag gcttgacctt atatcccctt catga cattgaagaa gactaaattt gCatgtgtcc cagagttgcc ccaggtatc t tgaagcaacc atccttcaca Lgat tcaaaa agaaagcttt tttcaaaaga gaatgggaaa ttataacttt taatgtgaaa tctgaaagct actggccagc cgtagtgatt atggctcaat tcacctgagt gttggtgctt aatcattcag tacagtgaat ctggccatct tgcttctcgg tgatatctcc tgctgatggg aattgtgaat ttctaatatc aacaattgat aac tcggaac ttttagcatc acaagtgga t agaagat tct ccaggatgta aaacattact t caggaagtg aggatggaac cctgtgtaac gttagatgca tgctattttt ttatccctcc cctcctagat cctgttgcat gtacattgct catcattggc caatgaagtc tcaagatcca gaacattgcc caaccggacc tctgt tgggc catgtacctc gctcccaatt tgtggagcaa ttttcaagtg gtgtccttaa gt tgcaaaaa aaagttggcc caattgctca tgtttgttga gaacagctct aactatgaaa ttgttgttgg cgactttgga gggaatgtag gaaagcaacc tgtgcagacc cagaacatcc tcaaccttcc gctggagagg tgggcccttc cagaagc tcc gtgagacaac atccaacctt atatgttttt aactgtttaa cagaacttaa aaagaagaaa ttaagcagtt gaattggcct ttggctctca ggtcttccaa ccac tggcat gtattagtta ggaccccaaa a tcc agaat c catcatccca acgtcaggat cacttcacac agaaacacta tcagcagcaa aaaatcttga ggctggatca ttcttccttc ctagttaaag tggggtttgc tatggaaaag gtcatatttt atgttcattg c tgagagaag atgacatggg ttctccatct gcatttatga ctgccaaagg actttagcat ggaatcaaaa gcatctctat atgaagacag gttttggaaa ataatgcatt gccttgtttg cagttccatg gctccaatca attttaccat tcgac tggca taagctgtgg tggggaccct ttcgtcaccc aaaat tggaa acaagat taa tagtttacaa taaaaaataa tgggtcattg ctgaatacgt acaatgctac aagaagcaaa cctcagccaa acattgatat cagacagtga tcaagataga gcgtatcatc gcaataatga ctgtaatttt gaagagcaca gaaaaacttt tgaaggatcc tctgtgcctt gtgttgcaca actttggagt aagtcctcac ctctcctgac tgaacctgag cctccttcaa tggcaacctt tatttaacac ctgccttagt aaagttatgg atgtgacctg tggtaatgg t aagtgttaag gttttgcatt tcaattcatt ctcattatcc cctatcattt ccagaagaaa ggtcatttta tccagagctc tgattggaca ggccaagagt acc tgtcaaa gaataattct tgattctacc aaatgaaatt gaatgccaaa aaatgacttc ttcctacctg ctgtcaagat tgaggtaaaa ctacacggtt agtcaagaga tgc taccaac tgagtccttg tcttgccatg tcttccttgt caacccattg tgaagttgct tat taccaac aacacttggc cttgcttgag cctaaatagc cctgttacca atcgtatt tc gcctccaaac gtttactttc agtgagttat tgt tcaaata ctgggatctg cagagattca tctgatggac t ttcatcagc atatgttgct cacagccc tg tgtggatgga tacctggatg ttacattcgc ggtgtcagtt gaaagaaaaa tgctgggtat gcagatctgt gaacc tgcgc ctttgcctgg acaaggtaag 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3255 <210> 56 <211> 1084 <212> PRT <213> homo sapiens <400> 56 Met Met Phe Arg Ser Asp Arg Met Trp Ser Cys 1 5 10 Pro Ser Pro Leu Leu Phe Leu Phe Ala Leu Tyr 25 His Ser Val Trp Gly Cys Ala Asn Cys Arg Val His Trp Lys Trp Lys Ile met Cys Val Pro Val Leu Ser Asn Pro 87 WO 01/18207 Ser Gin Ile Asp Ala Vai Ser 145 Pro Ile Gly Phe Ser 225 Glu Trp Glu Gly Gly 305 Ile Gin Asn Ala Arg 385 Val Asn Giu Val Giu 465 Asp Cys Pro Ser PCTUSOO/24591 Ser Gin Tyr Gly His Ala Leu 160 Ser Val1 Ser Leu Lys 240 Val1 Tyr Asn Lys Lys 320 Trp, Ser Leu Tyr Lys 400 Trp Gly Leu Leu Leu 480 His Gin Ala Trp 81 87 WO 01/18207 Gly Pro Val 545S Asn Gin Ile Asn Ile Thr Giu Asn Ile 595 Asn Ile Leu 610 Ala Leu Lys 625 Thr Ser His Ser Leu Leu Pro Ser Asn 675 Val Asp Pro 690 Leu Ser Pro 705 Phe Asn Lys Leu Val Ser Asn Leu Lys 755 Giu Val His 770 Ser Phe Gly 785 Asp Ala SerI Val Leu Met Thr Lys Val 835 Ile Phe Ser 850 Arg Arg Asp 865 Leu Phe Leu Asn Val Asp Leu Leu Ala 915 Ile Ala Leu1 930 Lys Phe Cys 945 Val Leu Ala Giy Lys Giu I Phe Tyr Val 995 Ilie Ala Met 1010 Lys Arg Ser 1025 Ser Val Val PCTIUSOO/2459 I Ile Asn 565 Ile Ile Ser Ile Asn 645 Giy Giu Ala Asp Giy 725 Val Pro Pro Trp, Thr 805 Leu Thr Ala Pro Leu 885 Leu Phe Lys Ile Arg 965 Gly Cys Ilie Arg Leu Asn Cys Leu Thr Ala Asp Giu Gin Val 585 Leu Gly Ser 600 Asp Ser Asp 615 Giu Leu Ala Thr Thr Arg Asn Aia Ilie 665 Tyr Phe Gin 680 Val Ile Leu 695 Val Leu Val Phe Gin Asp Ala Cys Ser 745 Gin Ile Lys 760 Cys Ala Phe 775 Thr Ser Gly Cys Leu Cys Arg Ser Ala 825 Ile Ser Tyr 840 Leu Leu Thr 855 Lys Ile Leu Phe Leu Leu Ile Ala Val 905 Trp Met Gly 920 Phe Asn Thr 935 Trp Gly Leu Asn Asn Giu Giu Phe Cys 985 Giy Tyr Phe 1000 Vai Met Val 1015 Leu Arg Giu Lys Giu 555 Giy Gin 570 Lys Arg Thr Leu Leu Leu Phe Lys 635 Asn Leu 650 Ser Asn Met Asp Pro Pro Arg Arg 715 Val Gly 730 Ile Giy Ile Lys Trp Asp Cys Val 795 Asn His 810 Ser Gin Ile Gly Tyr Vai Met Asn 875 Asp Gly 890 Ala Val Leu Giu Tyr Ilie Pro Ala 955 Val Tyr 970 Trp Ile Gly Val Gin Ile Glu Val Ala Asn Giu Val Asn Leu Thr Ser 575 Ile Val Asn Lys 590 Met Asn Ile Phe 605 Giu Ser Ser Ser 620 Ile Asp Leu Asn Ala Leu Ser Val 655 Phe Ser Ile Gly 670 Phe Giu Ser Gly 685 Asn Leu Leu Glu 700 Ala Gin Phe Thr Pro Gin Arg Lys 735 Asn Ile Thr Ile 750 His Thr Arg Thr 765 Leu Asn Lys Asn 780 Ala His Arg Asp Phe Thr His Phe 815 Leu Asp Ala Arg 830 Cys Giy Ile Ser 845 Ala Phe Giu Lys 860 Leu Ser Thr Ala Trp Ile Thr Ser 895 Leu Leu His Phe 910 Ala Ile His Met 925 Arg Arg Tyr Ile 940 Leu Val Vai Ser Gly Lys Glu Ser 975 Gin Asp Pro Val 990 Met Phe Phe Leu 1005 Cys Giy Arg Asn 1020 Leu Arg Asn Leu Ala 560 Al a Giu Ser Giu Ser 640 Ser Leu Gin Asn Phe 720 Thr Gin Gin Lys Ser 800 Gly Asn Aia Leu Leu 880 Phe Phe Tyr Leu Val1 960 Tyr Ile Asn Giy Arg 1040 Ala 1030 1035 Thr Phe Leu Leu Gly Met Thr Trp Gly Phe 82 87 WO 01/18207 WO 0118207PCTIUSOO/2459 I 1045 1050 1055 Phe Phe Ala Trp Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser 1060 1065 1070 Ile Phe Asri Ser Leu Gin Gly Lys Ile Asn Cys Thr 1075 1080 <210> 57 <211> 3579 <212> DNA <213> homo sapiens <400> 57 atgtttcgct ttcttatttg cgagtggttt ccaaacagcc acatttaacg gataatggag tcaagtgcga ttcaatgcca cagacatcag gctttcacac ttctcctact tactttctat aaagaagaca ggctctattg agtaaagtta tctctaaaag ctctccaacc aatatcccaa ccgctcccag attatctata cagagcaagg gtcgttaata cttgaggatg actaatttag gaaggc ttga gaacccaaag gacaagcctg acctactggg cagattttaa gtggaacagg actc taatga tcttctgaag tcacatgtga acaaatgcaa.

atggat tttg cttgagaatt aacaaaactg atggcgtgca atcaaacata aaaaacaaaa gcaagtgaga cc aagaag tg attgggtgtg gagaaattgc ttcctgaatc tgcattgctg ctagaagcaa tacattctaa ctagcgagca gatgaattct ggagtcatgt cagatcgaat ctttatatat tgtccaaccc aggcttgcat actttgacat agagccagac atgagatgca gctacatcag atgcttacca tctgctttga caaatgcatc ccatttctga tttttgcaga gtgtaaattt ttcctgggaa gggacattta.

tcagctgtaa acctagctct cagcagaact gaatatccgt tggcagaatg tcagttttca agccaaggtt aaggaaaaat ggctacatac gctactactg gcttttctgc gacctgttga atttaactgc tcaaaagaa t atatattttc ctttaaaaac atattacaac tttcaaattt agagtggaca taagtccaga gacttttcca gtattggaaa caagaactca gttttggagg cagtctgcct cctcacagtt gaatatc tgc gaaggga t a tcCtcttcct ttgcagtcct ttcacatgta aattctgcat gaaacaacaa gttggattca tttttctgaa gtggagctgc catgtgtgtt ttctgggacc gtggacgctc tgaagaagc t taaattttgt tgtgtccttt agttgccgtg ggtatctgtt agcaaccaaa cttcacacaa ttcaaaatgt aagctttgaa caaaagaaac tgggaaat tg taactttcga tgtgaaaggg gaaagctgaa ggccagctgt agtgattcag gctcaattca cctgagtgct ggtgctttgg cat tcagcag agtgaatgtg gccatctatc ttctcggata tatctccaac tgatgggcag tgtgaataaa taatatctta aattgatgaa tcggaacttg tagcattggt agtggatcca aga ttc tgta ggatgtagga cattactatc ggaagtgcat atggaacacg gtgtaaccac agatgcaaga tattttttca tccc Lccaaa cctagatggc gttgcatttc cattgctcta cattggctgg tgaagtctat agatccagtc cattgccatg cat tggaaat cctcactcag tttacttctc cgagccccca cccaattgca ggagcaactg tcaagtgact tccttaagga gcaaaaagca gttggccatg ttgctcagtt ttgttgaata cagctctgcc tatgaaacag ttgttgggct ctttggaatt aatgtzagtcg agcaacc taa gcagacctgg aacatccttc acct tccaaa ggagaggaca gcccttctag aagctcc taa agacaactgg caaccttctg tg Lt t ttaca tgtttaaaag aacttaacct gaagaaaaca agcagttcag ttggccttca gctctcagcg cttccaagca ctggcatctg ttagttagaa ccccaaagaa cagaa tctga catcccatct tcaggatgtg ttcacacact aacactaaag gcagcaactc atcttgatga tggatcacct ttccttctgg gttaaagtat ggtttgcctg ggaaaagaaa atattttatg ttcattgtgg ggaagcccag tgtggggatg catgctaccc ccggttatat tttatgactc ccaaaggcc t ttagcatcca atcaaaaggt tctctattcc aagacagtga ttggaaaggc atgcattacc ttgtttggaa ttccatgtga ccaatcaaaa ttaccatgaa ac tggcaaaa gctgtggttc ggaccctctg gtc accc tga attggaacta agattaaagt tttacaatgc aaaa taa tga gtcattgtct aatacgttct atgctaccaa aagcaaatga cagccaatat ttgatataac acagtgactt agatagacct tatcatccct ataatgaatc taattttgcc gagcacagtt aaactttagt aggatcctgt gtgccttctg ttgcacacag t tggag ttc t tcctcacttt tcctgacata acctgagcac ccttcaatgt caacctttac ttaacactta ccttagtggt gttatgggaa tgacctgtgc taatggtgca tcctc Lcctg tgccaac tgc taacgactac cattcagata attatccctt atcatttaac gaagaaaggt cattttaccc agagctcagt ttggacagct caagagtggc tgtcaaagaa taattctttg ttctaccatt tgaaattgtc tgccaaaatc tgacttctgg ctacctgatc tcaaga tgga.

ggtaaaagta cacggtttat caagagaagc taccaacaat gtccttggat tgccatggag tccttgtcca cccattggta agttgctaac taccaacatt acttggctca gcttgagtca aaatagcaca gttaccaggg gtatttccag tccaaac Lta tactttcttc gagttatgtg tcaaataaaa ggatctgaac agattcagat gatggacctt catcagctat tgttgctttt agccctgctg ggatggactt c tgga tgggg cattcgccga gtcagttgtt agaaaaaggt tgggtatttt gatctgtggg 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 83 87 WO 01/18207 PTUO/49 PCT/USOO/24591 aggaatggca gtggttagct cccttaaata atattcatct tgctgtggta atcaagaaaa tcaacctatc cacacagata ttccatggac agagaagcaa ccggaccctg agagaagaag tgttaaggaa cctgcgcagt tgacctttct gttgggcatg acatggggtt ttgcattctt tgcctgggga tccccttcat gtacctcttc tccatcttca attcattaca aggcttattt tccactgtgc tatgaaggag aatgttcaga aacagtggcg gcggcatctc gatttcggtt agcagataac tcagattgga gtaagacagc taccaatatc gttctgataa tctaggaaaa tctttgtctt caagctccat tggttccaac ttacatccaa atctaaatcc agctctacca cctatttcaa aaggaatagc atgtctccta tgagcattcc ttcaacaaaa gtggatcact cagacagtgc aagtccttgt caaaactggc ccatgctga 3120 3180 3240 3300 3360 3420 3480 3540 3579 <210> 58 <211> 1192 <212> PRT <213> homo sapiens <400> 58 Met 1e Ser Gly Ala Thr Ser Thr Ser Tyr 145 Gin Pro His Thr Ile 225 Lys Asn Thr Lys Asp 305 Leu Asn Leu Ser Phe Pro Val Thr Cys Phe Leu Ala Phe 130 Ile Thr Giu Glu Gin 210 Ser Glu Asn Val1 Leu 290 Ile Ser Asp Ser Cys Arg Leu Trp Phe Met Asn Ser Lys 115 Ser Arg Ser Leu Asp 195 Leu Asp Asp Ser Pro 275 Leu Tyr Asn Phe Cys 355 Ala Ser Leu 20 Gly Thr Trp Asp Leu 100 Giy Ser Val1 Asp Ser 180 Ser Leu Ser Ile Leu 260 Cys Leu Asn Leu Trp 340 Gly Asp Met Phe Asn Cys Arg Ile Gly Phe Ser 135 Ser Gin Thr Thr Gly 215 Leu Giu Ile Thr Asn 295 Leu Asn Pro Leu Thr Ser Leu 25 Arg Pro Pro Glu Ser 105 Ser Gin Arg Ser Cys 185 Phe Ala Asn Phe Val1 265 Ser Asn Asn Lys Leu 345 Pro Cys Trp, Vai Asn Asn Ile Ile Cys 110 Met Asn Ile le Lys 190 Ala Phe Val1 Leu Asn 270 Giy Leu Ala Asp Glu 350 Glu Ile Lys Pro Pro Se r Gin Tyr Gly His Ala Leu Ser 175 Val Ser Leu Lys Val 255 Tyr Asn Lys Lys Trp 335 Ser Leu Tyr 84 87 WO 01/18207 PCT/USOO/24591 370 375 380 Ile Ser Val Val Ilie Gin Asn Ile Leu Arg His Pro Giu Val Lys Val 385 390 395 400 Gin Ser Lys Val Ala Giu Trp Leu Asn Ser Thr Phe Gin Asn Trp Asn 405 410 415 Tyr Thr Val 'ryr Val Val Asn Ile Ser Phe His Leu Ser Ala Gly Giu 420 425 430 Asp Lys Ile Lys Val Lys Arg Ser Leu Giu Asp Giu Pro Arg Leu Val 435 440 445 Leu Trp Ala Leu Leu Val Tyr Asn Ala Thr Asn Asn 'rhr Asn Leu Giu 450 455 460 Gly Lys Ile Ile Gin Gin Lys Leu Leu Lys Asn Asn Giu Ser Leu Asp 465 470 475 480 Glu Gly Leu Arg Leu His Thr Val Asn Val Arg Gin Leu Giy His Cys 485 490 495 Leu Aia Met Giu Giu Pro Lys Gly Tyr Tyr Trp Pro Ser Ile Gin Pro 500 505 510 Ser Giu Tyr Val Leu Pro Cys Pro Asp Lys Pro Gly Phe Ser Ala Ser 515 520 525 Arg Ilie Cys Phe Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp Gly 530 535 540 Pro Val Asp Ile Ser Asn Cys Leu Lys Giu Ala Asn Giu Vai Ala Asn 545 550 555 560 Gin Ilie Leu Asn Leu Thr Ala Asp Gly Gin Asn Leu Thr Ser Ala Asn 565 570 575 Ile Thr Asn Ile Val Giu Gin Val Lys Arg Ile Val Asn Lys Giu Giu 580 585 590 Asn Ilie Asp Ile Thr Leu Gly Ser Thr Lea Met Asn Ile Phe Ser Asn 595 600 605 Ile Leu Ser Ser Ser Asp Ser Asp Leu Leu Giu Ser Ser Ser Giu Ala 610 615 620 Leu Lys Thr Ile Asp Giu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr 625 630 635 640 Ser His Val Asn Ilie Thr Thr Arg Asn Lea Ala Leu Ser Val Ser Ser 645 650 655 Leu Leu Pro Gly Thr Asn Ala Ile Ser Asn Phe Ser Ile Gly Leu Pro 660 665 670 Ser Asn Asn Giu Ser Tyr Phe Gin Met Asp Phe Giu Ser Gly Gin Val 675 680 685 Asp Pro Leu Ala Ser Val Ile Leu Pro Pro Asn Leu Leu Giu Asn Lea 690 695 700 Ser Pro Giu Asp Ser Val Leu Val Arg Arg Ala Gin Phe Thr Phe Phe 705 710 715 720 Asn Lys Thr Gly Leu Phe Gin Asp Val Gly Pro Gin Arg Lys Thr Lea 725 730 735 Val Ser Tyr Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gin Asn 740 745 750 Leu Lys Asp Pro Val Gin Ile Lys Ile Lys His Thr Arg Thr Gin Glu 755 760 765 Val His His Pro Ile Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser 770 775 780 Phe Gly Gly Trp Asn Thr Ser Giy Cys Val Ala His Arg Asp Ser Asp 785 790 795 800 Ala Ser Giu Thr Vai Cys Leu Cys Asn His Phe Thr His Phe Gly Val 805 810 815 Leu Met Asp Leu Pro Arg Ser Ala Ser Gin Leu Asp Ala Arg Asn Thr 820 825 830 Lys Val Leu Thr Phe Ile Ser Tyr Ile Gly Cys Giy Ile Ser Ala Ile 835 840 845 Phe Ser Ala Ala Thr Leu Leu Thr Tyr Val Ala Phe Giu Lys Leu Arg 850 855 860 Arg Asp Tyr Pro Ser Lys Ilie Leu Met Asn Leu Ser Thr Ala Leu Leu 865 870 875 880 87 WO 01/18207 WO 0118207PCTUSOO/24591 Phe Leu Asn Leu Phe Leu Leu Asp Trp Ile Thr Ser Phe Asn 895 Val Asp Gly Leu Ala Thr 915 Leu 900 Phe Ile Ala Val Leu Leu His Thr Trp Met Giu Ala Ile Phe Phe Leu 910 Met Tyr Ile Ile Leu Lys Ala Leu 930 Phe Cys Val Lys Val Phe Ile Ile Gly Trp Asn 935 Tyr Ile Arg Ala Ser Arg Asn Glu Lys Glu Lys Tyr Val Thr 995 Gly Leu Pro Ala Asn Glu Val Tyr 970 Phe Cys Trp Ile 985 Tyr Phe Gly Val 1000 Met Val Gin Ile 1015 Leu 955 Gly Lys Glu Ser Tyr Gly 975 Val Ser Val Gin Asp Pro Vai Ile Phe 990 Ala Gly Met Plie Phe Leu Asn Ile 1005 Ala Met 1010 Arg Ser2 ?he Ile Val Val Asn Arg 1025 Val Val Ser Leu Thr Leu Arg Glu Giu Val 1030 Thr Phe Leu Leu Gly Met 1045 1050 Pro Leu Asn Ile Pro Phe 1065 Cys Gly Arg Asn 1020 Leu Arg Asn Leu 1035 Thr Trp Giy Phe Gly Lys Arg Ser 1040 Ala Phe 1055 Ser Ile Phe Ala Trp Gly 1060 M4et Tyr Leu Phe 1070 Phe Asn Ser Leu Gin Gly Leu Phe Ile Phe Ile Phe His Cys Ala Met 1075 1080 1085 Lys Glu Asn Val Gin Lys Gin Trp, Arg Arg His Leu Cys Cys, Gly Arg 1090 1095 1100 Phe Arg Leu Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile 1105 1110 1115 1120 Ile Lys Lys Ser Ile Gly Ser Asn 1140 Thr Thr Tyr Phe 1155 His Ser Phe Asn Ser Asp 1125 Ser Thr Asn Leu Gly Tyr Leu Thr Lys Ser 1130 Ser L.ys Lys Arg Asn 1145 Ser His Thr Asp 1160 Ser Leu Arg Gin Leu Ser Ser Ser Lys Ser 1150 Asn Val Ser 1165 Cys Phe His 1180 Ser Ser 1135 Ser Ser Tyr Glu Gly Gin Lys Ser Gly 1170 Val Leu Val 1185 Lys Thr Gly 1190 1175 Pro Cys <210> 59 <211> 4446 <212> DNA <213> homo sapiens <400> 59 ttgcgccgtc ggcgcagggc gtggtggagg aacaaggagt ctccggaatc ccattggaaa tcctcactca ctttacttct cc gagcc ccc tcccaat tgc tggagcaact ttcaagtgac gtcc ttaagg tgcaaaaagc agttggccat at tgctcagt gggaaagccc tggggcgcct atgatcttgc aacaggcacc aacacctggg tggaagccca gtgtggggat cca tgctacc accggt tata at tta tgac t gccaaaggcc tttagcatcc aatcaaaagg atctctattc gaagacagtg tttggaaagg atgaactctc gggttccccc ggccaaaggg gctcctcagt ggc ttggaag gtcctctcct gtgccaactg ctaacgacta tcattcagat cattatccct.

tatcatttaa agaagaaagg tcattttacc cagagctcag attggacagc ccaagagtgg cagaaacggc tgggtggagc gacctcggcg ccaaaggcct gatgt ttcgc gttcttattt ccgagtggtt cccaaacagc aacatttaac tgataatgga ctcaagtgcg tttcaatgcc ccagacatca tgc tt tcaca tttctcctac ctactttcta g taaaggagg agcggcagca cagtaatgtc ggccctgcca tcagatcgaa gctttatata ttgtccaacc caggct tgca gactttgaca gagagccaga aatgagatgc agctacatca gatgct tacc ctctgctttg tcaaatgcat tccatttctg gtcccgccgc gagcgggaaa aacataatta agaaggcgc t tgtggagctg tcatgtgtgt cttctgggac tgtggacgct t tgaagaagc c taaat t ttg atgtgtcctt gagttgccgt aggtatctgt aagcaaccaa ccttcacaca attcaaaatg 86 87 WO 01/18207 tttgttgaat acagc tctgc ctatgaaaca gttgttgggc actt tggaat gaatgtagtc aagcaaccta tgcagacctg gaacatcctt aacc ttccaa tggagaggac ggcccttcta gaagctccta gagacaac tg ccaaccttct atgtttttac ctgtttaaaa gaacttaacc agaagaaaac aagcagttca attggccttc ggc tetcagc tcttccaagc actggcatct attagttaga accccaaaga ccagaatctg tcatcccatc gtcaggatgt cttcacacac aaacactaaa agcagcaact aatcttgatg ctggatcacc c tt cc ttc tg agttaaagta gggtttgcct tggaaaagaa catattttat g t tcat tg tg gagagaagaa gacatggggt ctccatcttc gaatgttcag ctcagattgg atctttgtct cagc tc tacc cttcaacaaa cccatgctga agggttattg tcagccacag aagatttgca tgcatatata ttttaatata catgactcag ataatgcagg agatagagct ttctttctca aaaaaa PCTIUSOO/24591 aatgcattac ct tgt ttgga gttccatgtg tccaatcaaa tttaccatga gactggcaaa agctgtggtt gggaccctct cgtcaccc tg aattggaact aagattaaag gtttacaatg aaaaataatg ggtcattgtc gaatacgttc aatgctacca gaagcaaatg tcagccaata attgatataa gacagtgact aagatagacc gtatcatccc aataatgaat gtaattttgc agagcacagt aaaactttag aaggatcctg tgtgccttct gt tgcacaca tttggagttc gtcctcactt c tcctgaca t aacctgagca tccttcaatg gcaaccttta tttaacactt gccttagtgg agttatggga gtgacctgtg gtaatggtgc gtgttaagga tttgcattct aattcattac aaacagtggc agtaagacag tcaagc tcca acctatttca agtggatcac tggaga tcaa caatgc tcat cacaaagttt agcagtgtaa taaggaatg t tttcttccat tagccacaga ggagacattc cattttactc acaataaaaa ctgtcaaaga ataattcttt attctaccat atgaaattgt atgccaaaat atgacttctg cctacctgat gtcaagatgg aggtaaaagt acacggttta tcaagagaag ctaccaacaa agtccttgga ttgccatgga ttccttgtcc acccattggt aagttgctaa ttaccaacat cacttggctc tgcttgagtc taaatagcac tgttaccagg cgtatttcca ctccaaactt ttactttctt tgagttatgt ttcaaataaa gggatctgaa gagattcaga tgatggacct tcatcagc ta atgttgcttt cagccctgct tggatggact cc tggatggg acattcgccg tgtcagttgt aagaaaaagg ctgggtattt agatctgtgg acctgcgcag ttgcctgggg aaggcttatt ggcggcatct ctaccaatat ttggttccaa aaaggaatag tcagacagtg acatcaatca tcagacaact taatgtcttt actgcaacta attttgttaa ggaagagttg agctatgatt aaattagaga cacctaatcg atgtaactat aaaagaagac gggctctatt tagtaaagt t ctctctaaaa cctctccaac gaatatccca cccgctccca aattatc tat acagagcaag tgtcgttaat ccttgaggat tactaattta tgaaggcttg ggaa ccc aaa agacaagcct aacctactgg ccagatttta tgtggaacag aactctaatg atcttctgaa atcacatgtg gacaaatgca gatggatttt act tgagaat caacaaaact gatggcgtgc aatcaaacat caaaaacaaa tgcaagtgag tccaagaagt tattgggtgt tgagaaattg gttcctgaat ttgcattgct gctagaagca atacattcta tctagcgagc tgatgaattc tggagtcatg gaggaatggc tgtggt tagc acccttaaat tatattcatz ctgctgtggt catcaagaaa ctcaacctat ccacacagat cttccatgga tccctgtcca tctataaaaa aagaaaaaga gtgatgtaaa gaaggctttt tcatcactaa tgtaaaatat caagggagaa ttatatctgg tttgaatgcc atttttgcag ggtgtaaatt attcctggga ggggacattt ctcagctgta aacctagctc gcagcagaac agaatatccg gtggcagaat atcagttttc gagccaaggt gaaggaaaaa aggctacata ggctactact ggcttttctg ggacctgttg aatttaactg gtcaaaagaa aatatatttt gctttaaaaa aatattacaa atttcaaatt gagagtggac ttaagtccag ggacttttcc agtattggaa acaagaac tc agttttggag acagtctgc gcctcacagt ggaatatctg cgaagggatt ctcctcttcc gttgcagtcc attcacatgt aaattctgca agaaacaaca tgttggattc ttttttctga aagagaagca t tgacc tt tc atccccttca ttccactgtg agatttcggt agttctgata cttacatcca aatgtctCCt caagtccttg tcaggtcatt tattatcatg aatcaatctg tgtgctatta gtgaaattca aacttcagta ataattgaat gcaatgctga atatacccat cacaaaaaaa aaagctttga tcaaaagaaa atgggaaatt ataactttcg atgtgaaagg tgaaagctga tggccagc eg tagtgattca ggctcaattc acc tgagtgc tggtgctttg tcattcagca cagtgaatgt ggccatctat cttctcggat atatctccaa ctgatgggca ttgtgaataa ctaatatctt caattgatga ctcggaactt ttagcattgg aagtggatcc aagattctgt aggatgtagg acattactat aggaagtgca gatggaacac tgtgtaacca tagatgcaag ctattttttZ atccctccaa tcctaga tgg tgttgcattt acattgctct tcattggc tg atgaagtcta aagatccagt acattgccat accggaccct tgttgggcat tgtacctctt ctatgaagga tagcagataa atctaggaaa aatctaaatc atgagcattc tcaaaactgg gataaggtca tcagacacct cagaaatgtg cctaggtaac gaatttttct ctgagagtaa cagagtaatc ggaaga'ccct tttctgcatZ aaaaaaaaaa 1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2880 2940 3000 3060 3120 3180 3240 3300 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4446 87 87

Claims (6)

1. An isolated nucleic acid molecule comprising the contiguous nucleotide sequence first disclosed in the NGPCR nucleotide sequence described in SEQ ID NO: 1.

2. An isolated nucleic acid molecule having a contiguous nucleotide sequence that: encodes the amino acid sequence shown in SEQ ID NO: 2; and hybridizes under stringent conditions to the nucleotide sequence of SEQ ID NO: 1 or the complement thereof.

3. An isolated nucleic acid molecule having a contiguous nucleotide sequence that: encodes the amino acid sequence shown in SEQ ID NO: 4; and hybridizes under stringent conditions to the '20 nucleotide sequence of SEQ ID NO: 3 or the complement thereof.

4. An isolated nucleic acid molecule having a contiguous nucleotide sequence that: encodes the amino acid sequence shown in SEQ ID NO: 40; and S" hybridizes under stringent conditions to the nucleotide sequence of SEQ ID NO: 39 or the complement thereof.

An isolated nucleic acid molecule having a contiguous nucleotide sequence that: encodes the amino acid sequence shown in SEQ ID NO: 58; and 57 hybridizes under stringent conditions to the nucleotide sequence of SEQ ID NO: 57 or the complement thereof.

6. An expression vector comprising an isolated polynucleotide encoding the amino acid sequence presented in SEQ ID NO: 2. Se *e *o Se*** 58