MXPA01000980A - Delta-related polypeptides - Google Patents

Abstract

Nucleic acid sequences are disclosed which encode polypeptide members of the Delta family of mammalian membrane surface-bound ligands;such sequences can be used, among other things, for chromosome mapping and analysis and to produce the polypeptides in abundance by recombinant expression of the corresponding DNA molecules.

Description

RELATED DELTA POLYPEPTIDES Field of Invention This invention relates to new polypeptide members of mammalian cells that develop cycles of families of proteins known as "Delta", to the corresponding nucleic acids, and to methods for making and using the nucleic acid molecules and polypeptides.

Background of the Invention The Notch gene family encodes the transmembrane receptors that control the decisXorres of cell fate; see a review in Fleming et al., Trends in Cell Biology, Volume 7, pages 437-441 (1997).

Currently, at least four members of these families are known in humans, who are designated as Notchl, Notch2, Notch3 and Notch4; for reference, see Ellisen et al., Cell, Volume 66, pages 649-661 (1991); Katsanis et al., Genomic, Volume 35, pages 101-108 (1996); Joutel et al., The Lancet, Ref: 126840 Volume 350, pages 1511-1515 (1997); and Uyttendaele et al., Development, Volume 122, pages 2251-2259 (1996), respectively. Many of the known actions of signaling have been documented during the development of lower organisms, such as worms and flies, but now an increased attention is given to the role these receptors can play during embryogenesis mamifera; Lewis, Current Opinion in Neurobiology, Volume 6, pages 3-10 (1996). However, relatively little is currently known about the function of these receptors in the biology of the adult mammal.

Activation of Notch receptors can be executed that belong to the Delta and Jagged gene families. These gene products also contain transmembrane domains, and the interaction of the ligand with the receptor occurs more frequently through cell-to-cell contact. Perhaps the best documented case of Delta-Notch signaling occurs in the production of neural precursor cells in Drosophilia. Due to the absence of Delta-Notch signaling, it results in excessive cell production neuronal, this signaling pathway is intended to inhibit the differentiation of precursors in a process known as lateral specification; see Lewis, above. This process allows a population of cells that adopt a particular cell destination, while allowing adjacent cells to commit.

There are two Delta ligands reported for the mouse, named, Delta 1 type (also referred to as "Dlll") and Delta 3 type (also referred to as "D113"). These genes are expressed first in the neuroectoderm and the presomitic mesoderm, and are tried to function in the formation of the nervous and muscular systems that are therapeutic; see Dunwoodie and collaborators, Development, Volume 124, pages 3065-3076 (1997).

Brief description of the invention.

This invention is based on the discovery and isolation of novel nucleic acids encoding polypeptides of the mouse species and that can be considered members of the Delta family of ligands.

Previously, the vertebrate Notch ligands have been divided into two classes: Delta and Serrate; see Nye and Kopan, Current Biology, Volume 5, Number 9, pages 966-969 (1995). The polypeptide members of both families contain a signal sequence, an amino-terminal domain Delta-Serrate-Lag (DSL), a series of EGF-like repeats, and a single transmembrane domain (hydrophobic). Members of the Serrate family also contain a region rich in cysteine in the extracellular portion and inserts that interrupt some of the EGF-like repeats. Characteristics of the Delta class, full-length polypeptides, according to the present invention, contain a signal sequence, a DSL domain, EGF-like repeats, and a transmembrane domain, but do not contain inserts that interrupt some of the type repeats EGF or a region rich in extracellular cysteine. On the other hand, the amino acid sequence of the present murine polypeptide is approximately fifty percent identical to that of murine Dlll and the one similar to Dlll, contains other EGF-like repeats. Accordingly, the polypeptides of this invention can be considered members of the Delta family.

The highly specific expression pattern of the recently discovered murine gene within the vascular endothelium is coupled with the known actions of the other members of the Delta family, indicating a role for the present polypeptides in the control of the biology of the endothelial cell .

Studies related to Notch-Delta signaling in non-human species indicate that such receptor-ligand interactions focus on vertebrate neurogenesis and influence the development of precursor cells for the retina and central nervous system; Nye et al., Current Biology, and Lewis, Current Opinion in Neurobiology, above.

Other studies suggest that Notch signaling is also involved in the regulation of angiogenesis that induces fibroblast growth factor; Zimrin et al., Journal of Biological Chemistry, Volume 271, Number 51, pages 32499-32502 (1996). Furthermore, autosomal dominant cerebral anorexia with subcortical infarctions and leukoencephalopathy (CADASIL), an autosomal dominant disorder that causes ischemic infarcts in adults, has recently had traces of a mutational defect in the Notch3 gene. Joutel et al., Lancet, above.

Based on such information, the current understanding of the behavior of the Notch leads to believe that the Notch controls the ability of the precursor cells to progress to the next differential state, more similarly through interactions with ligands such as Delta, among others. In this way, the Delta polypeptides try to play a fundamental role in the development of the cell. On the other hand, the possibility that malfunctions in Notch-Delta signaling and Delta genes may result in one or more diseases or disorders suggest a fertile ground for further research and studies.

In view of the foregoing, the full length of the DNA sequences given herein, or subsequent thereof, can be used for the identification of chromosome and gene map (not different from EST), which is a utility of the present invention. In such applications, a primary goal will be to determine whether the gene falls within a known area of a chromosome linked to a disease or genetic disorder, and that the gene itself is responsible for the abnormality. Such studies can be carried out with the murine as well as human sequences. For example, information regarding the murine gene and its biology may be useful for understanding the human gene if it associates abnormalities with the gene in a mouse having counterparts in humans.

Other potential uses for the molecules of this invention are further outlined below, including the use of the polypeptides to identify a corresponding receptor or receptors (possibly in the Notch family). Still other uses of the nucleic acid and the polypeptide molecules of this invention will become clear over time, based on the further elucidation of the biological activity of the polypeptides of this invention, particularly in light of the present disclosure.

This invention also includes fragments and biologically active analogues of the aforementioned polypeptides, DNA molecules encoding such fragments and analogs, as well as derivatives of such polypeptides as described above.

Additionally, this invention includes vectors for the recombinant expression of the aforementioned nucleic acid molecules in heterologous host cells, as well as host cells that have been modified (e.g., by transfection or transformation) to contain such expression vectors.

In addition, this invention comprises methods for the recombinant production of the polypeptides, fragments and analogues mentioned above, including the steps of the expression of the polypeptide, fragment or analogue 'encoded by a DNA molecule in a host cell and collecting the resulting expression product.

In yet a further aspect of the invention, the present polypeptides can be used in methods and systems for the identification of receptors that are linked and / or activated by the polypeptides. Such receptors can be found, for example, on the surface of adjacent cells that come into contact or in proximity with the present polypeptides, which are membranes linked in their naturally occurring state.

Brief Description of the Figures FIGURE 1 (A-B). This figure describes the DNA sequence encoding a murine polypeptide of this invention. The portion encoding the transmembrane region of the murine polypeptide is underlined.

FIGURE 2. This figure describes the amino acid sequence for the murine polypeptide encoded by the DNA molecule of Figure 1A-1B, -including a putative signal peptide region (amino acids 1-22, 1-23, 1-24, 1-25, 1-26, or 1-27), a putative extracellular domain (amino acids 23-532, 24-532, 25-532, 26-532, 27-532, or 28-532), a transmembrane region (amino acids 533-553), and an intracellular / cytoplasmic portion (amino acids 554-686). The transmembrane region is underlined.

FIGURE 3 (A-B). This figure describes the DNA sequence encoding a human polypeptide of this invention. The portion encoding the transmembrane region of the polypeptide is underlined.

FIGURE 4. This figure describes the amino acid sequence for the human polypeptide encoded by the DNA molecule of Figure 3A-3B, including a putative signal peptide region (amino acids 1-23, 1-24, 1-25, or 1 -26, or 1-27, or 1-28), a putative extracellular domain (amino acids 24-531, 25-531, 26-531, 27-531, or 28-531, or 29-531), a region of transmembrane (amino acids 532-552), and a portion intracellular / cytoplasmic (amino acids 553-685). The transmembrane region is underlined.

FIGURE 5 (A-P). This figure describes the expression pattern of the RNA messenger (mRNA) for the murine polypeptide in various tissues of adult mice, as analyzed by in s i t u hybridization using a labeled riboprobeta FIGURE 6 (A-P). This figure describes the expression pattern of mRNA for the murine polypeptide in various adult mouse tissues, as analyzed by in si t u hybridization using a 33P labeled riboprobe.

FIGURE 7 (A-D). This figure describes the mRNA expression pattern for murine polypeptide in mouse embryos at ten and a half days (Figures A and B) and at eleven and a half days (Figures C and D) after fertilization, as analyzed by in situ hybridization using a 33P labeled riboprobe.

Detailed description of the invention.

As indicated, a novel member of the human Delta family, and its murine counterpart, is provided by this invention. This discovery results from the identification of polymerase chain reaction (PCR) fragments isolated from a white adipose tissue cDNA library. As illustrated by the working examples given below, the PCR fragments enable identification of the full length of the nucleic acid sequence encoding the murine polypeptide of this invention (SEQ ID NO: 1 and its predicted amino acid sequence ( SEQ ID NO: 2) Probes or tests prepared from the murine sequence are then used to display a human brain cDNA collection, starting from the isolation and identification of a complete length of the nucleic acid sequence (SEQ ID NO. : 3) which encodes a human polypeptide counterpart (SEQ ID NO: 4).

Using the hydrophobicity analysis, the leader sequence ("signal") for the polypeptide of murine is equated to comprise amino acids 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, or 1-27. the first amino acid of the "mature" polypeptide is equal to be 23 (Q), 24 (R), 25 (A), 26 (A), 27 (G), or 28 (S). The beginning of the transmembrane domain appears to be located at position 533 (V). The end of the transmembrane domain appears to be located at position 533 (V). At a minimum, what is necessary for biological activity is the extracellular domain of the mature polypeptide, specifically, amino acids 23 (Q), 24 (R), 25 (A), 26 (A), 27 (G), or 28 (S) through amino acid 532 (A). in this manner, the murine polypeptides according to this invention can include any of those having the following amino acids: (a) 1-686 (SEQ ID NO: 2), (b) 23-532 (SEQ ID NO: 5), (c) 24-532 (SEQ ID NO: 6), (d) 25-532 (SEQ ID NO: 7), (e) 26-532 (SEQ ID NO: 8), (f) 27-532 (SEQ ID NO: 9), (g) 28-532 (SEQ ID NO: 10), (h ) 23-553 (SEQ ID NO: 11), (i) 24-553 (SEQ ID NO: 12) (j) 25-553 (SEQ ID NO: 13) (k) 26-553 (SEQ ID NO: 14) (1) 27-553 (SEQ ID NO: 15) (m) 28-553 (SEQ ID NO: 16) (n) 23-686 (SEQ ID NO: 17) (o) 24-686 (SEQ ID NO: 18) (p) 25-686 (SEQ ID NO: 19) (q) 26-686 (SEQ ID NO: 20) (r) 27-686 (SEQ ID NO: 21) and (s) 28-686 (SEQ • ID NO: 22) with or without a methionyl residue of amino (N) -terminal (- 1).

The leader sequence ("signal") for the human polypeptide probably comprises amino acids 1-23, 1-24, 1-25, 1-26, 1-27 or 1-28. the first amino acid of the mature polypeptide is possibly 24 (A), 25 (A), 26 (G), 27 (S), or 28 (G), or 29 (V). The start of the transmembrane domain appears to be located at position 532 (V). The end of the transmembrane domain appears to be located at position 552 (V). At a minimum, the extracellular domain of the "mature" polypeptide, specifically, amino acids 24 (A), 25 (A), 26 (G), 27 (S), or 28 (G), or 29 (V) through amino acid 531 (A) . Therefore, the human polypeptides of this invention include those that have the following amino acids: (a) 1- 685 (SEQ ID NO: 4), (b) 24 -531 (SEQ ID NO: 23), (c) 25 -531 (SEQ ID NO: 24), (d) 26--531 ( SEQ ID NO: 25), (e) 27--531 (SEQ ID NO: 26), (f) 28--531 (SEQ ID NO: 27), (g) 29--531 (SEQ ID NO: 28 ), (h) 24--552 (SEQ ID NO: 29), (i) 25--552 (SEQ ID NO: 30), (j) 26--552 (SEQ ID NO: 31), (k) 27--552 (SEQ ID NO: 32), (1) 28--552 (SEQ ID NO: 33), (m) 29--552 (SEQ ID NO: 34), (n) 24--685 ( SEQ ID NO: 35), (o) 25--685 (SEQ ID NO: 36), (P) 26--685 (SEQ ID NO: 37), (q) 27--685 (SEQ ID NO: 38 ), (r) 28--685 (SEQ ID NO: 39), (s) 29-685 SEQ ID NO: 40), with or without an N-terminal methionyl residue (-1) Tissue distribution analysis in mice (Example 5, below) demonstrates that the presence of nucleic acid encoding the polypeptide is reasonably ubiquitous, with expression of the gene being high in the lung, followed by the heart, kidney, muscle skeleton and brain, and to a lesser extent, the spleen and testicles.

The present invention provides purified and isolated polypeptide products which have part or all of their conformation of primary structure (ie, continuous sequence of amino acid residues) and one or more of the biological properties (e.g., immunological properties and biological activity) and physical properties (e.g., molecular weight) of the polypeptides (human and murine) occurring naturally of this invention, including allelic variants thereof. The term "purified and asylated" in the present means that they are substantially Free of unwanted substances for the present polypeptides are useful for an intended purpose. For example, a recombinant polypeptide substantially free of other human (or murine) proteins or pathological agents can be had. These polypeptides are also characterized as being a product of mammalian cells, or the product of synthetic chemical process or of prokaryotic or eukaryotic host expression (for example, by bacteria cells, yeast, higher plants, insects and mammals in culture) of sequences Exogenous DNA obtained by genomic or cDNA cloning or by synthesis of the gene. The expression products in typical yeast host cells (eg, Sa ccha romyces cerevi s i a e), insect, or prokaryotic (e.g., E. col i) are free from association with any of the mammalian proteins. The expression products in vertebrate cells (for example, of non-human mammals such as COS or CHO, and birds) are free from association with any of the human (or murine) proteins. Depending on the host employed, and other factors, polypeptides in accordance This invention can be glycosylated with mammalian or other eukaryotic carbohydrates or can be non-glycosylated. The nucleic acid can be modified so that the glycosylation sites are included in the resulting polypeptide. It may be chosen to partially or completely de-glycosylate a glycosylated polypeptide. The polypeptides may also include an initial methionine amino acid residue (at position 1 relative to the first amino acid residue of the mature polypeptide).

In addition to the naturally occurring allelic forms of the polypeptide, the present invention also encompasses other products such as polypeptide analogs. For example, modifications of the cDNA and genomic genes can be readily performed by well-known site-directed mutagenesis techniques and employed to generate analogues that differ in the primary conformations specified herein in terms of the identity or location of one or more residues ( example, substitutions, additions and terminal and intermediate withdrawals). Such products share at least one of the biological properties of the polypeptide that occurs naturally, but may differ in others. As an example, the projected products of the invention include those that are reduced, for example, withdrawals (ie, fragments or subsequent); or those that are more stable to hydrolysis (and, therefore, may have more pronounced or longer effects than those that occur naturally); or those that are altered to remove one or more potential sites for glycosylation (which can result in high activities for products produced by yeast); or those that have one or more cysteine residues removed or replaced by, for example, alanine or serine residues and are potentially more easily isolated in active form from microbial systems; or those that have one or more tyrosine residues replaced by phenylalanine; or have an altered lysine composition (such as those prepared for derivation purposes). Included are those polypeptides with amino acid substitutions that are conservative in accordance with acidity, charge, hydrophobicity, polarity, size, or any other known characteristic. by those skilled in the art. The selection of amino acids may be changed so that such changes retain the overall unit or activity of the protein, as discussed in further detail below. The small amino terminal extensions, such as an amino-terminal methionine residue, a small peptide bond of up to about 20-25 residues, or a small extension that facilitates purification, such as a poly-histidine tract, an antigenic epitope or a link domain, can also be presented. See, in general, Ford et al., Protein Expression and Purification Volume 2, pages 95-107 (1991).

Soluble forms of the polypeptides of (a) above, human or murine, can also be prepared by the removal of the transmembrane and intracellular regions; see (B), above, in this regard.

Of particular interest herein is the human polypeptide (SEQ ID NO: 4) and its fragments, analogs and derivatives, as well as the DNA molecules that encode such polypeptides.

However, as will be seen, the murine counterpart (SEQ ID NO: 2) may also be useful for the same purpose or the like.

Polypeptide analogues.

In addition to the polypeptides of the particular sequences delineated above, and fragments thereof, analogues of such polypeptides that are biologically equivalent or share one or more biological properties are also attempted as part of this invention. By "biologically equivalent" it means that it has the same properties of the polypeptides described herein. Preferably, such analogs will cross-react with antibodies raised against the polypeptides of SEQ ID NO: 4 (or of SEQ ID NO: 2).

The term "analogue" as applied for the polypeptides of this invention, is specifically intended to mean molecules that represent one or more amino acid substitutions, withdrawals and / or additions derived from the linear order of the amino acids of the polypeptide of full length of SEQ ID NO: 4 (or of SEQ ID NO: 2), and which are also substantially biologically equivalent or share one or more biological properties.

Especially preferred polypeptide analogs according to this invention are those that possess a degree of homology (ie, identity of the amino acid residues) with the polypeptide of SEQ ID NO: 4 (or of SEQ ID NO: 2). ) or in an excess of eighty percent (80%), and more preferably, in an excess of ninety percent (90%) or ninety-five (95%).

The percentage of the identity sequence can be determined by standard methods that are commonly used to compare the similarity of the amino acids of two polypeptides in order to generate an optimal alignment of the two respective sequences. By way of illustration, using a computer algorithm such as BLAST. BLAST2, or FASTA, the two polypeptides for which the percent identity has been determined, are aligned for an optimal labeling of their respective amino acids (the "span of marked ", which may include the full length of one or both sequences, or only a predetermined portion of one or both sequences.) Each computer algorithm provides an opening penalty for" omission "and a space penalty for" omission ", and a marker matrix such as a PAM 250 (by FASTA) or BLSUM 62 (by BLAST algorithms.) A preferred algorithm for the purposes of this invention is BLAST2.

A standard marker matrix can be used in conjunction with the computer algorithm; see Dayhoff et al., Atlas of Protein Sequence and Structure, Volume 5, Supplement 3 (1978). The identity percentage can then be determined using an algorithm such as the content in FASTA, as follows: Total number of identical markers xlOO [Length of the longest sequence within the marked span] + [Number of holes entered in the longest sequences in order to align the two sequences] Analogous polypeptides according to this invention that are at least eighty percent identical to the "wild-type" sequence of Figure 4 (or Figure 2) will typically have one or more amino acid substitutions, withdrawals and / or insertions, compared to the wild type. Usually, the substitutions will be conservative so as to have little or no effect on the overall net charge, polarity or hydrophobicity of the polypeptide. Examples of conservative substitutions are placed below.

Table 1 Conservative Amino Acid Substitutions Basic: arginma lis ina histidine Acid: glutamine asparagine acid aspartic acid glutamine asparagine Hydrophobic leucine isoleucine valine Aromatic: phenylalanine tryptophan tyrosine Small: glycine alanine serine threonine methionine When substitutions (or omissions) of particular amino acid residues are made within the wild-type (ie, "native") amino acid sequence of the wild-type, relatively conservative substitutions are preferred so as not to adversely affect the desired biological properties to any degree substantial. Thus, for example, residues or regions that are known or expected to be involved in the specificity of the heparin receptor or link will generally be avoided if alterations in these sites remove these properties.

In general, fragments of polypeptides and analogs according to this invention will be useful for the same purposes for which the polypeptide of SEQ ID NO: 4 (or SEQ ID NO: 2) is useful.

Nucleic acids In accordance with another aspect of the present invention, the DNA sequences described herein that encode the polypeptides are useful for generating new and useful DNA vectors, transforming and transfecting prokaryotic and eukaryotic host cells (including bacterial cells, yeast cells , insect cells, and mammalian cells growing in culture), and methods for the growth culture of such host cells capable of having the expression of the polypeptides and related products.

In addition to (a) the DNA molecules of Figure 1A-1B (SEQ ID NO: 1) and Figure 3A-3B (SEQ ID NO: 3), the allelic variant which is intended as part of this invention is also tried (b) occur naturally of the same that 'encode the same polypeptides, (c) the DNA molecules that selectively hybridize any of such DNA sequences, and (d) the DNA molecules which, but for the degeneracy of the genetic code, can hybridize any of the DNAs of (a), (b) and (c).

The complementary sequences of the aforementioned DNA molecules, or subsequent ones thereof, can be used to display the cDNA or genomic libraries to isolate the nucleic acid molecules of SEQ ID NO: 1 and SEQ ID NO: 3 and variants allelics thereof occurring naturally for use in recombinant expression (or for modification as described above). Alternatively, the nucleic acid molecules encoding the same polypeptides can be prepared by chemical synthesis using methods well known to the skilled artisan, such as those described by Engels et al., In Angew. Chem. Intl. Ed., Volume 28, pages 716-734 (1989). Such methods include, among others, the phosphotries ter, phosphoramidite and H-phosphonate methods for the synthesis of nucleic acid. A preferred method involves the synthesis of the supported polymer using standard phosphoramidite chemistry. Usually, the DNA molecules encoding the polypeptides of this invention will be several hundred nucleotides in length. Nucleic acid molecules larger than about one hundred nucleotides can be synthesized as several fragments in accordance with these methods, and the fragments can be ligated together to form a full length molecule encoding the complete polypeptide.

Optionally, the portion of the DNA encoding the (N) amino terminus of the polypeptide will contain an "ATG" codon, which encodes a methionine residue.

The variant nucleic acid molecules have sequences that differ from those that occur naturally and which encode the polypeptide analogs according to this invention, can be produced using site-specific mutagenesis, PCR amplification, or other appropriate methods known to those skilled in the art.; see, for example, Sambrook and collaborators, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (1989). Such variants will also include those containing nucleotide substitions taken into account for the codon preference in the host cell that is used for the expression.

The present invention also encompasses nucleic acid molecules that can encode additional amino acid residues flanked in portions 5 and 3 of the region encoding the "mature" polypeptide (that is, the processed expression product collected from the host cell), such as the sequences encoding the alternative pre / pro regions (that is, sequences responsible for the secretion of the polypeptide through the membranes of the cell) instead of the "native" pre / pro regions. Additional sequences may also constitute uncoded sequences, including regulatory sequences such as transcription or transfer promoters, depending on the host cell. Nucleic acid molecules can still include several Internal uncoded sequences (introns) known to occur within genes.

The nucleic acid molecules of this invention (depending on the genes or cDNA) can be inserted into an appropriate expression or amplification vector using standard binding techniques. The vector is selected to be functional in the particular host employed (that is, the vector is compatible with host cell machinery, such that amplification and / or expression of the nucleic acid encoding the polypeptide can occur). The polypeptide, fragment or analog can be amplified or expressed in prokaryotic, yeast, insect (bacilovirus systems) and / or eukaryotic host cells, or in non-human transgenic animal species such as the host. The selection of the host cell will depend at least in part on whether the polypeptide expression product is glycosylated and / or phosphorylated. If glycosylation and / or phosphorylation is desired, then it is preferred to use yeast, insect or mammalian host cells, in which, yeast cells glycosylan- polypeptide, and mammalian and insect cells can glycosylate and / or phosphorylate the polypeptide in a manner similar to glycosylation and / or "native" phosphorylation.

The vectors used in any of the host cells to express the polypeptide may contain a flanking sequence (also referred to as a "promoter") and other expression regulatory elements operably linked to the nucleic acid (DNA) molecule to be expressed, as well as enhancers, an origin of replication element, a transcriptional termination element, a complete intron sequence containing a donor and acceptor binding site, a peptide signal sequence, a ribosome binding site element, a polylinked region for inserting the nucleic acid encoding the polypeptide to be expressed, and a selectable labeling element, as discussed in greater detail below.

Flange sequence 5 ' The 5 'flanking sequence may be the native 5' flanking sequence, or it may be homologous (ie, from the same species and / or strains as the host), heterologous (ie, that is, from a different species than the host). the species or strains of the host cell), hybridizes (that is, a combination of 5 'flanking sequences from more than one source), or synthetic. The source of the 5 'flanking sequence can be any prokaryotic or eukaryotic unicellular organism, any vertebrate or invertebrate organism, any plant, with the proviso that the flanking sequence 5' is functional in, and can be activated by, the machinery of the host cell.

The 5 'flanking sequences useful in the vectors of this invention can be obtained from any of several methods well known in the art. Typically, the 5 'flanking sequences useful herein are different from the flanking sequences that have been previously identified by representation and / or by the restriction of endonuclease digestion and can in this way isolate themselves from their own tissue source using the appropriate endonuclease restriction. In some cases, the complete nucleotide sequence of the 5 'flanking sequence may be known. In such a case, the flanking sequence 5 'can be synthesized using the methods described above.

Where all or only a portion of the 5 'flanking sequence is known, this can be obtained by PCR and / or by the sample from a genomic library with an appropriate oligonucleotide and / or 5' flanking sequence fragments of the same or other species. Where the 5 'flanking sequence is not known, a DNA fragment containing the 5' flanking sequence can be isolated from a large piece of DNA that can contain it, eg, a coding sequence or even another gene or genes. Isolation can be done by restricting endonuclease digestion using one or more carefully selected enzymes to isolate the DNA fragment itself. After digestion, the desired fragment can be isolated by agarose gel purification, or by other methods known to the skilled artisan. The selection of appropriate enzymes to accomplish this purpose will be readily apparent to one skilled in the art.

Origin of the Replication Element.

The origin of the replication element is typically a part of the commercially available prokaryotic expression vectors, and aids in the amplification of the vector in a host cell. Amplification of the vector for a certain number of copies may, in some cases, be important for optimal expression of the polypeptide. If the chosen vector does not contain a site of origin and replication, one can be synthesized chemically in a known sequence and then ligated to the vector.

Transcription of the Termination Element.

The transcription of the terminating element is typically located at the 3 'end of the polypeptide coding sequence and serves to terminate transcription of the polypeptide. Usually, the termination element of Transcription in prokaryotic cells is a fragment rich in G-C followed by a poly-T sequence. Although the element is easily cloned from a collection or even commercially purchased as part of a vector, it can also be easily synthesized using methods for nucleic acid synthesis such as those referred to above.

Selectable Bookmark Element The selectable marker gene element encodes a protein necessarily for the survival and growth of a host cell seeded in a select culture medium. Typical selection labeling genes encode proteins that (a) confer resistance to antibiotics or other toxins, eg, ampicillin, tetracycline or kanamycin for prokaryotic host cells, (b) complement auxotrophic cell deficiencies or (c) supply critical nutrients not available from complex means. Preferred selectable markers are the gene resistant to kanamycin, the ampicillin-resistant gene, and the tetracycline-resistant gene.

Ribosome Link Element The ribosome binding element, commonly called the Shine-Dalgarno sequence (for prokaryotes) or the Kosak sequence (for eukaryotes), is necessary to initiate mRNA transport. The element is typically located at 3 'for the promoter and at 5' for the coding sequence for the polypeptide to be synthesized. The Shine-Dalgarno sequence is varied, but typically it is a polypurine (that is, it has a high content of A-G). Many Shine-Dalgarno sequences have been identified, each of which can be easily synthesized using the methods referred to above and used in a prokaryotic vector.

Peptide Signal Sequence In those cases where it is desirable for the polypeptide to be secreted from the host cell, a sequence signal can be used to direct the polypeptide outside the host cell, and the carboxy-terminal portion of the polypeptide can be removed in order to prevent anchoring of a membrane. Typically, the signal sequence is placed in the encoded region of the nucleic acid sequence, or directly at the 5 'end of the encoded region. Many signal sequences have been identified, and any which is functional in the selection of the host cell can be used.

Transcription Promoter The transcription of the gene can be increased by the presence of one or more introns in the vector.

This is particularly valuable where the polypeptide is produced in eukaryotic host cells, especially mammalian host cells. The introns used can occur naturally within the gene, especially where the gene is used in a full length genomic sequence or a fragment thereof.

Where intron does not occur naturally within the gene (as in the case of most cDNAs), the introns can be obtained from another source.

The position of the intron with respect to the 5 'flanking sequence and the encoded nucleic acid sequence is generally important, as the intron must be transcribed to be effective. As such, where the nucleic acid is a cDNA molecule, the preferred position for the intron is the 3 'for the transcription start site, and the 5' for the polyA transcription termination sequence. Preferably, the intron will be located on one side or the other (this is 5 'or 3') of the cDNA in such a way that it does not interrupt this coding sequence. Any intron from any source, including any viral, prokaryotic and eukaryotic organisms (plants or animals), can be used, provided that it is compatible with the host cell into which it is inserted.

Where one or more of the elements placed above are not already present in the vector to be used, these can be obtained individually and ligated into the vector. The methods used to obtain each of the elements are well known by the skilled technician and are comparable with the methods placed previously (ie, DNA synthesis, selection of the library or collection, and the like).

Vector and Host Cell Preferred vectors for practicing this invention are those that are compatible with host cells of bacteria, insects, and mammals. Such vectors include, by way of illustration, pCRII, pCR3, and pcDNA3 (Invitrogen Company, San Diego, California), pBSII (Stratagene Company, La Jolla, California), pETl5b (Novagen, Madison, Wisconsin), pGEX (Pharmacia Biotech, Piscataway, New Jersey), and pEGFP-N2 (Clontech, Palo Alto, California).

After the vector has been constructed and the nucleic acid molecule has been encoded to the full-length or truncated polypeptide, or an analogue thereof, is inserted into the vector site itself, the entire vector can be inserted into an appropriate host cell for the amplification or expression of the polypeptide.

The host cells can be prokaryotic host cells (such as E. coli) or eukaryotic host cells (such as yeast, insect or vertebrate cells). The host cell, when cultured under appropriate nutrient conditions, synthesizes the polypeptide, which can subsequently be collected by isolating it from the culture medium (if the host cell secretes in the medium) or directly from the host cell (if it is not secreted). For the polypeptide located in the cytoplasm and / or nucleus of the host cell, the host cells are typically broken first mechanically or with a detergent to release the intracellular contents in a buffer solution. The polypeptide can then be collected from this solution. After the collection, the polypeptide can be purified using methods such as molecular sieve chromatography, affinity chromatography, and the like.

The selection of the host cell for the production of the polypeptide will depend in part on whether the polypeptide is to be glycosylated or phosphorylated (in which case eukaryotic host cells are preferred), and the manner in which the The host cell is able to "bend" the protein into its native tertiary structure (eg, proper orientation or disulfide bridges, etc.) in such a way that the biologically active protein is prepared by the cell. Even where the host cell does not synthesize the pOlyopeptide in its own conformation, the polypeptide can be "doubled" after synthesis using appropriate chemical conditions as discussed below.

Appropriate cells or cell lines can be mammalian cells, such as Chinese hamster ovary (CHO) cells or 3T3 cells. The selection of the appropriate mammalian host cells and the methods for transformation, culture, amplification, sample and product production and purification are known in the art. Other appropriate mammalian cell lines are the COS cell line COS-1 and COS-7, and the CV-1 cell line. Additional exemplary mammalian host cells include lines of primate cells and rodent cell lines, including transformed cell lines. Normal diploid cells, cell strains derived from the in vitro culture of primary tissue, as well as primary explants, are also appropriate. The candidate cells may be genotypically deficient in the selection of the gene or may contain a dominantly active selection gene. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa, mouse L-929 cells, 3T3 lines derived from Balb-c mouse or Swiss NIH, BHK or hamster cell lines. HaK.

Similarly useful as host cells are the bacterial cells. For example, several strains of E. coli (eg, HB101, DH5a, DH10, and MC1061) are well known as host cells in the field of biotechnology. Several strains of B. subtilis, Pseudomona s spp. , others Ba ci l l us spp. , S trep t omyces spp. , and the like can be used in this method.

Insertion of the vector into the selected host cells (also referred to as "transformation" or "transfection") can be performed using known materials or methods such as calcium chloride, electroporation, microinj ection, lipofection or the DEAE-dextran method.

Host Cell Culture The host cells containing the vector can be cultured using a standard means well known to the skilled artisan. The medium can usually contain all the nutrients necessary for the growth and survival of the transformed cells. The appropriate medium for culturing E. coli cells are, for example, Luria broth (LB) and / or Terry broth (TB). The appropriate medium for culturing eukaryotic cells are RPMI 1640, MEM, DMEM, all of which can be supplemented with serum and / or growth factors as required by the particular cell line to be cultured. An appropriate medium for culturing insect cells is Grace medium supplemented with fermentor, hydrolyzed lactalbumin and / or fetal calf serum, as necessary.

Typically, an antibiotic or other compound useful for the selective growth of the transformed cells is added as a supplement to the growth medium. The compound to be used is dictated by the selectable labeling element present in the plasmid with which the host cells will be transformed or transfected. For example, where the selectable labeling element is resistant to kanamycin, the compound added to the culture medium will be kanamycin.

The amount of the polypeptide produced in the host cell can be evaluated using standard methods known in the art. Such methods include, without imitation, Western blot analysis, SDS-polyacrylamide gel electrophoresis, non-denatured gel electrophoresis, HPLC separation, immunoprecipitation, and / or activity assay such as DNA-binding gel grafting assays.

Recovery of the Expression Product The purification of the polypeptides according to this invention from a solution can be performed using a variety of techniques. If the polypeptide has been synthesized in such a way as to contain a label, it can be purified essentially in a one-step process, passing the solution through an affinity column where the column matrix has a high affinity for the label or for the label. polypeptide directly (that is, a monoclonal antibody that specifically recognizes the polypeptide). For example, polyistidine bonds with a high affinity and specificity to nickel, thus a nickel affinity column (such as Qiagen® nickel columns) can be used for purification. See, for example, Current Protocols in Molecular Biology, Volume 1, Edited by Ausubel et al., John Wiley and Sons, Inc. (1995).

Where the polypeptide is prepared without an attached label, and antibodies are not available, other methods may be used for well-known purification. Such methods include, without limitation, ion exchange chromatography, molecular sieve chromatography, HPLC, native gel electrophoresis in combination with elution gel, and preparative isoelectric focusing.

If the polypeptide has been formed with bodies included in the periplasm, the bodies included can often bind to the internal and / or external cell membranes and thus be found primarily in the pellet material after centrifugation. The pellet material can then be treated with a chaotropic agent, such as guanidine or urea to liberate it, break it, and solubilize the bodies included. The polypeptide is now in soluble form and can then be analyzed using gel electrophoresis, immunoprecipitation or the like. If it is desired to isolate it, the isolation can be performed using standard methods such as those described by Marston et al. In Meth. Enz., Volume 182, pages 264-275 (1990).

In those situations where it is preferable to partially or completely isolate the polypeptide, the purification can be performed using standard methods well known to the skilled artisan. Such methods include, without limitation, separation by electrophoresis followed by elect roelusion, various types of chromatography (immunoaffinity, molecular sieve, and / or ion exchange), and / or high pressure liquid chromatography. In some cases, it may be preferable to use more than one of these methods for complete purification.

Gene Therapy The human DNA molecules provided herein (or their corresponding RNAs) can also be used for gene therapy, depending on the biological activity and the desired effect. Currently, appropriate vectors for gene therapy (such as retroviral or adenoviral vectors modified for the purposes of gene therapy and pharmaceutical purity and acceptability) can be administered to be released into the lung, for example. Such Vectors can incorporate nucleic acid encoding the polypeptides present by the expression at the desired site. The gene therapy may involve more than one gene for a desired protein or different desired proteins.

Alternatively, a vector may not be used to relatively facilitate stable presence in the host. For example, homologous recombination of a DNA as provided herein or of an appropriate transcription control or transfer region can facilitate integration into expression from a host genome. (This may be executed for production purposes as such, for example, U.S. Patent No. 5,272,071, published December 21, 1993, and PCT application WO 91/09955, published June 11, 1991). The nucleic acid can be placed within a pharmaceutically acceptable carrier to facilitate cellular retrieval, such as a lipid solution carrier (e.g., a loaded lipid), a liposome, or a polypeptide carrier (e.g., polylysine).

In this manner the present invention is provided for a population of cells expressing the polypeptides of this invention. Such cells may be appropriate for transplantation or implant in an individual for therapeutic purposes. For example, a population of cells can be prepared to over express the polypeptide. Such cells can then be implanted in an individual. Such cells can be, for example, liver cells, spinal cord cells, or cells released from the umbilical cord. Alternatively, it may be desired to use expressed circulating cells such as blood progenitor cells, T cells, or other blood cells. Human cells can be used. The cells can be in the form of tissue. Such cells can be cultured before transplantation or implant. The expression in situ can be executed, for example, by altering the regulatory mechanism for the expression of the polypeptide, such as by using homologous recombination techniques as referred to above. In this manner, a population of modified host cells is provided so that the expression of the endogenous DNA polypeptide is increased.

Cells to be transferred to the container can be cultured using one or more factors that affect the growth or proliferation of such cells, if appropriate. Heme topoyetic factors can be used in the culture of heme topoytic cells. Such factors include G-CSF, EPO, MGDF, SCF, Flt-3 ligand, interleukins (e.g., IL-1 to IL-13), GM-CSF, LIF, and analogs and derivatives thereof as provided by someone skilled in the art. in the technique.

This may be a co-gene therapy that involves the transplantation of cells that express more than one desired protein.

For gene therapy doses, one will generally use between one copy and several hundred copies of the nucleic acid present per cell, depending on the vector, the expression system, the age, weight and condition of the receptor and other factors that will be apparent to those skilled in the art. The cellular release of the polypeptide (s) can be designated for the latter for a selected period of time, such as a period of days, weeks, months or years. At the end of the effective time period, the recipient of the transformed cells may receive another "dose" (e.g., cell transplantation). Cells can be selected for their length of life, their period of time of expression of the desired polypeptide, or their ability to be re-isolated from an individual (i.e., for blood cells, leucaphoresis can be used to recover the transformed cells using markers present in the surface of the cell). The vectors can similarly be designated using, for example, viruses that have a known period of expression of their DNA contained therein.

The cells of desired vectors can be stored using techniques, such as freezing, available to those in the art.

In this manner, the present invention also contemplates a method for administering the polypeptide to an individual, wherein the source of the polypeptide is selected from (i) a population of cells expressing the polypeptide and (ii) a population of vectors expressing the polypeptide. Such vectors can be virus vectors capable of infecting human cells. The cells can be selected from between tissues or individual cells. The cells can be selected from among adipocytes, fibroblasts, spinal cord cells, peripheral blood progenitor cells, red blood cells, and white blood cells, including T cells and nerve cells.

Polypeptide derivatives The polypeptides of this invention (including fragments and analogs), prepared as described above, can be modified to create a fusion molecule with another peptide sequence. For example, if it is desired to "tag" the polypeptide with an immunogenic peptide, a DNA resulting in such a fusion product can be constructed. The labeling can be in the term N or the term C. An example is a "FLAG-label" version of the polypeptide. This type of "labeling" is useful for binding the polypeptide using reagents, such as antibodies that are selective for the label. Such linkage may be for the detection of the polypeptide site or amount, or for polypeptide capture processes where, for example, an affinity column is used to bind the tag, and thus, the desired polypeptide. Other types of detectable labels, such as radioisotopes, luminous (for example, fluorescent or phosphorescent compounds), enzymatically divisible enzymes, detectable antibodies (or 'modifications thereof), or other substances may be used for such labeling of the present polypeptides.

For human therapeutic purposes, it may also be advantageous to derive the polypeptides described above by attaching one or more of the other chemical moieties to the polypeptide portion. Such chemical moieties may be selected from various water soluble polymers. The polymer should be soluble in water so that the polypeptide to which it will bind is miscible in an aqueous environment such as a physiological environment. The water-soluble polymer can be selected from the group consisting of, for example, polyethylene glycol, copolymers of ethylene glycol / propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymer, polyamino acids (either homopolymers or random or non-random copolymers) ) (see also below with respect to the fusion molecules), and dextran or poly (n-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polipolyoxyethylated polyols, polystyrene maleate, and polyvinyl alcohol. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water.

The fusion polypeptides according to this invention can be prepared by attaching polyamino acids to the polypeptide. For example, the polyamino acid can be a carrier protein that serves to increase the half-life of the polypeptide circulation. The polyamino acid should be one that does not create a neutralized antigenic response or other adverse response, if the derivative is intended for therapeutic use in alive. The polyamino acid can be selected from the group consisting of serum albumin (such as human serum albumin), an antibody or portion thereof (such as an antibody constant region, sometimes called "Fe") or other polyamino acids. The location of the polyamino acid linkage may be in the N-terminus of the polypeptide portion, or elsewhere, and may also be connected by a chemical "binding" portion to the polypeptide.

The polymer can be of any molecular weight, and can be branched or unbranched. For polyethylene glycol, the preferred molecular weight is between about 2 kilodaltons (kDa) and around 100 kDa (the term "around" indicates that in the poiliet ileglicol preparations, some molecules can weigh more, some less, than the molecular weight established) to facilitate their handling and manufacture. Other sizes may be used, depending on the desired therapeutic profile (e.g., the duration of the desired sustained release, effects, biological activity, ease of handling, degree or lack of antigenicity and other known effects of polyethylene glycol in a therapeutic protein).

The number of polymer molecules to be linked may vary, and one skilled in the art should be able to guess the effect on the function. It can be mono-derivatized, or it can be provided for a di-, tri-, tetra, - or some combination of derivatization with the same or different chemical portions (for example, polymers, such as, different weight of polyethylene glycol). The ratio of the polymer molecules to the polypeptide molecules will vary, as well as their concentrations in the reaction mixture). In general, the optimum ratio (in terms of reaction efficiency in that it does not exceed the unreacted polypeptide or polymer) will be determined by factors such as the desired degree of derivation (e.g., mono, di-, tri-, etc.). ), the molecular weight of the selected polymer, whether the polymer is branched or unbranched, and the reaction conditions.

The chemical portions will bind to the polypeptide with consideration of the effects on the functional or antigenic domains of the polypeptide. These are a number of link methods available to those skilled in the art. See, for example, EP 0 401 384 (PEG coupling to G-CSF), and Malik et al., Experimental Hematology, Volume 20, pages 1028-1035 (1992) (which reports pegylation of GM-CSF using tresyl chloride ). By way of illustration, the polyethylene glycol may be covalently linked through the amino acid residues by means of a reactive group, such as a free amino or carboxyl group, the reactive groups are those to which an activated polyethylene glycol molecule (or another chemical portion) can be linked. Amino acid residues that have a free amino group can include lysine residues and the N-terminal amino acid residue. Those having a free carboxyl group may include aspartic acid residues, glutamic acid residues, and the C-terminal amino acid residue. The sulfhydryl groups can also be used as the reactive group to link the polyethylene glycol molecule (s) (or other chemical portion). It is preferred for purposes of therapeutic manufacture to bind an amino group such as the N term or a lysine group. The binding on residues important to the linked receiver should be avoided if the linked receiver is desired.

Chemically modified N-terminal derivatives can be specifically desired. Using polyethylene glycol as an illustration, the proportion of polyethylene glycol molecules to the polypeptide molecules in the reaction mixture, the type of pegylation reaction to be performed can be selected from a variety of polyethylene glycol molecules (by molecular weight, branched, etc.). , and the method for obtaining the selected N-terminal pegylated polypeptides. The method for obtaining the N-terminal pegylated preparation (that is, separating its portions from other monopegylated portions if necessary), may be by purification of the N-terminal pegylated material from a population of pegylated polypeptide molecules. The selective N-terminal chemical modification can be executed by reductive alkylation whose differential reactivity of exploitation of different types of aminogroups primary, (lysine versus N-terminal) available for derivation in a particular protein. See PCT application WO 96/11953, published April 25, 1996. Under the appropriate reaction conditions, the substantially selective derivatization of the polypeptide in the N-terminus with a polymer-containing carbonyl group is performed. For example, N-terminally the polypeptide can be selectively pegilated by performing the reaction at a pH that allows taking advantage of the differences in pKa between the e-amino group of the lysine residues and that of the a-amino group of the N-terminal residue. of the polypeptide. By such selective derivation, the binding of a polymer to a polypeptide is controlled: the conjugation with the polymer takes place predominantly at the N-terminus of the polypeptide and no significant modification of other reactive groups, such as amino groups of the side chain of lysine, occurs. using reductive alkylation, the polymer can be of the type described above, and should have a simple reactive aldehyde for coupling the polypeptide. Polyethylene glycol propionaldehyde, contains a simple reactive aldehyde, and can be used In general, an N-terminal chemically modified derivative is preferred over other forms of chemical modification because of its ease in the production of a therapeutic. N-terminal chemical modification ensures a homogeneous product as a relatively simplified product characterization for di-, tri-, or other multi-derivative products. The use of the above reductive alkylation process for the preparation of an N-terminal chemically modified product is preferred for its ease in commercial manufacturing.

The chemically modified derivatives according to this invention can be further formulated for intharterial, intraperitoneal, intramuscular, subcutaneous, intravenous, oral, nasal, pulmonary, topical or other routes of administration, again depending on the biological activity of the polypeptide and the desired therapeutic effect . The chemical modification of the biologically active proteins are found to provide additional advantages under certain circumstances, such as the increase in stability and circulation time of the therapeutic protein and the reduction of immunogenicity. See, for example, United States Patent No. 4, 179, 337, published December 18, 1979 (Davis et al.), And Abuchowski et al., "Enzymes as Drugs", Edited by Holcerberg and Roberts, pages 367- 383 (1981). A publication describing the modification of protein and fusion proteins is Francis, Focus on Growth Factors, Volume 3, pages 4-10 published by Mediscript, Mountview Court, Friern Barnet Lane, London, England (1992). Preferably, for therapeutic use of the final product preparation, the chemical portion for derivatization will be pharmaceutically acceptable.

Therapeutic compositions Another aspect of the present invention involves the use of the polypeptide of SEQ ID NO: 4 and analogs and derivatives thereof in pharmaceutical compositions and in methods for the manufacture of medicines for human use. Such compositions may be for administration by injection or by oral, pulmonary, nasal, transdermal, or other forms of administration. In general, encompassed within the invention are pharmaceutical compositions comprising effective amounts of polypeptide or products derived from the invention together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and / or carriers. By "effective amount" means an amount sufficient to produce a biological effect that can be measured. Such compositions include diluents of various buffer contents (eg, tris-HCl, acetate, phosphate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., Tween 80, polysorbate 80), antioxidants (e.g., ascorbic acid, sodium tabisolide), preservatives eg timersol, benzyl alcohol) and bulking substances for example, lactose, mannitol) incorporation of the material in particular preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., or in liposomes See, for example, PCT application WO 96/29989, Collins et al., Published October 3, 1996. Hyaluronic acid may also be used, and this may have the effect of promoting a sustained duration in the circulation. Such compositions may influence the physical state, stability, release ratio in vivo, and release ratio in vivo of the present proteins and derivatives. See, for example, Remington Pharmaceutical Sciences, edition 18, Mack Publishing Co., Easton, Pennsylvania, pages 1435-1712 (1990). The compositions can be prepared in liquid form, or as dry powder, such as lyophilized form. Implantable sustained release formulations are also contemplated, as are the transdermal formulations.

Oral dosage forms of the above derived polypeptides are also contemplated. The proteins can be chemically modified so that their oral release of the derivative is effective. Generally, the chemical modification contemplated for the present purpose is accompanied by at least a portion to the polypeptide molecule per se. same, where this portion allows (a) the inhibition of proteolysis and (b) the incorporation into the bloodstream from the stomach or intestine. The increase in the overall stability of the protein and the increase in circulation time in the body are also desired. See PCT application WO 95/21629 (Habberfield, "Oral Delivery of Chemically Modified Proteins"), published August 17, 1995; and United States patent No .5, 57, 018, published on November 12, 1996 (Habberfield et al., "Conjugates of Vitamin B12 and Proteins "), published on 12 November of 1996.

The pulmonary release of such polypeptides and derivatives are also contemplated herein. The polypeptide or polypeptide analogue or derivative is released into the lungs of a mammal while inhaling and traversing through the epithelial lung reinforcing the bloodstream. For illustration see PCT application WO 94/20069, Niven et al., "Pulmonary Administration of Granulocyte Colony Stimulating Factor", published on September 15, 1994.

Nasal release of the polypeptide (or analogue or derivative) may also be possible. The nasal release allows the passage of the polypeptide (or derivative) into the bloodstream directly after administering the therapeutic product to the nose, without the need to deposit the product in the lung. Formulations for nasal release include those with absorption-enhancing agents, such as dextran or cyclodexthane. Release through transport through other mucous membranes is also contemplated.

If desired, the polypeptides of this invention can also be administered systemically in a sustained release formulation or preparation. Suitable examples of preparations of sustained release preparations include semipermeable polymer matrices in the form of formed articles, for example, films or microcapsules. Sustained-release matrices include polyesters, hydrogels, polylactides (U.S. Pat.

No. 3,773, 919, published November 20, 1973), copolymers of L-acid glutamic and gamma and il-L-glutamine (Sidman et al., Biopolymers, Volume 22, pages 547-556, 1983), poly (2-hydroxyethyl-methacrylate) (Langer et al., J. Biomed, Mater, Res. , volume 15, pages 167-277, 1981, and Langer, Chem. Tech., volume 12, pages 98-105, 1982), ethylene vinyl acetate (Langer et al., as above) or poly-D (-) acid 3-hydroxybutyric. Sustained release compositions can also include liposomes, which can be prepared by any of several methods known in the art; see, for example, Epstein et al, Proceedings of the National Academy of Science USA, volume 82 pages 3688-3692 (1985), and Hwang et al., Proceedings oh the National Academy of Sciences USA, Volume 77, pages 4030-4034 ( 1980).

Typically, the polypeptide will be in a highly purified form, and the composition will normally be sterilized for use, such as by filtration through sterile filtration membrane.

The amount of polypeptide that will be effective in vivo depends on the nature of the application. Someone skilled in the art will be able to effectively hit the doses for administration and observation of the desired therapeutic effects. The particular effects that are not within this range depend on the particular disorder or condition to be treated, as well as the age and general health of the recipient, and can be determined by standard clinical procedures. Where possible, it is desirable to determine the dose-response curve of the pharmaceutical composition first in vitro, as in biological analysis systems, and then in animal model systems useful in vivo before testing in humans. The skillful practitioner will consider the therapeutic context, type of disorder under treatment, and other applicable factors, being able to guess the proper dose without undue effort. Typically, a practitioner will administer the polypeptide composition at a dose that will achieve the desired effect. The composition can be administered as a single dose, or as two or more doses (which may or may not be contain the same amount of polypeptide) for a time, or on a continuous basis.

Diagnostic Materials and Methods The nucleic acid products of the invention can be labeled with detectable labels (such as radiolabels and non-isotopic labels such as biotin) and used in hybridization processes to locate the gene position and / or the position of any related gene family in a chromosome map. These can also be used to identify gene disorders at the DNA level and use as gene markers to identify neighboring genes and their disorders. Such nucleic acid sequences can be used for the detection or measurement of the mRNA level of a biological sample. Cassettes containing such marker materials are contemplated herein.

The polypeptides and / or nucleic acids provided herein may be part of a kit or article of manufacture. An example is an article of manufacture that comprises a packaging material and one or more preparations of the presently provided compositions. Such packaging material comprises a mark indicating that polypeptide or nucleic acid preparation is useful for detecting and / or quantifying the amount of polypeptide in a biological sample, or defects in a biological sample. As such, the kit may optionally include materials to perform such a test, such as reagents useful for performing DNA or RNA hybridization assays, or PCR analysis in blood, urine, or tissue samples.

A further aspect of the invention is the binding of molecules, such as polyclonal antibodies, or preferably, monoclonal antibodies that selectively bind the polypeptides of this invention. The hybridoma technique originally described by Kohler and Milstein in the European Journal of Immunology, Volume 6, pages 511-51 (1976), has been widely applied to produce hybrid cell lines that secrete high levels of monoclonal antibodies against many specific antigens. The recombinant antibodies can also get prepared; see Huse et al., Science, Volume 246, on page 1275 (1989). Such recombinant antibodies can be further modified, such as by a modification of the determining regions in addition to increase or alter their affinity, or "humanize" such antibodies, and incorporated into a kit for diagnostic purposes. A diagnostic kit can be used to determine the location and / or amount of the polypeptide of this invention in an individual. Diagnostic kits can also be used to determine if an individual has receptors, or those that, to varying degrees, have reduced binding ability or ability. Such antibodies can be prepared using immunogenic portions of the polypeptide. Such selective binding molecules can, by themselves, be alternatives to the polypeptide, and can be formulated for pharmaceutical use.

Such polypeptides and / or nucleic acids can be used for tissue distribution assays (e.g., as provided in the example of work below) or by other assays to determine the polypeptide expression pattern.

The biological function of the polypeptides of this invention can be studied in vivo by breaking the expression of the corresponding gene in non-human animals such as mice, in such a way that the level of expression of this gene is significantly reduced or completely abolished (also called "eliminated" animals). Such animals can be prepared with the use of techniques and methods described in U.S. Patent No. 5,557,032, published on September 17, 1996, for example. Additionally, or alternatively, mice can be prepared in which the gene for the polypeptide is overexpressed ("transgenic" animals) in order to evaluate the effects of overexpression. Appropriate methods for the preparation of such transgenic animals are described in U.S. Patent No. 5,489,743, published February 6, 1996, and PCT application WO 94/28122, published December 8, 1994. useful transgenics will be those that exhibit a detectable phenotype associated with the expression of the polypeptide.

Another potential use of the present polypeptides is in assays and methods for the identification of a receptor or receptors to which they are linked, and are activated by the polypeptides. This can be done, for example, by contacting a recombinant host cell (bacterial, yeast, etc.) expressing the polypeptide of this invention ("ligand") on the surface with a receptor to be identified under conditions that allow binding or activation. of the receiver, and detect the occurrence of any such links or activation. Such "ligand-receptor" interactions can take place on a cell-to-cell basis, since the membrane-bound polypeptide of this invention is considered to interact through contact with the receptor in an adjacent cell. In this way, the assay may involve the recombinant expression of the "ligand" and the "receptor" on the surface of the separated host cells, which are then conducted in proximity or direct contact to determine whether the ligand-receptor binding or receptor activation occurs. The binding or activation event will then be detected by means of standards, such as by measuring the change in an analytically detectable tag that has been linked to either the ligand or the receptor, or by measuring the receptor's autophosphorylation (if the latter is capable of phosphorylation during activation).

Alternatively, the assay can be carried out using a "soluble" version of the polypeptide of the invention, which consists of the extracellular domain (with or without the peptide signal region) that has been recombinantly expressed and harvested from the host. The soluble polypeptide can be used alone, or in a derivatized form, for example, a "Fe fusion" product such as that described above (and exemplified below). The soluble polypeptide or derivative is then brought into proximity or contact with a substrate to which the receptor to be identified has been linked, and the binding or activation event is detected in the same manner as described above. The procedure can also be conducted in reverse, that is, with the receiver to be identified by being linked to an appropriate substrate and the unbound or derived soluble polypeptide being connected to these, etc.

The purified polypeptide of this invention will also be useful for structural studies as a means for the rational design of novel drugs that affect viral function and polypeptide activity. For example, the recombinant protein can be used to derive the structure of the protein through X-ray crystallography, NMR or molding of published structures of related proteins. The knowledge of the structure will favor an understanding of the manner of the peptide bonds, and can lead to the design or discovery of compounds that can either block or mimic the activity of the polypeptide, depending on what is desired.

Description of Preferred Forms of Realization.

The invention is described in greater detail with respect to the following working examples, which they are included only for purposes of illustration and are not intended to be limiting.

Example 1.

Construction of the cDNA Collection.

Normal white adipose tissue from 1 mouse CD was collected, and the total mRNA was isolated using an RNeasy Maxi® kit (Qiagen, Santa Clara, California) in accordance with the manufacturer's instructions. The proportion of RNA containing a polyA sequence was subsequently isolated (Oligotex kit, Qiagen, Santa Clara, California) - by its instructions, except for the omission of the DNase step.

The cDNA library was constructed with this mRNA using the Super Scrip® Plasmid System (Gibco BRL, Gaithersburg, Maryland). The manufacturer's protocol was followed, except that the common random oligonucleotide priming containing a Notl restriction site was replaced by the first step of braiding synthesis and a PCR cleaning kit was used (Qiagen, Santa Clara, California) to purify the products of the second braid synthesis and the ligation adapter passages. The cDNA was fractionated in size using agarose gel electrophoresis (Maniatis, Molecular Cloning, CSH Press, 1991) and the base pairs 200-800 were excised. These fragments were then ligated into a release vector pYYA-41L that has previously been digested with the Xhol and Notl enzymes. The vector pYYA-4lL was deposited at the American Type Culture Collection, Manassas, Virginia, on February 13, 1998, under accession number 209636.

The pYYA-4lL vector contains the ampicillin resistant gene and the Trpl gene for selection in E. co l i and S. Cerevi s i a e, respectively. In addition, the vector contains a yeast promoter upstream of the yeast amylase gene in which the peptide signal sequence is removed. The vector is constructed in such a way that the insertion of a functional signal sequence into the Xhol-Notl restriction sites results in the secretion of the amylase gene product out from the wall of the yeast cell. The ligated vector is amplified by transformation into E. col i (DHlOb, Gibco BRL, Gaithersburg, Maryland), and then isolated using a Qiagen plasmid purification kit (Qiagen, Santa Clara, California).

The resulting DNA is used to transform yeast YPH449 using lithium acetate; for reference, see Gíetz et al., Nucleic Acids Research, Volume 20, page 1425 (1992). The transformed yeast cells are then placed on agar containing azur starch (Sigma, St. Louis, Missouri) and lacking tryptophan. After incubation at 30 ° C, the yeast colonies were cast around by rinsing the azure tray (the secretion is indicative of the amylase gene). The individual yeast colonies were isolated by realigning in the trays and growing in a liquid culture, and the DNA vector was then isolated using a Qiagen plasmid purification kit (Qiagen, Santa Clara, California). The inserted vector DNA sequences were determined by PCR amplification (Perkin Elmer, Sunnyvale, California) using specific vector primers, amplified DNA purification (Qiagen, Santa Clara, California), and automated DNA sequence (Perkin Elmer / Applied Biosystems, Foster City, California).

The resulting DNA sequences and predicted protein sequences are searched against databases available to the public that contain nucleotide and protein sequences. A sequence (SEQ ID NO: 41) composed of 402 base pairs shows significant homology to previously isolated members of the Delta gene family.

Example 2 Cloning of the Murina gene Murine adipose cDNA longer than eight hundred base pairs were ligated to the adapter priming, using a Marathon® cDNA amplification kit (Clontech, Palo Alto, California) and the manufacturer's protocol. The final cDNA products were purified from the unlinked adapted primers (PCR cleaning kit, Qiagen, Catsworth, California) and then used as templates for subsequent rapid amplification reactions of cDNA ends (RACE) using a polymerase chain reaction (PCR).

For the RACE 3 reaction, the PCR was run on the templates or cDNA standards using the components of the Adyantage® PCR kit (Clontech, Palo Alto, California) and the following primers: TGCTGTGGGTAAGATTTGGCGAACA (SEQ ID NO: 42) and CCATCCTAATACGACTCACTATAGGGC (SEQ ID NO: 43).

After denaturation (94 ° C for one minute), the amplification procedure was conducted as follows; five cycles at 94 ° C for five seconds and at 72 ° C for four minutes; five cycles at 94 ° C for five seconds and at 70 ° C for four minutes; and twenty-five cycles at 94 ° C for five seconds and at 68 ° C for four minutes. All reactions were run on a Perkin Elmer 2400 PCR machine (Sunnyvale, California).

The reaction mixture was treated by electrophoresis on a 1% agarose gel, and a single band migration of approximately 3 kilobases were excised and purified through a Genelute® column (Sulpeco, Bellefonte, Pennsylvania), and then ligated into a pCR-Blunt plasmid (Invitrogen, Carlsbad, California). The bacterial host cells are then transformed with this plasmid and grown overnight. Plasmid DNA is isolated from bacterial host cells using the Qiagen mini-preparation protocol and digested with EcoRI and NotI to confirm the presence and size of the inserts. A clone containing an insert of approximately 3 kilobases (SEQ ID NO: 44) is sequenced and found to contain a novel cDNA encoding the murine polypeptide. This DNA sequence is used to designate primers for the RACE 5 reaction.

For the RACE 5 reaction, the PCR is run on the cDNA standards, using the components of the Advantage® PCR kit (Clontech, Palo Alto, California) together with the following primers: GGTGAGTCCGCACAGGTCAAGGTAC (SEQ ID NO: 45) and CCATCCTAATACGACTCACTATAGGGC (SEQ ID NO: 43) After an initial denaturation step (94 ° C for one minute), the amplification was carried out as follows: five cycles at 94 ° C for five seconds and at 72 ° C for four minutes; five cycles at 94 ° C for five seconds and at 70 ° C for four minutes; and twenty-five cycles at 94 ° C for five seconds and at 68 ° C for four minutes.

The reaction mixture was treated by 1% agarose gel electrophoresis, and a single band migration of approximately 1.5 kilobases was excised, purified as above, and re-amplified using the components of the Advantage® PCR kit with the following oligonucleotides: GACAGGGGTTGCTGGCACACTTGTT (SEQ ID NO: 46) and CCATCCTAATACGACTCACTATAGGGC (SEQ ID NO: 43).

After denaturation (94 ° C for one minute), the template was amplified for thirty-five cycles at 94 ° C for ten seconds and at 72 ° C for two and a half minutes.

The reaction mixture was treated by electrophoresis on a 1% agarose gel, and a single band migration of approximately 1.7 kilobases was excised and purified through a Genelute® column and then ligated into a pCR2.1 plasmid (Invitrogen , Carlsbad, California). The bacterial host cells are then transformed with this plasmid and grown overnight. Plasmid DNA is isolated from bacterial host cells using the Qiagen mini-preparation protocol and digested with EcoRI to confirm the presence and size of the inserts. Three clones, containing an insert of approximately 1.5 kilobases, were sequenced and shown to contain the additional murine 5 cDNA sequence composed of 982 base pairs (SEQ ID NO: 47).

The sequence of this 5 'RACE clone (SEQ ID NO: 47) was fused with the 3' RACE clone sequence (SEQ ID NO: 44) to give the open reading structure sequence of full-length murine cDNA (FIG. 1A-1B, and SEQ ID NO: 1).

To generate a full-length murine cDNA clone of SEQ ID NO: 1 (above), PCR is performed on the white murine adipose pattern from the RACE reactions using the components of the Advantage® PCR kit and the following nucleotides: AGCCACCATGACGCCTGCGTCCCG (SEQ ID NO: 48) and TCTATTATACCTCTGTGGCAATCAC (SEQ ID NO: 49).

After denaturation (94 ° C for one minute), the standard was amplified with ten heating cycles at 94 ° C for ten seconds, 55 ° C for ten seconds, and at 72 ° C for two and a half minutes; followed by twenty-five heating cycles at 94 ° C for ten seconds, 62 ° C for ten seconds and 72 ° C for two and a half minutes.

The reaction mixture was treated by electrophoresis on a 1% agarose gel, and a single band migration of approximately 2.2 kilobases was excised and purified through a Genelute® column and then ligated into a pCR2.1 plasmid (Invitrogen , Carlsbad, California). The bacterial host cells are they transform then with this plasmid and they are cultivated during the night. Plasmid DNA is isolated from bacterial host cells using the Qiagen mini-preparation protocol and digested with EcoRI to confirm the presence and size of the inserts. Three clones, containing an insert of approximately 2.2 kilobases, were sequenced and shown to contain the complete murine cDNA sequence (SEQ ID NO: 1, Figure 1A-1B). This cDNA molecule encodes a murine polypeptide (herein with the term "D114") having the predicted amino acid sequence of Figure 2 (SEQ ID NO: 2).

Example 3 Identification of the Human Gene The murine DNA sequence (SEQ ID NO: 1) is corroborated against the GenBank database (Wisconsin Pakage Version 9.1, Genetics Computer Group, Madison, Wisconsin), and a pair sequence of 409 bases was found (SEQ ID NO. : 50) of a collection of human brain cDNA had a 81.37% identity sequence for the murine polypeptide.

The following oligonucleotides were designated from areas of high homology between SEQ ID NO: 50 and SEQ ID NO: 1: AAGAAGGAGCTGGAAGTGGACTGTG (SEQ ID NO: 51) and ATCAAACACACAGACTGGTACATGG (SEQ ID NO: 52).

These oligonucleotides are used to amplify a collection of human brain cDNA Marathon (Clontech, Palo Alto, California) using the components of the Advantage® PCR Case (Clontech, Palo Alto, California). After an initial denaturation step (94 ° C for one minute), the amplification was carried out as follows: five cycles at 94 ° C for five seconds and 72 ° C for two and a half minutes; five cycles at 94 ° C for five seconds and 70 ° C for two and a half minutes; and twenty-five cycles at 94 ° C for five seconds and 68 ° C for two and a half minutes.

The reaction mixture was treated by 1% agarose gel electrophoresis, and a Single-band migration of approximately 245 base pairs was excised, purified through a Genelute® column, and amplified again under the same reaction conditions.

The resulting product of 245 base pairs was purified with a PCR cleaning kit (Qiagen, Chatsworth, California) and labeled with a-32P-dCTP (RediVue, Amersham, Ariington Heights, Illinois), using a RediPrime random priming reaction kit. ® (Amersham, Ariington Heights, Illinois). Unincorporated radioactivity was excluded by size exclusion chromatography (5Prime-3 Prime, Boulder, Colorado). A gtlO lambda collection of Strech Plus 5 human fat cell cDNA (Clontech, Palo Alto, California) was then purified for the human gene with this cDNA probe labeled with a-32-P-d-CTP. Seventy-two filters were hybridized with the labeled cDNA probe in 100 milliliters of RapidHyb® buffer solution (Amersham, Ariington Heights, Illinois) for approximately sixty hours at 65 ° C. The filters were then washed twice in 2x SSC (0.3 M sodium chloride / 0.3 M sodium citrate) with 0.2% SDS at room temperature for thirty minutes, followed by two washes in SSC OXX with 0.2% SDS at 65 ° C for thirty minutes. The filters were placed in autoradiography kits and exposed to Hyperfilm (Amersham, Ariington Heights, Illinois) at -80 ° C overnight. The film was revealed, and a clone that hybridized on the probe was identified.

This phage clone was purified on plate using standard methods, was isolated using the System DNA Purification Wizard Lambda prep. (Promega, Madison, Wisconsin), and it was sequenced. Sequence (SEQ ID NO: 53) showed that this clone contains approximately 215 base pairs of the untranslated region 5 and 1980 base pairs of the region encoded for the human polypeptide. The clone also lacked at least 85 base pairs of the encoded region.

To amplify the excess end 3 of the human gene, the oligonucleotide primers shown below are designated from the cj_on of SEQ ID NO: 50 current below the codon termination and the sequence for the human phage clone mentioned above (SEQ. ID NO: 53).

ACCTGATTCCTGCCGCCAGCT (SEQ ID NO: 54) and GATGTCCAGGTAGGCTCCTGC (SEQ ID NO: 55).

These oligonucleotides are used to amplify a human lung cDNA collection from Marathon (Clontech, Palo Alto, California) using the pfu polymerase (Stratagene, La Jolla, California). After denaturation at 94 ° C for one minute, the amplification was carried out for thirty cycles at 94 ° C for fifteen seconds, 68 ° C for fifteen seconds, and 74 ° C for one minute.

The reaction mixture was treated by 1% agarose gel electrophoresis and a single band migration of approximately 300 base pairs was excised and purified through a Genelute® column and then ligated into a pCR-Blunt plasmid (Invitrogen , Carlsbad, California). The bacterial host cells are then transformed with this plasmid and grown overnight. Plasmid DNA is isolated from bacterial host cells using the Qiagen mini-preparation protocol and digested with EcoRI to confirm the presence and size of the inserts. Three clones containing an insert of approximately 300 base pairs were sequenced and compared with SEQ ID NO: 50 and SEQ ID NO: 53. One clone was chosen, and three protection sequences of this clone revealed that it has the sequence SEQ ID NO: 56 This sequence (SEQ ID NO: 56) and the sequence of SEQ ID NO: 53 were merged using a Sequencer computer program (Genes Code, Ann.

Arbor, Michigan) in the full length of the human open reading structure sequence (Figure 3A-3B, SEQ ID NO: 3). This DNA sequence encodes a human polypeptide having the predicted amino acid sequence of Figure 4 (SEQ ID NO: 4).

Example 4 Expression of the murine gene To evaluate the expression pattern of the murine polypeptide gene, an RT-PCR was run on ten nanograms of mRNA from several murine tissues using the PCR kit GeneAmp EZ rTht RNA (Perkin-Elmer, Norwalk, Connecticut) and the following oligonucleotide primers: AACCTGGACGGCAGATG (SEQ ID NO: 27) and AGATTTGGCGAACAGACGA (SEQ ID NO: 58).

After the first synthesis of braiding cDNA at 60 ° C for thirty minutes and denaturation at 94 ° C for two minutes, the amplification was carried out using thirty cycles at 94 ° C for fifteen seconds, followed by 66 ° C for one minute. The reactions were run with a Perkin 2400 PCR machine. The reaction mixtures were then purified with a CPR cleaning kit (Qiagen, Chatwsort, California), an aliquot of each was run on a 1% agarose gel, and A fragment of 275-base pair expected was observed in most tissues. The highest level of expression has been observed in the lung, followed by black and white adipose tissue. Other tissues that express the murine polypeptide at lower levels of expression are the adrenal gland, spleen, brain, eye, kidney, and liver. Skin and skeletal muscles are negative at this level of examination..

These same oligonucleotide primers are used to amplify a region of the clone of SEQ ID NO: 41 using a PCR Core kit (Boehringer Manneheim, Indianapolis, Indiana) as a probe. After an initial purification step (94 ° C for one minute), the amplification procedure consists of thirty cycles at 94 ° C for fifteen seconds followed by 66 ° C for one minute. An aliquot of the reaction mixture was treated by 1% agarose gel electrophoresis and a single band migration of approximately 275 base pairs was observed. The remainder of the reaction mixture was purified with a PCR cleaning kit (Qiagen, Chatsworth, California) and labeled with a-32P-dCTP (RediVue®, Amersham, Ariington Heights, Illinois) using a RediPrime random priming reaction kit. ® (Amersham, Ariington Heights, Illinois). The incorporated radioactivity was excluded by size exclusion chromatography (5Prime-3Prime, Boulder, Colorado).

This murine probe was used to purify the northern spot containing two microorganisms via polyA + RNA from several murine tissues (Clontech, Palo Alto, California) in ten milliliters of RapiHyb buffer (Amersham, Ariington Heights, Illinois). The purification was carried out for approximately one hour at a temperature of 65 ° C. The filters were then washed twice in 2X SSC with 0.2% SDS at room temperature for thirty minutes, followed by two washes in OXX SSC with 0.2% SDS at 65 ° C for thirty minutes. The stains were then exposed to phosphor boxes (Molecular Dynamics, Sunnyvale, California) overnight and were developed with a Molecular Dyanamics Stor 820 system.

Northern spot analyzes showed that the level of murine gene expression was highest in the lung, followed by the heart, kidney, muscle skeleton and brain. Transcriptionists were poorly detected in spleen and testis tissues, and hybridization of GAPDH showed little RNA in these pathways.

Example 5 Hybridization In Si t u of the Murina Gene A panel of tissues from normal adult mice and embryos (E10.5 to E18.5) were placed in 4% paraformaldehyde, and then embedded in paraffin and cut into five microns. Prior to hybridization, the tissues were permeabilized with 0.2M HCL, followed by digestion with Proteinaza K and acetylation with triethanolamine and acetic anhydride. The sections were hybridized overnight at 55 ° C with a labeled 33P rhinoprobe of 2058 base pairs corresponding to nucleotides 1 to 2058 of the mouse sequence, then subjected to a high stringency wash in SSC 0. IX at 55 ° C. The slides were soaked in a Kodak NTB2 emulsion (Eastman Kodak, Rochester, New York), exposed at 4 ° C for two to three weeks, revealing, and then placing contrast dye with heme toxylin / eosin. The sections were examined with standard illumination (luminous field) and dark field to allow the simultaneous evaluation of tissue morphology and the hybridization signal. The nuclei were differentially decolorized with hematoxylin / eosin and the cytoplasm and allowed, under bright field illumination, the visualization of cell morphology and the identification of cell types expressing the gene of interest. The autoradiography of the emulsion allowed the microscopic evaluation of the hybridization signal (from the hybridized radiolabeled probe) under dark field illumination, in which it revealed traces of silver appearing as bright spots on a dark background.

The tissues examined in this way include: Gl (esophagus, stomach, duodenum, jejunum, ileus, distant and nearby colon), brain (one sagittal, two coronal section), liver, lung, heart, spleen, thymus, lymph nodes, kidney , adrenal, vesicle, pancreas, salivary gland, reproductive organs of males and females (ovary, oviduct and uterus in females, testes, epididymal, prostate, seminal vesicle and vas deferens in males), BAT and WAT (subcutaneous, peri-renal, peri-ovary or epididymal), bone (femur), skin, chest, and muscular skeleton.

The results for the tissues of an adult mouse are shown in Figures 5 and 6. The results of an embryo mouse are shown in Figure 7. The illumination of the light field is shown in the upper part of the panel and the illumination of the dark field It is shown in the background of the panel of each game in pair of photographs. Figures 5A and 5B: lung. Figures 5C and% d: liver. Figures 5E and 5F: brain. Figures 5G and 5H: colloidal plexus. Figures 51 and 5J: kidney. Figures 5K and 5L: adrenal gland. Figures 5M and 5N: spleen. Figures 50 and 5P: thymus gland. Figures 6A and 6B: white adipose tissue. Figures 6C and 6D: Brown adipose tissue. Figures 6E and 6F: muscular skeleton. Figures 6G and 6H: skin. Figures 61 and 6J: duodenum. Figures 6K and 6L: pancreas. Figures 6M and 6: ovaries. Figures 60 and 6P: testicles. Figures 7A and 7B: Mouse embryo E10.5. Figures 7C and 7D: mouse embryo Eli.5 / "E10.5" and "Eli.5" indicate the day of embryo development; "H" and "L" indicate heart and lung, respectively).

As shown in these photographs, the probe produces a clear signal, with little or no backup signal, in sections of the tissue of both the embryo and adult mice. In all the embryonic stages examined and in all adult tissues, the signal was restricted to cells with an endothelial-like morphology in blood vessels or capillaries. The signal in the heart was confined to the microvasculature (see Figure 7).

Example 6 Preparation of the Fe Fusion Derivative A "Fe" fusion derivative of the polypeptide of this invention (using murine species as an example) and a polyamino acid can be prepared as follows: The majority of the extracellular region of the murine Delta4 (nucleotides 1-1587 of SEQ ID NO: 1 and Figure 1A-1B) were amplified with the following oligos to be added to the Spe I site at the 5 'end and to the Not site. I at the 3 'end.

GAACTAGTCCACCATGACGCCTGCGTCCCG (SEQ ID NO: 59) TCGCGGCCGCGGGGAAGCTGGGTGGCAA (SEQ ID NO: 60).

After an initial denaturation step of 94 ° C for one minute, the amplification was carried out for thirty cycles at 94 ° C for fifteen seconds, 58 ° C for fifteen seconds, and 74 ° C for one minute. The reaction mixture was treated by 1% agarose gel electrophoresis, and a single band migration of approximately 1600 base pairs was excised and purified through a Genelute® column. This fragment was digested with Spe I and Not I, purified with a PCR cleaning kit (Qiagen, Chatsworth, California), and ligated into a plasmid containing the Fe region of human IgG also digested with Spe I and Not I. Not I site introduced three alanine residues in place of "WVA" at positions 530, 531 and 532 of the normal amino acid sequence of the extracellular region of the murine polypeptide, which allows a structure linked between the murine polypeptide sequence and the Fe sequence. The bacterial host cells are then transformed with this plasmid and grown overnight. Plasmid DNA is isolated from cells bacterial hosts using the Qiagen miniprep protocol, and then digested with Spe I and Not I to confirm the presence and size of the inserts. A clone containing an insert of approximately 1.6 kilobases, is made in sequence and shown to code; amino acid residue 1-529 of the extracellular region of the murine polypeptide in the structure with the human IgG Fe region (SEQ ID NO: 61 and SEQ ID NO: 62 for the DNA and amino acid sequences, respectively, with the Fe portion initiating at position 533 of the amino acid sequence).

Biology .

As mentioned, Delta-Notch signaling is known to regulate cell development, and more specifically, the differentiation of endothelial cells into more specialized cells. The studies shown in Examples 4 and 5, in particular, reveal that the polypeptide is strongly expressed in the vascular endothelium in both embryo and adult stages, consequently it is not limited to only one developed organism, but has a role in the biology of the adult organism as such. In the particular case of angiogenesis, Delta-Notch signaling should be expected to influence the development of the endothelium in the blood vessels. Because the development of blood vessels is critical for supporting the growth of a tumor, the polypeptide binding for angiogenesis will provide an "objective" for use in programs for the identification and / or development of an appropriate agonist (stimulator) or antagonist (inhibitor) of this effect.

Specific examples of the biology of another endothelial cell that can be influenced include endothelial cell proliferation, migration, chemotaxis, vascular changes in permeability (possibly associated with inflammation), stimulation of endothelial cell production by other factors (eg, example, metalloproteinases, growth factors, and inhibitors of angiogenesis), and apoptosis.

The invention described above is now defined in the appended claims.

SEQUENCE LIST < 110 > Amgen Inc < 120 > RELATED DELTA POLYPEPTIDES < 130 > Revised A531US < 140 > 09/123, 168 < 141 > 1998 - 07-27 < 160 > 80 < 170 > Patentln Ver. 2.1 < 210 > 1 < 211 > 2058 < 212 > DNA < 213 > Mus musculus < 400 > 1 atgacgcctg cgtcccggag cgcctgtcgc tgggcgctac tgctgctggc ggtactgtgg 60 ccgcagcagc gcgctgcggg ctccggcatc ttccagctgc ggc gcagga gttcgtcaac 120 tgctggccaa cagcgcggta tgggcagtcc tgcgaaccgg gctgccggac tttcttccgc 180 atttgcctta agcacttcca ggcaaccttc tccgagggac cctgcacctt tggcaatgtc 240 tccacgccgg tattgggcac caactccttc gtcgtcaggg acaagaatag cggcagtggt 300 cgcaaccctc tgcagttgcc cttcaatttc acctggccgg gaaccttctc actcaacatc 360 caagcttggc acacaccggg agacgacctg cggccagaga cttcgccagg aaactctctc 420 tcatcatcca atcagccaaa aggctctctt gctgtgggta agatttggcg aacagacgag 480 caaaacgaca ccctcaccag actgagctac tcttaccggg tcatctgcag tgacaactac 540 tatggagaga gctgttctcg cctatgcaag aagcgcgatg accacttcgg acattatgag 600 tgccagccag atggcagcct gtcctgcctg ccgggctgga ctgggaagta ctgtgaccag 660 cccatatgtc tttctggctg tcatgagcag aatggttact gcagcaagcc agatgagtgc 720 caggttggca atctgccgtc gggtcgcctg tgcaatgaat gtatccccca gt caatggc 780 cgtcatggca cctgcagcat cccctggcag tgtgcctgcg atgagggatg gggaggtctg 840 ttttgtgacc aagatctc aa ctactgtact caccactctc cgtgcaagaa tggatcaacg 900 gtgggccaaa tgttccaaca gggttatacc tgcacctgtc tcccaggcta cactggtgag 960 cactgtgagc tgggactcag caagtgtgcc agcaacccct gtcgaaatgg tggcagctgt 1020 aaggaccagg agaatagcta ccactgcctg tgtcccccag gctactatgg ccagcactgt 1080 ccttgacctg gagcatagta ccctgcttca tgcggactca atgggggctc ttgccgggag 1140 ggtccagtta cgcaaccagg tgcctgcgaa tgccccccca actttaccgg ctctaactgt 1200 gagaagaaag tagacaggtg taccagcaac atggaggcca ccgtgtgcca gtgcctgaac 1260 agaggtccaa gccgaacctg ccgctgccgg caggcaccca cctggattca ctgtgaactg 1320 cacatcagcg attgtgcccg aagtccctgt gcccacgggg gcacttgcca cgatctggag 1380 aatgggcctg tgtgcacctg ccccgctggc ttctctggca ggtgcggata ggcgctgcga 1440 acccacgatg cctgtgcctc cggaccctgc ttcaatgggg ccacctgcta cactggcctc 1500 tccccaaaca acttcgtctg caactgtcct tatggctttg tgggcagccg ctgcgagttt 1560 cccgtgggct tgccacccag cttcccctgg gtagctgtct cgctgggcgt ggggctagtg 1620 gtactgctgg tgctgctggt catggtggta gtggctgtgc ggcagctgcg gcttcggagg 1680 agagcaggga cccgatgacg agcca tgaac aatctgtcag acttccagaa ggacaaccta 1740 atccctgccg cccagctcaa aaacacaaac cagaagaagg agctggaagt ggactgtggt 1800 ctggacaagt ccaattgtgg caaactgcag aaccacacat tggactacaa tctagccccg 1860 ggactcctag gacggggcag catgcctggg aagtatcctc gagcttagga acagtgacaa 1920 gagaaggtgc cacttcggtt acacagtgag aagccagagt gtcgaatatc agccatttgc 1980 tctcccaggg actctatgta ccaatcagtg tgtttgatat cagaagagag gaacgagtgt cagaggta gtgattgcca 2040 2058 < 210 > 2 < 211 > 686 < 212 > PRT < 213 > Mus musculus < 400 > 2 Met Thr Pro Ala Ser Arg Be Ala Cys Arg Trp Ala Leu Leu Leu Leu 1 5 10 15 Wing Val Leu Trp Pro Gln Gln Arg Wing Wing Gly Ser Gly He Phe Gln 20 25 30 Leu Arg Leu Gln Glu Phe Val Asn Gln Arg Gly Met Leu Wing Asn Gly 35 40 45 Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg lie Cys Leu Lys 50 55 60 His Phe Gln Wing Thr Phe Ser Glu Gly Pro Cys Thr Phe Gly Asn Val 65 70 75 80 Be Thr Pro Val Leu Gly Thr Asn Ser Phe Val Val Arg Asp Lys Asn 85 90 95 Ser Gly Ser Gly Arg Asn Pro Leu Gln Leu Pro Phe Asn Phe Thr Trp 100 105 110 Pro Gly Thr Phe Ser Leu Asn He Gln Wing Trp His Thr Pro Gly Asp 115 120 125 Asp Leu Arg Pro Glu Thr Ser Pro Gly Asn Ser Leu He Ser Gln He 130 135 140 He He Gln Gly Ser Leu Ala Val Gly Lys He Trp Arg Thr Asp Glu 145 150 155 160 Gln Asn Asp Thr Leu Thr Arg Leu Ser Tyr Ser Tyr Arg Val He Cys 165 170 175 Being Asp Asn Tyr Tyr Gly Glu Being Cys Being Arg Leu Cys Lys Lys Arg 180 185 190 Asp Asp His Phe Gly His Tyr Glu Cys Gln Pro Asp Gly Ser Leu Ser 195 200 205 Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys Asp Gln Pro He Cys Leu 210 215 220 Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys Pro Asp Glu Cys 225 230 235 240 He Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu Cys He Pro 245 250 255 His Asn Gly Cly Arg His Gly Thr Cys Ser He Pro Trp Gln Cys Wing 260 265 270 Cys Asp Glu Gly Trly Gly Gly Leu Phe Cys Asp Gln Asp Leu Asn Tyr 275 280 285 Cys Thr His His Ser Pro Cys Lys Asn Gly Ser Thr Cys Ser Asn Ser 290 295 300 Gly Pro Lys Gly Tyr Thr Cys Thr Cys Leu Pro Gly Tyr Thr Gly Glu 305 310 315 320 His Cys Glu Leu Gly Leu Ser Lys Cys Wing Ser Asn Pro Cys Arg Asn 325 330 335 Gly Gly Ser Cys Lys Asp Glp Glu Asn Ser Tyr His Cys Leu Cys Pro 340 345 350 Pro Gly Tyr Tyr Gly Gln His Cys Glu His Ser Thr Leu Thr Cys Ala 355 360 365 Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg Asn Gln Gly 370 375 380 Ser Ser Tyr Ala Cys Glu Cys Pro Pro Asn Phe Thr Gly Ser Asn Cys 385 390 395 400 Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro Cys Wing Asn Gly Gly 405 410 415 Gln Cys Leu Asn Arg Gly Pro Be Arg Thr Cys Arg Cys Arg Pro Gly 420 425 430 Phe Thr Gly Thr His Cys Glu Leu His He Ser Asp Cys Ala Arg Ser 435 440 445 Pro Cys Ala His Gly Gly Thr Cys His Asp Leu Glu Asn Gly Pro Val 450 455 460 Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg Cys Glu Val Arg He 465 470 475 480 Thr His Asp Wing Cys Wing Ser Gly Pro Cys Phe Asn Gly Wing Thr Cys 485 490 '495 Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val Cys Asn Cys Pro Tyr Gly 500 505 510 Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro Pro Ser Phe 515 520 525 Pro Trp Val Wing Val Ser Leu Gly Val Gly Leu Val Val Leu Leu Val 530 535 540 Leu Leu Val Val Val Val Ala Val Arg Gln Leu Arg Leu Arg Arg 545 550 555 560 Pro Asp Asp Glu Be Arg Glu Ala Met Asn Asn Leu Be Asp Phe Gln 565 570 575 Lys Asp Asn Leu He Pro Wing Wing Gln Leu Lys Asn Thr Asn Gln Lys 580 585 590 Lys Glu Leu Glu Val Asp Cys Gly Leu Asp Lys Ser Asn Cys Gly Lys 595 600 605 Leu Gln Asn His Thr Leu Asp Tyr Asn Leu Ala Pro Gly Leu Leu Gly 610 615 620 Arg Gly Ser Met Pro Gly Lys Tyr Pro His Ser Asp Lys Ser Leu Gly 625 630 635 640 Glu Lys Val Pro Leu Arg Leu His Ser Glu Lye Pro Glu Cys Arg He 645 650 655 Be Ala He Cys Ser Pro Arg Asp Ser Met Tyr Gln Ser Val Cys Leu 660 665 670 He Ser Glu Glu Arg Asn Glu Cys Val He Ala Thr Glu Val 675 680 685 < 210 > 3 < 211 > 2055 < 2I2 > AON < 213 > Homo sapiens < 400 > 3 atggcggcag cgtcccggag cgcctctggc tgggcgctac tgctgctggt ggcactttgg 60 cagcagcgcg cggccggc c cggcgtcttc cagctgcagc tgcaggagtt catcaacgag 120 cgcggcgtac tggccagtgg gcggccttgc gagcccggct gccggacttt cttccgcgtc 180 tgccttaagc acttccaggc ggtcgtctcg cccggaccct gcaccttcgg gaccgtctcc 240 acgccggtat tgggcaccaa ctccttcgct gtccgggacg acagtagcgg cggggggcgc 300 aaccctctcc aactgccctt caatttcacc tggccgggta ccttctcgct catcatcgaa 360 gcttggcacg cgccaggaga cgacctgcgg ccagaggcct tgccaccaga tgcactcatc 420 agcaagatcg ccatccaggg ctccctagct gtgggtcaga actggttatt ggatgagcaa 480 accagcaccc tcacaaggct gcgctactct taccgggtca tctgcagtga caactactat 540 ggagacaact gctcccgcct gtgcaagaag cgcaatgacc acttcggcca ctatgtgtgc 600 cagccagatg gcaacttgtc ctgcctgccc ggttggactg gggaatattg ccaacagcct 660 atctgtcttt cgggctgtca tgaacagaat ggctactgca gcaagccagc agagtgcctc 720 tgccgcccag gctggcaggg ccggctgtgt aacgaatgca tcccccacaa tggctgtcgc 780 cacggcacct gcagcactcc ctggcaatgt acttgtgatg agggctgggg aggcctgttt 840 tgtgaccaag atctcaacta ctgcacccac cactccccat gcaagaatgg ggcaacgtgc 900 tccaacagcg ggcagcgaag ctacacctgc acctgtcgcc caggctacac tggtgtggac 960 tgtgagctgg agctcagcga gtgtgacagc aacccctgtc gcaatggagg cagctgtaag 1020 atggctacca gaccaggagg ctgcctgtgt cctccgggct actatggcct gcattgtgaa 1080 cacagcacct tgagctgcgc cgactccccc tgcttcaatg ggggctcctg ccgggagcgc 1140 aaccaggggg ccaactatgc ttgtgaatgt ccccccaact tcaccggctc caactgcgag 1200 aagaaagtgg acaggtgcac cagcaacccc tgtgccaacg ggggacagtg cctgaaccga 1260 ggtccaagcc gcatgtgccg ctgccgtcct ggattcacgg gcacctactg tgaactccac 1320 gtgcccgtaa gtcagcgact cacggtggca cccttgcgcc cttgccatga cctggagaat 1380 gggctcatgt gcacctgccc tgccggcttc tctggccgac gc gtgaggt gcggacatcc 1440 atcgatgcct gtgcctcgag tccctgcttc aacagggcca cctgctacac cgacctctcc 1500 acagacacct ttgtgtgcaa ctgcccttat ggctttgtgg gcagccgctg cgagttcccc 1560 gtgggcttgc cgcccagctt cccctgggtg gccgtctcgc tgggtgtggg gctggcagtg 1620 ctgctggtac tgctgggcat ggtggcagtg gctgtgcggc agctgcggct tcgacggcc 1680 g gacgacggca gcagggaagc catgaacaac ttgtcggact tccagaagga caacctgatt 1740 cctgccgccc agcttaaaaa cacaaaccag aagaaggagc tggaagtgga ctgtggcctg 1800 actgtggcaa gacaagtcca acagcaaaac cacacattgg actataatct ggccccaggg 1860 cccctggggc gggggaccat gccaggaaag tttccccaca gtgacaagag cttaggagag 1920 tgcggttaca aaggcgccac cagtgaaaag ccagagtgtc ggatatcagc gatatgctcc 1980 ccatgtacca cccagggact gtctgtgtgt ttgatatcag aggagaggaa tgaatgtgtc attgccacgg AGGTA 2040 2055 < 210 > 4 < 211 > 685 < 212 > PRT < 213 > Homo sapiens < 400 > 4 Met Wing Wing Wing Being Arg Being Wing Being Gly Trp Wing Leu Leu Leu Leu 1 5 10 15 Val Wing Leu Trp Gln Gln Arg Wing Wing Gly Being Gly Val Phe Gln Leu 20 25 30 Gln Leu Gln Glu Phe He Asn Glu Arg Gly Val Leu Wing Ser Gly Arg 35 40 45 Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg Val Cys Leu Lys His 50 55 60 Phe Gln Wing Val Val Ser Pro Gly Pro Cys Thr Phe Gly Thr Val Ser 65 70 75 80 Thr Pro Val Leu Gly Thr Asn Ser Phe Wing Val Arg Asp Asp Ser Ser 85 90 95 Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro Phe Asn Phe Thr Trp Pro 100 105 110 Gly Thr Phe Ser Leu He He Glu Wing Trp His Wing Pro Gly Asp Asp 115 120 125 Leu Arg Pro Glu Wing Leu Pro Pro Asp Wing Leu He Ser Lys He Wing 130 135 140 He Gln Gly Ser Leu Wing Val Gly Gln Asn Trp Leu Leu Asp Glu Gln 145 150 155 160 Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser Tyr Arg Val He Cys Ser 165 170 175 Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu Cys Lys Lys Arg Asn 180 185 190 Asp His Phe Gly His Tyr Val Cys Gln Pro Asp Gly Asn Leu Ser Cys 195 200 205 Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln Gln Pro He Cys Leu Ser 210 215 220 Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys Pro Wing Glu Cys Leu 225 230 235 240 Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu Cys He Pro His 245 • 250 255 Asn Gly Cys Arg His Gly Thr Cys Ser Thr Pro Trp Gln Cys Thr Cys 260 265 270 Asp Glu Gly Trly Gly Gly Leu Phe Cys Asp Gln Asp Leu Asn Tyr Cys 275 280 285 Thr His His Ser Pro Cys Lys Asn Gly Ala Thr Cys Ser Asn Ser Gly 290 295 300 Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro Gly Tyr Thr Gly Val Asp 305 310 315 320 Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser Asn Pro Cys Arg Asn Gly 325 330 335 Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr His Cys Leu Cys Pro Pro 340 345 350 Gly Tyr Tyr Gly Leu His Cys Glu His Ser Thr Leu Ser Cys Wing Asp 355 360 365 Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg Asn Gln Gly Wing 370 375 380 Asn Tyr Wing Cys Glu Cys Pro Pro Asn Phe Thr Gly Ser Asn Cys Glu 385 390 395 400 Lys Lys Val Asp Arg Cys Thr Ser Asn Pro Cys Wing Asn Gly Gly Gln 405 410 415 Cys Leu Asn Arg Gly Pro Be Arg Met Cys Arg Cys Arg Pro Gly Phe 420 425 430 Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp Cys Ala Arg Asn Pro 435 440 445 Cys Ala His Gly Gly Thr Cys His Asp Leu Glu Asn Gly Leu Met Cys 450 455 460 Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg Cys Glu Val Arg Thr Ser 465 470 475 480 He Asp Wing Cys Wing Being Ser Pro Cys Phe Asn Arg Wing Thr Cys Tyr 485 490 495 Thr Asp Leu Ser Thr Asp Thr Phe Val Cys Asn Cys Pro Tyr Gly Phe 500 505 510 Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro Pro Ser Phe Pro 515 520 525 Trp Val Val Val Ser Leu Val Val Gly Leu Val Val Leu Leu Val Leu 530 535 540 Leu Gly Met Val Wing Val Wing Val Arg Gln Leu Arg Leu Arg Arg Pro 545 550 555 560 Asp Asp Gly Ser Arg Glu Wing Met Asn Asn Leu Ser Asp Phe Gln Lys 565 570 575 Asp Asn Leu He Pro Wing Wing Gln Leu Lys Asn Thr Asn Gln Lys Lys 580 585 590 Glu Leu Glu Val Asp Cys Gly Leu Asp Lys Ser Asn Cys Gly Lys Gln 595 600 • 605 Gln Asn His Thr Leu Asp Tyr Asn Leu Ala Pro Gly Pro Leu Gly Arg 610 615 620 Gly Thr Met Pro Gly Lys Phe Pro His Ser Asp Lys Ser Leu Gly Glu 625 630 635 640 Lys Ala Pro Leu Arg Leu His Ser Glu Lys Pro Glu Cys Arg He Ser 645 650 655 Wing He Cys Ser Pro Arg Asp Ser Met Tyr Gin Ser Val Cys Leu He 660 665 670 Ser Glu Glu Arg Asn Glu Cys Val He Wing Thr Glu Val 675 680 685 < 210 > 5 < 211 > 510 < 212 > PRT < 213 > Mus musculus < 400 > 5 Gln Arg Ala Ala Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe 1 5 10 15 Val Asn Gln Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly 25 30 Cys Arg Thr Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe 35 40 45 Ser Glu Gly Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly 50 55 60 Thr Asn Ser Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn 65 70 75 80 Pro Leu Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu 85 90 95 Asn He Gln Wing Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr 100 105 110 Ser Pro Gly Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu 115 120 125 Wing Val Gly Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr 130 135 140 Arg Leu Ser Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly 145 150 155 160 Glu Ser Cys Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His 165 170 175 Tyr Glu Cys Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr 180 185 190 Gly Lys Tyr Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln 195 200 205 Asn "Gly Tyr Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp 210 215 220 Gln Gly Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His 225 230 235 240 Gly Thr Cys Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly 245 250 255 Gly Leu Phe As Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro 260 265 270 Cys Lys Asn Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr 275 '280 285 Cys Thr Cys Leu Pro Gly Tyr Thr Gly Glu His Cye Glu Leu Gly Leu 290 295 300 Ser Lys Cys Wing Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp 305 310 315 320 Gln Glu Asn Ser Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln 325 330 335 His Cys Glu His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn 340 345 350 Gly Gly Ser Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu 355 360 365 Cys Pro Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg 370 375 380 Cys Thr Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly 385 390 395 400 Pro Ser Arg Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys 405 410 415 Glu Leu His He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly 420 425 430 Thr Cys His Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly 435 440 445 Phe Ser Gly Arg Arg Cys Glu Val Arg He Thr His Asp Ala Cys Wing 450 455 460 Ser Gly Pro Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro 465 470 475 480 Asn Asn Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys 485 490 495 Glu Phe Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Ala 500 505 510 < 210 > 6 < 211 > 509 < 212 > PRT < 213 > Mus musculus < 400 > 6 Arg Ala Ala Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val 1 5 10 15 Asn Gln Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys 20 25 30 Arg Thr Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser 35 40 45 Glu Gly Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr 50 55 60 Asn Ser Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro 65 70 75 80 Leu Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn 85 90 95 He Gln Wing Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser 100 105 - 110 Pro Gly Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu Wing 115 120 125 Val Gly Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg 130 135 140 Leu Ser Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu 145 150 155 160 Ser Cys Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr 165 170 175 Glu Cys Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly 180 185 190 Lys Tyr Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn 195 200 205 Gly Tyr Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln 210 215 220 Gly Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly 225 230 235 240 Thr Cys Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly 245 250 255 Leu Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys 260 265 270 Lys Asn Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys 275 280 285 Thr Cys Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser 290 295 300 Lys Cys Wing Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln 305 310 315 320 Glu Asn Ser Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His 325 330 335 Cys Glu His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly 340 345 350 Gly Ser Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys 355 360 365 Pro Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lye Val Asp Arg Cys 370 375 380 Thr Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro 385 390 395 400 Being Arg Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu 405 410 415 Leu His He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr 420 425 430 Cys His Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe 435 440 445 Ser Gly Arg Arg Cys Glu Val Arg He Thr His Asp Wing Cys Wing Ser 450 455 460 Gly Pro Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn 465 470 475 480 Asn Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu 485 490 495 Phe Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Ala 500 505 < 210 > 7 < 211 > 508 < 212 > PRT < 213 > Mus musculus < 400 > 7 Ala Ala Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn 1 5 10 15 Gln Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg 20 25 30 Thr Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu 35 40 45 Gly Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn 50 55 60 Ser Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu 65 70 75 80 Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He 85 90 95 Gln Ala Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro 100 105 110 Gly Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu Ala Val 115 120 125 Gly Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu 130 135 140 Ser Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser 145 150 155 160 Cys Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu 165 170 175 Cys Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys 180 185 190 Tyr Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly 195 200 205 Tyr Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly 210 215 220 Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr 225 230 235 240 Cys Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu 245 250 255 Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cye Lys 260 265 270 Asn Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr 275. 280 285 Cys Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys 290 295 300 Cys Ala Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu 305 310 315 320 -Asn Ser Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys 325 330 335 Glu His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly 340 345 350 Ser Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys Pro 355 360 365 Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr 370 375 380 Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser 385 390 395 400 Arg Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu 405 410 415 His He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys 420 425 430 His Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser 435 440 445 Gly Arg Arg Cys Glu Val Arg He Thr His Asp Ala Cys Wing Ser Gly 450 455 460 Pro Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn 465 470 475 480 Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe 485 490 495 Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Ala 500 505 < 210 > 8 < 211 > 507 < 212 > PRT < 213 > Mus musculus < 400 > 8 Wing Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn Gln 1 5 10 '15 Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg Thr 20 25 30 Phe Phe Arg He Cys Leu Lys His Phe Glp Wing Thr Phe Ser Glu Gly 35 40 45 Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn Ser 50 55 60 Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu Gln 65 70 75 80 Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He Gln 85 90 95 Wing Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro Gly 100 105 110 Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu Ala Val Giy 115 120 125 Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu Ser 130 135 140 Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser Cys 145 150 155 160 Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu Cys 165 170 175 Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys Tyr 180 185 190 Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr 195 200 205 Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly Arg 210 215 220 Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys 225 230 235 240 Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu Phe 245 250 255 Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn 260 265 270 Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr Cys 275 280 285 Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys Cys 290 295 300 Aia Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asn 305 310 • 315 320 Ser Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys Glu 325 330 335 His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser 340 345 350 Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys Pro Pro 355 360 365 Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser 370 375 380 Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg 385 390 395 400 Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu His 405 410 415 He Be Asp Cys Ala Arg Ser Pro Cys Ala His Gly Gly Thr Cys His 420 425 430 Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser Gly 435 440 445 Arg Arg Cys Glu Val Arg He Thr His Asp Wing Cys Wing Ser Gly Pro 450 455 460 Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn Phe 465 470 475 480 Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro 485 490 495 Val Gly Leu Pro Pro Ser Phe Pro Trp Val Wing 500 505 < 210 > 9 < 211 > 506 < 212 > PRT < 213 > Mus musculus < 400 > 9 Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn Gln Arg 1 5 10 15 Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe 20 25 30 Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu Gly Pro 35 40 45 Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe 50 55 60 Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu Gln Leu 65 70 75 80 Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He Gln Wing 85 90 95 Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro Gly Asn 100 105 110 Ser Leu He Ser Gln He He He Gln Gly Ser Leu Ala Val Gly Lys 115 120 125 He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu Ser Tyr 130 135 140 Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser Cys Ser 145 150 155 160 Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu Cys Gln 165 170 175 Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys 180 185 190 Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys 195 200 205 Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly Arg Leu 210 215 220 Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser 225 230 235 240 He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys 245 250 255 Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly 260 265 270 Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr Cys Leu 275 280 285 Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys Cys Wing 290 295 300 Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asn Ser 305 310 315 320 Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys Glu His 325 330 335 Be Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys 340 345 350 Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys Pro Pro Asn 355 360 365 Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn 370 375 380 Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Thr 385 390 395 400 Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu His He 405 410 415 Be Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys His Asp 420 425 430 Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg 435 440 445 Arg Cys Glu Val Arg He Thr His Asp Ala Cys Ala Ser Gly Pro Cys 450 455 460 Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val 465 470 475 480 Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val 485 490 495 Gly Leu Pro Pro Ser Phe Pro Trp Val Wing 500 505 < 210 > 10 < 211 > 505 < 212 > PRT < 213 > Mus musculus < 400 > 10 Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn Gln Arg Gly 15 Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu Gly Pro Cys 35 40 45 Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Val 50 55 60 Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu Gln Leu Pro 65 70 75 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He Gln Wing Trp 85 90 95 His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro Gly Asn Ser 100 105 110 Leu He Ser Gln He He He Gln Gly Ser Leu Wing Val Gly Lys He 115 120 125 Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu Ser Tyr Ser 130 135 140 Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser Cys Ser Arg 145 150 155 160 Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu Cys Gln Pro 165 170 175 Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys Asp 180 185 190 Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 195 200 205 Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys 210 215 220 Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser He 225 230 235 240 Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245 250 255 Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ser 260 265 270 Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr Cys Leu Pro 275 280 285 Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys Cys Wing Ser 290 295 300 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asn Ser Tyr 305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys Glu His Ser 325 330 335 Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Asn Gln Gly Be Ser Tyr Wing Cys Glu Cys Pro Pro Asn Phe 355 360 365 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 Cye Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Thr Cys 385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu His He Ser 405 410 415 Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys His Asp Leu 420 425 430 Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg He Thr His Asp Wing Cys Wing Gly Pro Cys Phe 450 455 460 Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val Cys 465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 Leu Pro Pro Ser Phe Pro Trp Val Ala 500 505 < 210 > 11 < 211 > 531 < 212 > PRT < 213 > Mus musculus < 400 > 11 Gln Arg Ala Ala Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe 1 5 10 15 Val Asn Gln Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly 20 25 30 Cys Arg Thr Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe 35 40 • 45 Ser Glu Gly Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly 50 55 60 Thr Asn Ser Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn 65 70 75 80 Pro Leu Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu 85 90 95 Asn He Gln Wing Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr 100 105 110 Ser Pro Gly Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu 115 120 125 Wing Val Gly Lys He Trp Arg Thr Asp Glu Gln Aen Asp Thr Leu Thr 130 135 140 Arg Leu Ser Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly 145 150 155 160 Glu Ser Cys Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His 165 170 175 Tyr Glu Cys Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr 180 185 190 Gly Lys Tyr Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln 195 200 205 Asn Gly Tyr Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp 210 215 220 Gln Gly Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His 225 230 235 240 Gly Thr Cys Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly 245 250 255 Gly Leu Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro 260 265 270 Cys Lys Asn Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr 275 280 285 Cys Thr Cys Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu 290 295 300 Ser Lys Cye Wing Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp 305 310 315 320 Gln Glu Asn Ser Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln 325 330 335 His Cys Glu His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn 340 345 350 Gly Gly Ser Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu 355 360 365 Cys Pro Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg 370 375 380 Cys Thr Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly 385 390 395 400 Pro Ser Arg Thr Cys Arg Cys Arg Pro Gly Phe Thr.Gly Thr His Cys 405 410 415 Glu Leu His He Ser Asp Cys Wing Arg Ser Pro Cys Wing Hie Gly Gly 420 425 430 Thr Cys His Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly 435 440 445 Phe Ser Gly Arg Arg Cys Glu Val Arg He Thr His Asp Ala Cys Wing 450 455 460 Ser Gly Pro Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro 465 470 475 480 Asn Asn Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys 485 490 495 Glu Phe Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Val Val Ser 500 505 510 Leu Gly Val Val Le Val Val Val Leu Leu Val Leu Le Val Val Val Val 515 520 525 Val Val Val 530 < 210 > 12 < 211 > 530 < 212 > PRT < 213 > Mus musculus < 400 > 12 Arg Ala Ala Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val 1 5 10 15 Asn Gln Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys 20 25 30 Arg Thr Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser 35 40 45 Glu Gly Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr 50 55 60 Asn Ser Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro 65 70 75 80 Leu Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn 85 90 95 He Gln Wing Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser 100 105 110 Pro Gly Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu Ala 115 120 125 Val Gly Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg 130 135 140 Leu Ser Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu 145 150 155 160 Ser Cys Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr 165 170 175 Glu Cys Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly 180 185 190 Lys Tyr Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn 195 200 205 Gly Tyr Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln 210 215 220 Gly Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly 225 230 235 240 Thr Cys Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly 245 250 '255 Leu Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys 260 265 270 Lys Asn Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys 275 280 285 Thr Cys Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser 290 295 300 Lys Cys Wing Ser Asn Pro Cye Arg Asn Gly Gly Ser Cys Lys Asp Gln 305 310 315 320 Glu Asn Ser Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His 325 330 335 Cys Glu His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly 340 345 350 Gly Ser Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys 355 360 365 Pro Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys 370 375 380 Thr Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro 385 390 395 400 Being Arg Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu 405 410 415 Leu His He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr 420 425 430 Cys His Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe 435 440 445 Ser Gly Arg Arg Cys Glu Val Arg He Thr His Asp Wing Cys Wing Ser 450 455 460 Gly Pro Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn 465 470 475 480 Asn Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu 485 490 495 t • Phe Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Ala Val Ser Leu 500 505 510 Gly Val Gly Leu Val Val Leu Leu Val Leu Le Val Val Val Val 515 520 525 Val 530 Val < 210 > 13 < 211 > 529 < 212 > PRT < 213 > Mus musculus < 400 > 13 Ala Ala Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn 1 5 10 15 Gln Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg 20 25 30 Thr Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu 35 40 45 Gly Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asr. 50 55 60 Ser Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu 65 70 75 80 Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He 85 90 95 Gln Ala Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro 100 105 110 Gly Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu Ala Val 115 120 125 Gly Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu 130 135 140 Ser Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser 145 150 155 160 Cys Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu 165 170 175 Cys Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys 180 185 190 Tyr Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly 195 200 205 Tyr Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly - 210 215 220 Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr 225 230 235 240 Cys Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu 245 250 255 Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys 260 265 270 Asn Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr 275 280 285 Cys Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys' 290 295 300 Cys Wing Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu 305 310 315 320 Asn Ser Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys 325 330 335 Glu His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly 340 345 350 Ser Cys Arg Glu Arg Asn Gln Gly Be Ser Tyr Wing Cys Glu Cys Pro 355 360 365 Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr 370 375 380 Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg-Gly Pro Ser 385 390 395 400 Arg Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu 405 410 415 His He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys 420 425 430 His Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser 435 440 445 Gly Arg Arg Cys Glu Val Arg He Thr His Asp Ala Cys Wing Ser Gly 450 455 460 Pro Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn 465 470 475 480 Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe 485 490 495 Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly 500 505 510 Val Gly Leu Val Val Leu Leu Val Val Leu Leu Val Val Val Val Ala 515 520 525 Val < 210 > 14 < 211 > 528 < 212 > PRT < 213 > Mus musculue < 400 > 14 Wing Gly Ser Gly lie Phe Gln Leu Arg Leu Gln Glu Phe Val Asn Gln 1 5 10 15 Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg Thr 20 25 30 Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu Gly 35 40 45 Pro Cye Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn Ser 50 55 60 Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu Gln 65 70 75 80 Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He Gln 85 90 95 Wing Trp Hie Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro Gly 100 105 110 Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu Wing Val Gly 115 120 125 Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu Ser 130 135 140 Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser Cys 145 150 155 160 Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu Cys 165 170 175 Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys Tyr 180 185 190 Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr 195 200 205 Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly Arg 210 215 220 Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cye 225 230 235 240 Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu Phe 245 250 255 Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn 260 265 270 Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr Cys 275 280 285 Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys Cys 290 295 300 Wing Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asn 305 310 315 320 Ser Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys Glu 325 330 335 His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser 340 345 350 Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys Pro Pro 355 360 365 Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser 370 375 380 Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg 385 390 395 400 Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu His 405 410 415 He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys His 420 425 430 Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser Gly 435 440 445 Arg Arg Cys Glu Val Arg He Thr His Asp Wing Cys Wing Ser Gly Pro 450 455 460 Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn Phe 465 470 475 480 Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro 485 490 495 Val Gly Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val 500 505 510 Gly Leu Val Val Leu Leu Val Val Leu Leu Val Val Val Val Ala Val 515 520 525 < 210 > 15 < 211 > 527 < 212 > PRT < 213 > Mus musculus < 400 > 15 Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn Gln Arg 1 5 10 15 Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe 20 25 30 Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu Gly Pro 35 40 45 Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe 50 55 60 Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu Gln Leu 65 70 75 80 Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He Gln Wing 85 90 - 95 Trp His Thr Pro Gly Asp Aep Leu Arg Pro Glu Thr Ser Pro Gly Asn 100 105 110 Ser Leu He Ser Gln He He He Gln Gly Ser Leu Wing Val Gly Lys 115 120 125 He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu Ser Tyr 130 135 140 Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser Cys Ser 145 150 155 160 Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu Cys Gln 165 170 175 Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys 180 185 190 Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys 195 200 205 Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly Arg Leu 210 215 220 Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser 225 230 235 240 He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys 245 250 255 Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly 260 265 270 Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr Cys Leu 275 280 285 Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lye Cys Wing 290 295 300 Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asn Ser 305 310 315 320 Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys Glu His 325 330 335 Be Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys 340 345 350 Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys Pro Pro Asn 355 360 365 Phe Thr Gly Ser Asn Cys Glu Lys Lye Val Asp Arg Cys Thr Ser Asn 370 375 380 Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Thr 385 390 395 400 Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu His He 405 410 415 Be Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys His Asp 420 425 430 Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg 435 440 445 Arg Cys Glu Val Arg He Thr His Asp Ala Cys Ala Ser Gly Pro Cys 450 455 460 Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val 465 470 475 480 Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val 485 490 495 Gly Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly 500 505 510 Leu Val Val Leu Leu Val Leu Val Val Met Val Val Val Ala 515 520 525 < 210 > 16 < 211 > 526 < 212 > PRT < 213 > Mus musculus < 400 > 16 Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn Gln Arg Gly 1 5 10 15 Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu Gly Pro Cys 35 40 45 Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Val 50 - 55 60 Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu Gln Leu Pro 65 70 75 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He Gln Wing Trp 85 90 95 His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro Gly Asn Ser 100 105 110 Leu He Ser Gln He He He Gln Gly Ser Leu Wing Val Gly Lys He 115 120 125 Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu Ser Tyr Ser 130 135 140 Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser Cys Ser Arg 145 150 155 160 Leu Cys Lys Lys Arg Asp Ásp His Phe Gly His Tyr Glu Cys Gln Pro 165 170 175 Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys Asp 180 185 190 Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 195 200 205 Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys 210 215 220 Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser He 225 230 235 240 Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245 250 '255 Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ser 260 265 270 Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr Cys Leu Pro 275 280 285 Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys Cys Wing Ser 290 295 300 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asn Ser Tyr 305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys Glu His Ser 325 330 335 Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys Pro Pro Asn Phe 355 360 365 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Thr Cye 385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr Hie Cys Glu Leu His He Ser 405 410 415 Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys His Asp Leu 420 425 430 Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg He Thr His Asp Wing Cys Wing Gly Pro Cys Phe 450 455 460 Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val Cys 465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly Leu 500 505 510 Val Val Leu Leu Val Val Leu Leu Val Val Val Val Val Val 515 520 525 < 210 > 17 < 211 > 664 < 212 > PRT < 213 > Mus musculus < 400 > 17 Gln Arg Ala Ala Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe 1 5 10 15 Val Asn Gln Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly 20 25 30 Cys Arg Thr Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe 35 40 45 Ser Glu Gly Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly 50 55 60 Thr Asn Ser Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn 65 70 75 80 Pro Leu Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu 85 90 95 Asn He Gln Wing Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr 100 105 110 Ser Pro Gly Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu 115 120 125 Wing Val Gly Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr 130 135 140 Arg Leu Ser Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly 145 150 155 160 Glu Ser Cys Ser Arg Leu Cye Lys Lys Arg Asp Asp His Phe Gly His 165 170 175 Tyr Glu Cys Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr 180 185 190 Gly Lys Tyr Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln 195 200 205 Asn Gly Tyr Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp 210 215 220 Gln Gly Arg Leu Cys Aen Glu Cys He Pro His Asn Gly Cys Arg His 225 230 235 240 Gly Thr Cys Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly 245 250 255 Gly Leu Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro 260 265 270 Cys Lys Asn Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr 275 280 285 Cys Thr Cys Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu 290 295 300 Ser Lys Cys Wing Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp 305 310 315 320 Gln Glu Asn Ser Tyr His Cye Leu Cys Pro Pro Gly Tyr Tyr Gly Gln 325 330 335 His Cys Glu His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn 340 345 350 Gly Gly Ser Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu 355 360 365 Cys Pro Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg 370 375 380 Cys Thr Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly 385 390 395 400 Pro Ser Arg Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys 405 410 415 Glu Leu His He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly 420 425"430 Thr Cys His Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly 435 440 445 Phe Ser Gly Arg Arg Cys Glu Val Arg He Thr His Asp Ala Cys Aia 450 455 460 Ser Gly Pro Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro 465 470 475 480 Asn Asn Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys 485 490 495 Glu Phe Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser 500 505 510 Leu Gly Val Val Val Val Leu Leu Val Leu Leu Val Met Val Val 515 520 525 Val Val Val Arg Gln Leu Le Arg Le Arg Pro Asp Asp Glu Ser Arg 530 535 540 Glu Wing Met Asn Asn Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro 545 550 555 560 Ala Ala Gln Leu Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp 565 570 575 Cys Gly Leu Asp Lys Ser Asn Cys Gly Lys Leu Gln Asn His Thr Leu 580 585 590 Asp Tyr Asn Leu Wing Pro Gly Leu Leu Gly Arg Gly Be Met Pro Gly 595 600 605 Lys Tyr Pro His Ser Asp Lys Ser Leu Gly Glu Lys Val Pro Leu Arg 610 615 620 Leu His Ser Glu Lys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro 625 630 635 640 Arg Asp Ser Met Tyr Gln Ser Val Cys Leu He Ser Glu Glu Arg Asn 645 650 655 Glu Cys Val He Wing Thr Glu Val 660 < 210 > 18 < 211 > 663 < 212 > PRT < 213 > Mus musculus < 400 > 1.8 Arg Ala Ala Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val 1 5 '10 15 Asn Gln Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys 20 25 30 Arg Thr Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser 35 40 45 Glu Gly Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr 50 55 60 Asn Ser Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro 65 70 75 80 Leu Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn 85 90 95 He Gln Wing Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser 100 105 110 Pro Gly Asn Ser Leu He Ser Gl'n He He He Gln Gly Ser Leu Aia 115 120 125 Val Gly Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg 130 135 140 Leu Ser Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu 145 150 155 160 Ser Cys Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr 165 170 175 Glu Cys Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly 180 185 190 Lys Tyr Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn 195 200 205 Gly Tyr Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln 210 215 220 Gly Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly 225 230, 235 240 Thr Cys Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly 245 250 255 Leu Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys 260 265 270 Lys Asn Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys 275 280 285 Thr Cys Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser 290 295 300 Lys Cys Wing Ser Aen Pro Cye Arg Asn Gly Gly Ser Cys Lys Asp Gln. 305 310 315 320 Glu Asn Ser Tyr Hie Cye Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His 325 330 335 Cys Glu His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly 340 345 350 Gly Ser Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys 355 360 365 Pro Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys 370 375 380 Thr Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro 385 390 395 400 Being Arg Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu 405 410 415 Leu His He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr 420 425 430 Cys His Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe 435 440 445 Ser Gly Arg Arg Cys Glu Val Arg He Thr Hie Asp Wing Cys Wing Ser 450 455 460 Gly Pro Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn 465 470 475 480 Asn Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu 485 490 495 Phe Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu 500 505 510 Gly Val Gly Leu Val Val Leu Val Leu Leu Val Val Val Val 515 520 525 Val Val Arg Gln Leu Arg Leu Arg Arg Pro Asp Asp Glu Ser Arg Glu 530 535 540 Wing Met Asn Asn Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro Wing 545 550 555 560 Wing Gln Leu Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys 565 570 575 Gly Leu Asp Lys Ser Asn Cys Gly Lys Leu Gln Asn His Thr Leu Asp 580 585 590 Tyr Asn Leu Wing Pro Gly Leu Leu Gly Arg Gly Be Met Pro Gly Lys 595 600 605 Tyr Pro His Ser Asp Lys Ser Leu Gly Glu Lys Val Pro Leu Arg Leu 610 615 620 His Ser Glu Lys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg 625 630 635 640 Asp Ser Met Tyr Gln Ser Val Cys Leu He Ser Glu Glu Arg Asn Glu 645 650 655 Cys Val He Ala Thr Glu Val 660 < 210 > 19 < 211 > 662 < 212 > PRT < 213 > Mus musculus < 400 > 19 Ala Ala Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn 1 5 10 15 Gln Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg 20 25 30 Thr Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu 35 40 45 Gly Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn 50 55 60 Ser Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu 65 70 75 80 Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He 85 90 95 Gln Ala Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro 100 105 110 Gly Asn Ser Leu He Ser Gln He He He Gln Gly Ser Leu Ala 115 115 Val. 125 Gly Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu 130 135 140 Ser Tyr Ser Tyr Arg Val He Cye Ser Asp Asn Tyr Tyr Gly Glu Ser 145 150 155 160 Cys Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu 165 170 175 Cys Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys 180 185 190 Tyr Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly 195 200 205 Tyr Cys Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly 210. 215 220 Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr 225 230 235 240 Cys Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu 245 250 255 Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys 260 265 270 Asn Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr 275 280 285 Cys Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys 290 295 300 Cys Wing Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu 305 310 315 320 Asn Ser Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys 325 330 335 Glu His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly 340 345 350 Ser Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys Pro 355 360 365 Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr 370 375 380 Be Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser 385 390 395 400 Arg Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu 405 410 415 His He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys 420 425 430 His Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser 435 440 445 Gly Arg Arg Cys Glu Val Arg He Thr His Asp Ala Cys Wing Ser Gly 450 455 460 Pro Cys Phe Asn Gly Wing Thr Cys Tyr Thr -Gly Leu Ser Pro Asn Asn 465 470 475 480 Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe 485 490 495 Pro Val Gly Leu Pro Pro Be Phe Pro Trp Val Wing Val Ser Leu Gly 500 505 510 Val Gly Leu Val Val Leu Leu Val Leu Val Val Met Val Val Ala 515 520 525 Val Arg Gln Leu Arg Leu Arg Arg Pro Asp Asp Glu Ser Arg Glu Ala 530 535 540 Met Asn Asn Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro Ala Ala 545 550 555 560 Gln Leu Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly 565 570 575 Leu Asp Lys Ser Asn Cys Gly Lys Leu Gln Asn His Thr Leu Asp Tyr 580 585 590 Asn Leu Wing Pro Gly Leu Leu Gly Arg Gly Ser Met Pro Gly Lys Tyr 595 600 605 Pro His Ser Asp Lys Ser Leu Gly Glu Lys Val Pro Leu Arg Leu His 610 615 620 Ser Glu Lys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg Asp 625 630 635 640 Ser Met Tyr Gln Ser Val- Cys Leu He Ser Glu Glu Arg Asn Glu Cys 645 650 655 Val He Ala Thr Glu Val 660 < 210 > 20 < 211 > 661 < 212 > PRT < 213 > Mus usculue < 400 > 20 Wing Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn Gln 1 5 10 15 Arg Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg Thr 20 25 30 Phe Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu Gly 35 40 45 Pro Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn Ser 50 55 60 Phe Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg 'Asn Pro Leu Gln 65 70 75 80 Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn lie Gln 85 90 95 Wing Trp His Thr Pro Gly Asp Aep Leu Arg Pro Glu Thr Ser Pro Gly 100 105 110 Aen Ser Leu He Ser Gln He He He Gln Gly Ser Leu Wing Val Gly 115 120 125 Lys He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu Ser 130 135 140 Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser Cys 145 150 155 160 Ser Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu Cys 165 170 175 Gln Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys Tyr 180 185 190 Cys Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr 195 200 205 Cys Ser Lys Pro Asp Glu Cys He Cye Arg Pro Gly Trp Gln Gly Arg 210 215 220 Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys 225 230 235 240 Ser He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu Phe 245 250 255 Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn 260 265 270 Gly Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr Cys 275 280 285 Leu Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys Cys 290 295 300 Wing Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asn 305 310 315 320 Ser Tyr His Cye Leu Cye Pro Pro Gly Tyr Tyr Gly Gln His Cys Glu 325 330 335 His Ser Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser 340 345 350 Cys Arg Glu Arg Asn Gln Gly Ser Ser Tyr Ala Cys Glu Cys Pro Pro 355 360 365 Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser 370 375 380 Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg 385 390 395 400 Thr Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu His 405 410 415 He Ser Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys His 420 425 430 Asp Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser Gly 435 440 445 Arg Arg Cys Glu Val Arg He Thr His Asp Ala Cys Wing Ser Gly Pro 450 455 460 Cys Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn Phe 465 470 475 480 Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro 485 490 495 Val Gly Leu Pro Pro Be Phe Pro Trp Val Wing Val Ser Leu Gly Val 500 505 510 Gly Leu Val Val Leu Leu Val Leu Val Val Met Val Val Val Val 515 520 525 Arg Gln Leu Arg Leu Arg Arg Pro Asp Asp Glu Ser Arg Glu Ala Met 530 535 540 Asn Asn Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro Ala Ala Gln 545 550 555 560 Leu Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu 565 570 575 Asp Lys Ser Asn Cys Gly Lys Leu Gln Asn His Thr Leu Asp Tyr Asn 580 585 590 Leu Wing Pro Gly Leu Leu Gly Arg Gly Ser Met Pro Gly Lys Tyr Pro 595 600 605 His Ser Asp Lys Ser Leu Gly Glu Lys Val Pro Leu Arg Leu His Ser 610 615 620 Glu Lys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg Asp Ser 625 630 635 640 Met Tyr Gln Ser Val Cys Leu He Ser Glu Glu Arg Asn Glu Cys Val 645 650 655 He Ala Thr Glu Val 660 < 210 > 21 < 211 > 660 < 212 > PRT < 213 > Mus musculus < 400 > 21 Gly Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn Gln Arg 1 5 10 15 Gly Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe 20 25 30 Phe Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu Gly Pro 35 40 45 Cys Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe 50 55 60 Val Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu Gln Leu 65 70 75 80 Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He Gln Wing 85 90 95 Trp His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro Gly Asn 100 105 110 Ser Leu He Ser Gln He He He Gln Gly Ser Leu Ala Val Gly Lys 115 120 125 He Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu Ser Tyr 130 135 140 Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser Cys Ser 145 150 155 160 Arg Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu Cys Gln 165 170 175 Pro Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys 180 185 190 Asp Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys 195 200 205 Ser Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly Arg Leu 210 215 220 Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser 225 230 235 240 He Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys 245 250 255 Asp Gln Asp Leu Aen Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly 260 265 270 Ser Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr Cys Leu 275 280 285 Pro Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys Cys Wing 290 295 300 Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asn Ser 305 310 315 320 Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys Glu His 325 330 335 Be Thr Leu Thr Cye Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys 340 345 350 Arg Glu Arg Asn Gln Gly Be Ser Tyr Wing Cys Glu Cys Pro Pro Asn 355 360 365 Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn 370 375 380 Pro Cys Wing Asn Gly Gly Glp Cys Leu Asn Arg Gly Pro Ser Arg Thr 385 390 395 400 Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu His He 405 410 415 Be Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys His Asp 420 425 430 Leu Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg 435 440 445 Arg Cys Glu Val Arg He Thr His Asp Ala Cys Ala Ser Gly Pro Cys 450 455 460 Phe Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val 465 470 475 480 Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val 485 490 495 Gly Leu Pro Pro Be Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly 500 505 510 Leu Val Val Leu Leu Val Val Leu Leu Val Val Val Val Val Val Arg 515 520 525 Gln Leu Arg Leu Arg Arg Pro Asp Aslu Glu Arg Glu Ala Met Asn 530 535 540 Asn Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro Ala Ala Gln Leu 545 550 555 560 Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu Asp 565 570 575 Lys Ser Asn Cys Gly Lys Leu Gln Asn His Thr Leu Asp Tyr Asn Leu 580 585 590 Wing Pro Gly Leu Leu Gly Arg Gly Be Met Pro Gly Lys Tyr Pro Hie 595 600 605 Be Asp Lys Ser Leu Gly Glu Lys Val Pro Leu Arg Leu His Ser Glu 610 615 620 Lys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg Asp Ser Met 625 630 635 640 Tyr Gln Ser Val Cys Leu He Ser Glu Glu Arg Asn Glu Cys Val He 645 650 655 Ala Thr Glu Val 660 < 210 > 22 < 211 > 659 < 212 > PRT < 213 > Mus musculus < 400 > 22 Ser Gly He Phe Gln Leu Arg Leu Gln Glu Phe Val Asn Gln Arg Gly 1 5 10 15 Met Leu Wing Asn Gly Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg He Cys Leu Lys His Phe Gln Wing Thr Phe Ser Glu Gly Pro Cys 35 40 45 Thr Phe Gly Asn Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Val 50 55 60 Val Arg Asp Lys Asn Ser Gly Ser Gly Arg Asn Pro Leu Gln Leu Pro 65 70 75 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu Asn He Gln Wing Trp 85 90 95 His Thr Pro Gly Asp Asp Leu Arg Pro Glu Thr Ser Pro Gly Asn Ser 100 105 110 Leu He Ser Gln He He He Gln Gly Ser Leu Wing Val Gly Lys He 115 120 125 Trp Arg Thr Asp Glu Gln Asn Asp Thr Leu Thr Arg Leu Ser Tyr Ser 130 135 140 Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Glu Ser Cys Ser Arg 145 '150 155 160 Leu Cys Lys Lys Arg Asp Asp His Phe Gly His Tyr Glu Cys Gln Pro 165 170 175 Asp Gly Ser Leu Ser Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys Aep 180 185 190 Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 195 200 205 Lys Pro Asp Glu Cys He Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys 210 215 220 Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser He 225 230 235 240 Pro Trp Gln Cys Wing Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245 250 255 Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ser 260 265 270 Thr Cys Ser Asn Ser Gly Pro Lys Gly Tyr Thr Cys Thr Cys Leu Pro 275 280 285 Gly Tyr Thr Gly Glu His Cys Glu Leu Gly Leu Ser Lys Cys Ala Ser 290 295 300 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asn Ser Tyr 305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Gln His Cys Glu His Ser 325 330 335 Thr Leu Thr Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Aen Gln Gly Ser Ser Tyr Ala Cys Glu Cys Pro Pro Asn Phe 355 360 365 Thr Gly Ser Asn Cys Glu Lys Lys "Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Thr Cys 385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr His Cys Glu Leu His He Ser 405 410 415 Asp Cys Wing Arg Ser Pro Cys Wing His Gly Gly Thr Cys His Asp Leu 420 425 430 Glu Asn Gly Pro Val Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg He Thr His Asp Wing Cys Wing Gly Pro Cys Phe 450 455 460 Asn Gly Wing Thr Cys Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val Cys 465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly Leu 500 505 510 Val Val Leu Leu Val Val Leu Leu Val Val Val Val Ala Val Arg Gln 515 520 525 Leu Arg Leu Arg Arg Pro Asp Aslu Glu Ser Arg Glu Wing Met Asn Asn 530 535 540 Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro Wing Wing Gln Leu Lys 545 550 555 560 Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu Asp Lys 565 570 575 Be Asn Cys Gly Lys Leu Gln Asn His Thr Leu Asp Tyr Asn Leu Wing 580 585 590 Pro Gly Leu Gly Arg Le Gly Gly Met Pro Gly Lys Tyr Pro His Ser 595 600 605 Asp Lys Ser Leu Gly Glu Lys Val Pro Leu Arg Leu His Ser Glu Lys 610 615 620 Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg Asp Ser Met Tyr 625 630 635 640 Gln Ser Val Cys Leu He Ser Glu Glu Arg Asn Glu Cys Val He Ala 645 650 655 Thr Glu Val < 210 > 23 < 211 > 508 < 212 > PRT < 213 > Homo sapiens < 400 > 23 Ala Ala Gly Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn 1 5 10 15 Glu Arg Gly Val Leu Wing Be Gly Arg Pro Cye Glu Pro Gly Cys Arg 20 25 30 Thr Phe Phe Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro 35 40 45 Gly Pro Cys Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn 50 55 60 Ser Phe Wing Val Arg Asp Asp Ser Gly Gly Gly Arg Asn Pro Leu 65 70 75 80 Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He 85 90 95 Glu Ala Trp His Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro 100 105 110 Pro Asp Ala Leu He Ser Lys He Ala He Gln Gly Ser Leu Ala Val 115 120 125 Gly Gln Asn Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu 130 135 140 Arg Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn 145 150 155 160 Cys Ser Arg Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val 165 170 175 Cys Gln Pro Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu 180 185 190 Tyr Cys Gln Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly 195 200 205 Tyr Cys Ser Lys Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly 210 215 220 Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr 225 230 235 240 Cys Ser Thr Pro Trp Gln Cye Thr Cys Asp Glu Gly Trp Gly Gly Leu 245 250 255 Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys 260 265 270 Asn Gly Wing Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr 275 280 285 Cys Arg Pro Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Giu 290 295 300 Cys Asp Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu 305 310 315 320 Asp Gly Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys 325 330 335 Glu His Ser Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly 340 345 350 Ser Cys Arg Glu Arg Aen Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro 355 360 365 Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr 370 375 380 Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser 385 390 395 400 Arg Met Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu 405 410 415 His Val Ser Asp Cys Wing Arg Asn Pro Cye Wing His Gly Gly Thr Cys 420 425 430 His Asp Leu Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser 435 440 445 Gly Arg Arg Cys Glu Val Arg Thr Ser He Asp Ala Cys Wing Ser Ser 450 455 460 Pro Cys Phe Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr 465 470 475 480 Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe 485 490 495 Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Ala 500 505 < 210 > 24 < 211 > 507 < 212 > PRT < 213 > Homo sapiens < 400 > 24 Wing Gly Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu 1 5 10 15 Arg Gly Val Leu Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr 20 25 30 Phe Phe Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly 35 40 45 Pro Cys Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser 50 55 60 Phe Wing Val Arg Asp Asp Ser Gly Gly Gly Arg Asn Pro Leu Gln 65 70 75 80 Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu 85 90 95 Wing Trp His Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro 100 105 110 Asp Wing Leu He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly 115 120 125 Gln Asn Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg 130 135 140 Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys 145 150 155 160 Being Arg Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys 165 170 175 Gln Pro Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr 180 185 190 Cys Gln Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr 195 200 205 Cys Ser Lys Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg 210 215 220 Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys 225 230 235 240 Be Thr Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe 245 250 255 Cys Asp Gln Asp Leu Asn Tyr Cys Thr His Hie Ser Pro Cys Lys Asn 260 265 270 Gly Wing Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys 275 280 285 Arg Pro Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys 290 295 300 Asp Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp 305 310 315 320 Gly Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu 325 330 335 His Ser Thr Leu Ser Cys Wing Aep Ser Pro Cye Phe Asn Gly Gly Ser 340 345 350 Cys Arg Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro 355 360 365 Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser 370 375 380 Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg 385 390 395 400 Met Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His 405 410 415 Val Ser Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His 420 425 430 Aep Leu Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly 435 440 445 Arg Arg Cys Glu Val Arg Thr Ser He Asp Ala Cys Wing Ser Ser Pro 450 455 460 Cys Phe Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe 465 470 475 480 Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro 485 490 495 Val Gly Leu Pro Pro Ser Phe Pro Trp Val Wing 500 505 < 210 > 25 < 211 > 506 < 212 > PRT < 213 > Homo sapiene < 400 > 25 Gly Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg 1 5 10 15 Gly Val Leu Wing Be Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe 20 25 30 Phe Arg Val Cys Leu Lys Hie Phe Gln Wing Val Val Ser Pro Gly Pro 35 40 45 Cys Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe 50 55 60 Wing Val Arg Asp Asp Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu 65 70 75 80 Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing 85 90 95 Trp His Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp 100 105 110 Wing Leu He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln 115 120 125 Asn Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Ar 'Leu Arg Tyr 130 135 140 Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser 145 150 155 160 Arg Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln 165 170 175 Pro Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys 180 185 190 Gln Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys 195 200 205 Ser Lys Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu 210 215 220 Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser 225 230 235 240 Thr Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys 245 250 255 Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly 260 265 270 Wing Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg 275 280 285 Pro Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp 290 295 300 Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly 305 310 315 320 Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His 325 330 335 Ser Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys 340 345 350 Arg Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn 355 360 365 Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn 370 375 380 Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met 385 390 395 400 Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val 405 410 415 Be Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cye His Asp 420 425 430 Leu Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg 435 440 445 Arg Cys Glu Val Arg Thr Ser He Asp Wing Cys Wing Be Ser Pro Cys 450 455 460 Phe Asn Arg Wing Thr Cye Tyr Thr Aep Leu Ser Thr Aep Thr Phe Val 465 470 475 480 Cye Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val 485 490 495 Gly Leu Pro Pro Ser Phe Pro Trp Val Wing 500 505 < 210 > 26 < 211 > 505 < 212 > PRT < 213 > Homo sapiens < 400 > 26 Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg Gly 1 5 10 15 Val Leu Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro Cys 35 40 45 Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Wing 50 55 60 Val Arg Asp Asp Being Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro 65 70 75 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing Trp 85 90 95 His Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp Wing 100 105 110 Leu He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln Asn 115 120 125 Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser 130 135 140 Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg 145 150 155 160 Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro 165 170 175 Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln 180 185 190 Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 195 200 205 Lys Pro Wing Glu Cye Leu Cye Arg Pro Gly Trp Gln Gly Arg Leu Cys 210 215 220 Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr 225 230 235 240 Pro Trp Gln Cys Thr Cye Asp Glu Gly Trp Gly Gly Leu Phe Cye Aep 245 250 255 Gln Aep Leu Aen Tyr Cys Thr Hie His Ser Pro Cye Lys Asn Gly Wing 260 265 270 Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro 275 280 285 Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser 290 295 300 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr 305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser 325 330 335 Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn Phe 355 360 365 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys 385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser 405 410 415 Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp Leu 420 425 430 Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg Thr Ser He Asp Wing Cys Wing Ser Pro Cys Phe 450 455 460 Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys 465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 Leu Pro Pro Ser Phe Pro Trp Val Ala 500 505 < 210 > 27 < 211 > 504 < 212 > PRT < 213 > Homo sapiens < 400 > 27 Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg Gly Val 1 5 10 15 Leu Wing Be Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg 20 25 30 Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro Cys Thr 35 40 45 Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala Val 50 55 60 Arg Asp Asp Be Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro Phe 65 70 75 80 Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing Trp His 85 90 95 Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp Wing Leu 100 105 110 He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln Asn Trp 115 120 125 Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser Tyr 130 135 140 Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu 145 150 155 160 Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro Asp 165 170 175 Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln Gln 180 185 190 Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys 195 200 205 Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn 210 215 220 Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr Pro 225 230 235 240 Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln 245 250 255 Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Wing Thr 260 265 270 Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro Gly 275 280 285 Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser Asn 290 295 300 Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr His 305 310 315 320 Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser Thr 325 330 335 Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu 340 345 350 Arg Asn Gln Gly Wing Asn Tyr Wing Cye Glu Cye Pro Pro Aen Phe Thr 355 360 365 Gly Ser Aen Cye Glu Lye Lys Val Asp Arg Cys Thr Ser Asn Pro Cys 370 375 380 Wing Aen Gly Gly Gln Cye Leu Aen -Arg Gly Pro Ser Arg Met Cys Arg 385 390 395 400 Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp 405 410 415 Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp Leu Glu 420 425 430 Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg Cys 435 440 445 Glu Val Arg Thr Ser He Asp Wing Cys Wing Being Pro Cys Phe Asn 450 455 460 Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys Asn 465 470 475 480 Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu 485 490 495 Pro Pro Ser Phe Pro Trp Val Ala 500 < 210 > 28 < 211 > 503 < 212 > PRT < 213 > Homo sapiens < 400 > 28 Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg Gly Val Leu 1 5 10 15 Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg Val 20 25 30 Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro Cys Thr Phe 35 40 45 Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala Val Arg 50 55 60 Asp Asp Be Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro Phe Asn 65 70 75 80 Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing Trp His Wing 85 90 95 Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Aep Wing Leu He 100 105 110 Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln Asn Trp Leu 115 120 125 Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser Tyr Arg 130 135 140 Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu Cys 145 150 155 160 Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro Asp Gly 165 170 175 Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln Gln Pro 180 185 190 He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys Pro 195 200 205 Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu 210 215 220 Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr Pro Trp 225 230 235 240 Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln Asp 245 250 255 Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Ala Thr Cys 260 265 270 Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro Gly Tyr 275 280 285 Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser Asn Pro 290 295 300 Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr His Cys 305 310 315 320 Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser Thr Leu 325 330 335 Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg 340 345 350 Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn Phe Thr Gly 355 360 • 365 Ser Asn Cys Glu Lys Lys Val Asp Arg Cye Thr Be Asn Pro Cys Wing 370 375 380 Asn Gly Gly Gln Cye Leu Asn Arg Gly Pro Be Arg Met Cye Arg Cys 385 390 395 400 Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp Cys 405 410 415 Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp Leu Glu Asn 420 425 430 Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg Cys Glu 435 440 445 Val Arg Thr Ser He Asp Wing Cys Wing Ser Ser Pro Cys Phe Asn Arg - 450 455 460 Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys Asn Cys 465 470 475 480 Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro 485 490 495 Pro Ser Phe Pro Trp Val Ala 500 < 210 > 29 < 211 > 529 < 212 > PRT < 213 > Homo sapiens < 400 > 29 Ala Ala Gly Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn 1 5 10 15 Glu Arg Gly Val Leu Wing Gly Arg Pro Cys Glu Pro Gly Cys Arg 20 25 30 Thr Phe Phe Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro 35 40 45 Gly Pro Cys Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn 50 55 60 Ser Phe Wing Val Arg Asp Asp Ser Gly Gly Gly Arg Asn Pro Leu 65 70 75 80 Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He 85 90 95 Glu Ala Trp His Ala Pro Gly Asp Asp Leu Arg Pro Glu Ala Leu Pro 100 105 110 Pro Asp Ala Leu He Ser Lys He Ala He Gln Gly Ser Leu Ala Val 115 120 125 Gly Gln Asn Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu 130 135 140 Arg Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn 145 150 155 160 Cys Ser Arg Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val 165 170 175 Cys Gln Pro Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu 180 185 190 Tyr Cys Gln Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly 195 200 205 Tyr Cys Ser Lys Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly • 210 215 220 Arg Leu Cys Aen Glu Cys He Pro Hie Asn Gly Cys Arg His Gly Thr 225 230 235 240 Cys Ser Thr Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu 245 250 255 Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys 260 265 270 Asn Gly Wing Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr 275 280 285 Cys Arg Pro Gly Tyr Thr Gly Val Asp Cye Glu Leu Glu Leu Ser Glu 290 295 300 Cys Asp Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu 305 310 315 320 Asp Gly Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys 325 330 335 Glu His Ser Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly 340 345 350 Ser Cys Arg Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro 355 360 365 Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr 370 375 380 Ser Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser 385 390 395 400 Arg Met Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu 405 410 415 His Val Ser Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys 420 425 430 His Asp Leu Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser 435 440 445 Gly Arg Arg Cys Glu Val Arg Thr Ser He Asp Ala Cys Wing Ser Ser 450 455 460 Pro Cys Phe Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr 465 470 475 480 Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe 485 490 495 Pro Val Gly Leu Pro Pro Ser Phe Pro Trp Val Ala Val Ser Leu Gly 500 505 510 Val Gly Leu Ala Val Leu Leu Val Leu Leu Gly Met Val Ala Ala Ala 515 520 525 Val < 210 > 30 < 211 > 528 < 212 > PRT < 213 > Homo sapiens < 400 > 30 Wing Gly Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu 1 5 10 15 Arg Gly Val Leu Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr 20 25 30 Phe Phe Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly 35 40 45 Pro Cys Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser 50 55 60 Phe Wing Val Arg Asp Asp Ser Gly Gly Gly Arg Asn Pro Leu Gln 65 70 75 80 Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu 85 90 95 Wing Trp His Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro 100 105 110 Asp Wing Leu He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly 115 120 125 Gln Asn Trp Leu Leu * Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg 130 135 140 Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys 145 150 155 160 Being Arg Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys 165 170 175 Gln Pro Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr 180 185 190 Cye Gln Gln Pro He Cye Leu Ser Gly Cye Hie Glu Gln Aen Gly Tyr 195 200 205 Cys Ser Lys Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg 210 215 220 Leu Cye Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys 225 230 235 240 Be Thr Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe 245 250 255 Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn 260 265 270 Gly Wing Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cye Thr Cys 275 280 285 Arg Pro Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys 290 295 300 Asp Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp 305 310 315 320 Giy Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu 325 330 335 His Ser Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser 340 345 350 Cys Arg Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro 355 360 365 Asn Phe Thr Gly Ser Asn Cys Glu Lys ys Val Asp Arg Cys Thr Ser 370 375 380 Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Aen Arg Gly Pro Ser Arg 385 390 395 400 Met Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His 405 410 415 Val Ser Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His 420 425 430 Asp Leu Glu Aen Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly 435 440 445 Arg Arg Cys Glu Val Arg Thr Ser He Asp Ala Cys Wing Ser Ser Pro 450 455 460 Cys Phe Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe 465 470 475 480 Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro 485 490 495 Val Gly Leu Pro Pro Be Phe Pro Trp Val Wing Val Ser Leu Gly Val 500 505 510 Gly Leu Wing Val Leu Leu Val Leu Glu Val Met Val Wing Val Wing 515 520 525 < 210 > 31 < 211 > 527 < 212 > PRT < 213 > Homo sapiens < 400 > 31 Gly Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg 1 5 10 15 Gly Val Leu Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe 20 25 30 Phe Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro 35 40 45 Cye Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe 50 55 60 Wing Val Arg Asp Asp Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu 65 70 75 80 Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing 85 90 95 Trp His Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp 100 105 110 Wing Leu He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln 115 120 125 Asn Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr 130 135 140 Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser 145 150 155 160 Arg Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln 165 170 175 Pro Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys 180 185 190 Gln Gln Pro He Cys Leu Ser Gly Cye Hie Glu Gln Asn Gly Tyr Cys 195 200 205 Ser Lys Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu 210 215 220 Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser 225 230 235 240 Thr Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys 245 250 255 Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly 260 265 270 Wing Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg 275 280 285 Pro Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp 290 295 300 Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly 305 310 315 320 Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His 325 330 335 Ser Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys 340 345 350 Arg Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn 355 360 365 Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn 370 375 380 Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met 385 390 395 400 Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val 405 410 415 Be Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp 420 425 430 Leu Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg 435 440 445 Arg Cys Glu Val Arg Thr Ser He Asp Wing Cys Wing Be Ser Pro Cys 450 455 460 Phe Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val 465 470"475 480 Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val 485 490 495 Gly Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly 500 505 510 Leu Wing Val Leu Leu Val Leu Glu Val Met Val Wing Val Wing 515 520 525 < 210 > 32 < 211 > 526 < 212 > PRT < 213 > Homo sapiens < 400 > 32 Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg Gly 1 5 10 15 Val Leu Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg Val Cys Leu Lys His Phe Gln Wing Val Val Pro Pro Giy Pro Cys 35 40 45 Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Wing 50 55 60 Val Arg Asp Asp Be Ser Gly Gly Arg Asn Pro Leu Gln Leu Pro 65 70 75 80 Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing Trp 85 90 95 His Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp Wing 100 105 110 Leu He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln Asn 115 120 125 Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser 130 135 140 Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg 145 150 155 160 Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro 165 170 175 Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln 180 185 190 Gln Pro He Cys Leu Ser Gly Cys Hie Glu Gln Asn Gly Tyr Cys Ser 195 200 205 Lye Pro Wing Glu Cye Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys 210 215 220 Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr 225 230 235 240 Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245 250 255 Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Wing 260 265 270 Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro 275 280 285 Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser 290 295 300 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr 305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser 325 330 335 Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn Phe 355 360 365 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys 385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser 405 410 415 Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp Leu 420 425 430 Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg Thr Ser He Asp Wing Cys Wing Ser Pro Cys Phe 450 455 460 Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys 465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly Leu 500 505 510 Wing Val Leu Leu Val Leu Leu Gly Val Val Val Wing Ala Val 515 520 525 < 210 > 33 < 211 > 525 < 212 > PRT < 213 > Homo sapiens < 400 > 33 Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg Gly Val 1 5 10 15 Leu Wing Be Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg 20 25 30 Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro Cys Thr 35 40 45 Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala Val 50 55 60 Arg Asp Asp Be Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro Phe 65 70 75 80 Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing Trp His 85 90 95 Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp Wing Leu 100 105 110 He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln Asn Trp 115 120 125 Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser Tyr 130 135 140 Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu 145 150 155 160 Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro Asp 165 170 175 Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln Gln 180 185 190 Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys 195 200 205 Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn 210 215 220 Glu Cye He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr Pro 225 230 235 240 Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln 245 250 255 Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Wing Thr 260 265 270 Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro Gly 275 280 285 Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser Asn 290 295 300 Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr His 305 310 315 320 Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser Thr 325 330 335 Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu 340 345 350 Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn Phe Thr 355 360 365 Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro Cys 370 375 380 Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys Arg 385 390 395 400 Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp 405 410 415 Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp Leu Glu 420 425 430 Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg Cys 435 440 445 Glu Val Arg Thr Ser He Asp Wing Cys Wing Being Pro Cys Phe Asn 450 455 460 Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys Asn 465 470 475 480 Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu 485 490 495 Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly Leu Wing 500 505 510 Val Leu Leu Val Leu Leu Gly Val Val Val Wing Ala Val 515 520 525 < 210 > 34 < 211 > 524 < 212 > PRT < 213 > Homo sapiens < 400 > 34 Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg Gly Val Leu 1 5 10 15 Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg Val 20 25 30 Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro Cys Thr Phe 35 40 45 Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala Val Arg 50 55 60 Asp Asp Be Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro Phe Asn 65 70 75 80 Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing Trp His Wing 85 90 95 Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp Wing Leu He 100 105 110 Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Glh Asn Trp Leu 115 120 125 Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser Tyr Arg 130 135 140 • Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu Cys 145 150 155 160 Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro Asp Gly 165 170 175 Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln Gln Pro 180 185 190 He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys Pro 195 200 205 Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu 210 215 220 Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr Pro Trp 225 230 235 240 Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln Asp 245 250 255 Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Wing Thr Cys 260 265 270 Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro Gly Tyr 275 280 285 Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser Asr. Pro 290 295 300 Cys Arg Asn Gly Gly Ser 'Cys Lys Asp Gln Glu Asp Gly Tyr His Cys 305 310 315 320 Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser Thr Leu 325 330 335 Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg 340 345 350 Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn Phe Thr Gly 355 360 365 Be Asn Cys Glu Lys Lys Val Asp Arg Cye Thr Ser Asn Pro Cys Wing 370 375 380 Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys Arg Cys 385 390 395 400 Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp Cys 405 410 415 Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp Leu Glu Asn 420 425 430 Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg Cys Glu 435 440 445 Val Arg Thr Ser He Asp Wing Cys Wing Ser Ser Pro Cys Phe Asn Arg '450 455 460 Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys Asn Cys 465 470 475 480 Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro 485 490 495 Pro Ser Phe Pro Trp Val Val Val Ser Leu Gly Val Gly Leu Ala Val 500 505 '510 Leu Leu Val Leu Leu Gly Val Val Val Ala Ala 515 520 < 210 > 35 < 211 > 682 < 212 > PRT < 213 > Homo sapiens < 400 > 35 Ala Ala Gly Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn 1 5 10 15 Glu Arg Gly Val Leu Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg 20 25 30 Thr Phe Phe Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro 35. 40 45 Gly Pro Cys Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn 50 55 60 Ser Phe Wing Val Arg Asp Asp Be Ser Gly Gly Gly Arg Asn Pro Leu 65 70 75 80 Gln Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He 85 90 95 Glu Wing Trp His Wing Pro Gly Aep Aep Leu Arg Pro Glu Wing Leu Pro 100 105 110 Pro Aep Wing Leu He Ser Lye He Wing He Gln Gly Ser Leu Wing Val 115 120 125 Gly Gln Asn Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu 130 135 140 Arg Tyr Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn 145 150 155 160 Cys Ser Arg Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val 165 170 175 Cys Gln Pro Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu 180 185 190 Tyr Cys Gln Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly 195 200 205 Tyr Cys Ser Lye Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly 210 215 220 Arg Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr 225 230 235 240 Cys Ser Thr Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu 245 250 255 Phe Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys 260 265 270 Asn Gly Wing Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cye Thr 275 280 285 Cys Arg Pro Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu 290 295 300 Cys Asp Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu 305 310 315 320 Asp Gly Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys 325 330 335 Glu His Ser Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly 340 345 350 Ser Cys Arg Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro 355 360 365 Pro Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr 370 375 380 Be Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser 385 390 395 400 Arg Met Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu 405 410 415 His Val Ser Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys 420 425 430 His Asp Leu Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser 435 440 445 Gly Arg Arg Cys Glu Val Arg Thr Ser He Asp Ala Cys Wing Ser Ser 450 455 460 Pro Cys Phe Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr 465 470 475 480 Phe Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe 485 490 495 Pro Val Gly Leu Pro Pro Be Phe Pro Trp Val Wing Val Ser Leu Gly 500 505 510 Val Gly Leu Wing Val Leu Leu Val Leu Leu Gly Met Val Wing Val Wing 515 520 525 Val Arg Gln Leu Arg Leu Arg Arg Pro Asp Asp Gly Ser Arg Glu Ala 530 535 540 Met Asn Asn Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro Ala Ala 545 550 555 560 Gln Leu Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly 565 570 575 Leu Asp Lys Ser Asn Cys Gly Lys Gln Gln Asn His Thr Leu Asp Tyr 580 585 590 Asn Leu Wing Pro Gly Pro Leu Gly Arg Gly Thr Met Pro Gly Lys Phe 595 600 605 Pro His Ser Asp Lys Ser Leu Gly Glu Lys Wing Pro Leu Arg Leu His 610 615 620 Ser Glu Lys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg Asp 625 630 635 640 Being Met Tyr Gln Ser Val Cye Pro Glu Cye Arg He Ser Wing He Cye 645 • 650 655 Ser Pro Arg Asp Ser Met Tyr Gln Ser Val Cys Leu He Ser Glu Glu 660 665 670 Arg Asn Glu Cys Val He Wing Thr Glu Val 675 680 < 210 > 36 < 211 > 681 < 212 > PRT < 213 > Homo sapiens < 400 > 36 Wing Gly Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu 1 5 10 15 Arg Gly Val Leu Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr 20 25 30 Phe Phe Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly 35 40 45 Pro Cys Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser 50 55 60 Phe Wing Val Arg Asp Asp Ser Gly Gly Gly Arg Asn Pro Leu Gln 65 70 75 80 Leu Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu 85 90 95 Ala Trp His Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro 100 105 110 Asp Wing Leu He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly 115 120 125 Gln Asn Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg 130 135. 140 Tyr Ser Tyr Arg Val He Cys Ser Asp Aen Tyr Tyr Gly Aep Asn Cys 145 150 155 160 Being Arg Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys 165 170 175 Gln Pro Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr 180 185 190 Cys Gln Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr 195 200 205 Cys Ser Lys Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg 210 215 220 Leu Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys 225 230 235 240 Be Thr Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe 245 250 255 Cys Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn 260 265 270 Gly Wing Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys 275 280 285 Arg Pro Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys 290 295 300 Asp Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp 305 310 315 320 Gly Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu 325 330 335 His Ser Thr Leu Ser Cys Wing Asp Ser Pro Cye Phe Asn Gly Gly Ser 340 345 350 Cys Arg Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro 355 360 365 Asn Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser 370 375 380 Asn Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg 385 390 395 400 Met Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His 405 410 415 Val Ser Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His 420 425 430 Asp Leu Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly 435 440 445 Arg Arg Cys Glu Val Arg Thr Ser He Asp Ala Cys Wing Ser Ser Pro 450 455 460 Cys Phe Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe 465 470 475 480 Val Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro 485 490 495 Val Gly Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val 500 505 510 Gly Leu Wing Val Leu Leu Val Leu Le Gly Met Val Wing Val Wing Val 515 520 525 Arg Gln Leu Arg Leu Arg Arg Pro Asp Asp Gly Ser Arg Glu Ala Met 530 535 540 Asn Asn Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro Ala Ala Gln 545 550 555 560 Leu Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu 565 570 575 Asp Lys Ser Asn Cys Gly Lys Gln Gln Asn His Thr Leu Asp Tyr Asn 580 585 590 Leu Wing Pro Gly Pro Leu Gly Arg Gly Thr Met Pro Gly Lys Phe Pro 595 600 605 His Ser Asp Lys Ser Leu Gly Glu. Lys Ala Pro Leu Arg Leu His Ser 610 615 620 Glu Lys Pro Glu Cys Arg He Ser Ala He Cys Ser Pro Arg Asp Ser 625 630 635 640 Met Tyr Gln Ser Val Cys Pro Glu Cys Arg He Ser Ala He Cys Ser 645 650 655 Pro Arg Asp Ser Met Tyr Gln Ser Val Cys Leu He Ser Glu Glu Arg 660 665 670 Asn Glu Cys Val He Wing Thr Glu Val 675 680 < 210 > 37 < 211 > 680 < 212 > PRT < 213 > Homo sapiens < 400 > 37 Gly Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg 1 5 10 15 Gly Val Leu Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe 20 25 30 Phe Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro 35 40 45 Cys Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe 50 55 60 Wing Val Arg Asp Asp Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu 65 70 75 80 Pro Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing 85 90 95 Trp His Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp 100 105 110 Wing Leu He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln 115 120 125 Asn Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr 130 135 140 Ser Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser 145 150 155 160 Arg Leu Cys Lys Lys Arg Asn Asp His Phe Gly Hie Tyr Val Cys Gln 165 170 175 Pro Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys 180 185 190 Gln Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys 195 200 205 Ser Lys Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu 210 215 220 Cys Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser 225 230 235 240 Thr Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys 245 250 255 Asp Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly 260 265 270 Wing Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg 275 280 285 Pro Gly Tyr Thr Gly Val Aep Cye Glu Leu Glu Leu Ser Glu Cye Asp 290 295 300 Ser Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly 305 310 315 320 Tyr His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His 325 330 335 Ser Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys 340 345 350 Arg Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn 355 360 365 Phe Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn 370 375 380 Pro Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met 385 390 395 400 Cys Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val 405 410 415 Be Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Aep 420 425 430 Leu Glu Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg 435 440 445 Arg Cys Glu Val Arg Thr Ser He Asp Wing Cys Wing Be Ser Pro Cys 450 455 460 Phe Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Aep Thr Phe Val 465 470 475 480 Cys Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val 485 490 495 Gly Leu Pro Pro Be Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly 500 505 510 Leu Wing Val Leu Leu Val Leu Leu Gly Val Val Wing Val Wing Val Arg 515 520 525 Gln Leu Arg Leu Arg Arg Pro Asp Asp Gly Ser Arg Glu Ala Met Asn 530 535 540 Asn Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro Ala Ala Gln Leu 545 550 555 560 Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu Asp 565 570 575 Lys Ser Asn Cys Gly Lys Gln Gln Asn His Thr Leu Asp Tyr Asn Leu 580 585 590 Wing Pro Gly Pro Leu Gly Arg Gly Thr Met Pro Gly Lys Phe Pro His 595 600 605 Ser Asp Lys Ser Leu Gly Glu Lys Ala Pro Leu Arg Leu His Ser Glu 610 615 620 Lys Pro Glu Cys Arg He Ser Wing He Cye Ser Pro Arg Asp Ser Met 625 630 635 640 Tyr Gln Ser Val Cys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro 645 650 655 Arg Asp Ser Met Tyr Gln Ser Val Cys Leu He Ser Glu Glu Arg Asn 660 665 670 Glu Cye Val He Wing Thr Glu Val 675 680 < 210 > 38 < 211 > 679 < 212 > PRT < 213 > Homo sapiens < 400 > 38 Ser Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg Gly 1 5 10 15 Val Leu Wing Ser Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe 20 25 30 Arg Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro Cys 35 40 45 Thr Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Wing 50 55 60 Val Arg Asp Asp Being Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro 65 70 75 80 • Phe Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing Trp 85 90 95 His Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp Wing 100 105 110 Leu He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln Asn 115 120 125 Trp Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser 130 135 140 Tyr Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg 145 150 155 160 Leu Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro 165 170 175 Asp Gly Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln 180 185 190 Gln Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser 195 200 205 Lys Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys 210 215 220 Asn Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr 225 230 235 240 Pro Trp Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp 245 250 255 Gln Asp Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Aia 260 265 270 Thr Cys Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cys Thr Cys Arg Pro 275 280 285 Gly Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser 290 295 300 Asn Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr 305 310 315 320 His Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser 325 330 335 Thr Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg 340 345 350 Glu Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn Phe 355 360 365 Thr Gly Ser Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro 370 375 380 Cys Wing Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys 385 390 395 400 Arg Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser 405 410 415 Asp Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp Leu 420 425 430 Glu Asn Gly Leu Met Cys Thr Cye Pro Wing Gly Phe Ser Gly Arg Arg 435 440 445 Cys Glu Val Arg Thr Ser He Asp Wing Cys Wing Ser Pro Cys Phe 450 455 460 Asn Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys 465 470 475 480 Asn Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly 485 490 495 Leu Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly Leu 500 505 510 Wing Val Leu Leu Val Leu Leu Gly Met Val Wing Val Wing Val Arg Gln 515 520 525 Leu Arg Leu Arg Arg Pro Asp Asp Gly Ser Arg Glu Wing Met Asn Asn 530 535 540 Leu Ser Asp Phe Gln Lys Asp Asn Leu He Pro Wing Wing Glp Leu Lys 545 550 555 560 Ace? Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu Asp Lys 565 570 575 Be Asn Cys Gly Lys Gln Gln Asn His Thr Leu Asp Tyr Asn Leu Wing 580 585 590 Pro Gly Pro Leu Gly Arg Gly Thr Met Pro Gly Lys Phe Pro His Ser 595 600 605 Asp Lys Ser Leu Gly Glu Lys Wing Pro Leu Arg Leu His Ser Glu Lys 610 615 620 Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg Asp Ser Met Tyr 625 630 635 640 Gln Ser Val Cys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg 645 650 655 Asp Ser Met Tyr Gln Ser Val Cye Leu He Ser Glu Glu Arg Aen Glu 660 665 670 Cys Val He Wing Thr Glu Val 675 < 210 > 39 < 211 > 678 < 212 > PRT < 213 > Homo sapiens < 400 > 39 Gly Val Phe Gln Leu Gln Leu Gln Glu Phe He Asn Glu Arg Gly Val 1 5 10 15 Leu Wing Be Gly Arg Pro Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg 20 25 30 Val Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro Cys Thr 35 40 45 Phe Gly Thr Val Ser Thr Pro Val Leu Gly Thr Asn Ser Phe Ala Val 50 55 60 Arg Asp Asp Be Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro Phe 65 70 75 80 Asn Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing Trp His 85 90 95 Wing Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp Wing Leu 100 105 110 He Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln Asn Trp 115 120 125 Leu Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser Tyr 130 135 140 Arg Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu 145 150 '155 160 Cys Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cye Gln Pro Aep 165 170 175 Gly Aen Leu Ser Cye Leu Pro Gly Trp Thr Gly Glu Tyr Cye Gln Gln 180 185 190 Pro He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys 195 200 205 Pro Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn 210 215 220 Glu Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr Pro 225 230 235 240 Trp Gln Cys Thr Cye Asp Glu Gly Trp Gly Gly Leu Phe Cye Aep Gln 245 250 255 Asp Leu Aen Tyr Cye Thr His His Ser Pro Cys Lys Asn Gly Wing Thr 260 265 270 Cys Ser Aen Ser Gly Gln Arg Ser Tyr Thr Cye Thr Cys Arg Pro Gly 275 280 285 Tyr Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser Asn 290 295 300 Pro Cys Arg Asn Gly Gly Ser Cys Lys Asp Gln Glu Asp Gly Tyr Hie 305 310 315 320 Cys Leu Cys Pro Pro Gly Tyr Tyr Gly Leu His Cys Glu His Ser Thr 325 330 335 Leu Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu 340 345 350 Arg Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Aen Phe Thr 355 360 365 Gly Ser Asn Cys Glu Lys Lys Val Aep Arg Cye Thr Ser Aen Pro Cys 370 375 380 Wing Aen Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys Arg 385 390 395 400 Cys Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp 405. 410 415 Cys Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp Leu Glu 420 425 430 Asn Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg Cys 435 440 445 Glu Val Arg Thr Ser He Asp Wing Cys Wing Being Pro Cys Phe Asn 450 455 460 Arg Wing Thr Cys Tyr Thr Asp Leu Ser Thr Asp Thr Phe Val Cys Asn 465 470 475 480 Cys Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu 485 490 495 Pro Pro Ser Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly Leu Wing 500 505 510 Val Leu Leu Val Leu Leu Gly Val Val Ala Wing Val Arg Gln Leu 515 520 525 Arg Leu Arg Arg Pro Asp Asp Gly Ser Arg Glu Ala Met Asn Asn Leu 530 535 540 Ser Asp Phe Gln Lys Asp Asn Leu He Pro Ala Wing Gln Leu Lys Asn 545 550 555 560 Thr Asn Gln Lye Lys Glu Leu Glu Val Aep Cys Gly Leu Asp Lys Ser 565 570 575 Aen Cys Gly Lys Gln Gln Asn His Thr Leu Asp Tyr Asn Leu Wing Pro 580 585 590 Gly Pro Leu Gly Arg Gly Thr Met Pro Gly Lys Phe Pro His Ser Asp 595 600 605 Lys Ser Leu Gly Glu Lye Wing Pro Leu Arg Leu Hie Ser Glu Lys Pro 610 615 620 Glu Cye Arg He Ser Wing He Cys Ser Pro Arg Asp Ser Met Tyr Gln 625 630 635 640 Ser Val Cys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg Asp 645 650 655 Being Met Tyr Gln Being Val Cys Leu He Being Glu Glu Arg Asn Glu Cys 660 665 670 Val He Wing Thr Glu Val 675 < 210 > 40 < 211 > 677 < 212 > PRT < 213 > Homo sapiene < 400 > 40 Val Phe Gln Leu Gln Leu Gln Glu Phe He Aen Glu Arg Gly Val Leu 1 5 10 15 Wing Ser Gly Arg Pro Cye Glu Pro Gly Cys Arg Thr Phe Phe Arg Val 20 25 30 Cys Leu Lys His Phe Gln Wing Val Val Ser Pro Gly Pro Cys Thr Phe 35 40 45 Gly Thr Val Ser Thr Pro Val Leu Gly Thr Aen Ser Phe Ala Val Arg 50 55 60 Asp Asp Be Ser Gly Gly Gly Arg Asn Pro Leu Gln Leu Pro Phe Asn 65 70 75 80 Phe Thr Trp Pro Gly Thr Phe Ser Leu He He Glu Wing Trp His Wing 85 90 95 Pro Gly Asp Asp Leu Arg Pro Glu Wing Leu Pro Pro Asp Wing Leu He 100 105 110 Ser Lys He Wing He Gln Gly Ser Leu Wing Val Gly Gln Asn Trp Leu 115 120 125 Leu Asp Glu Gln Thr Ser Thr Leu Thr Arg Leu Arg Tyr Ser Tyr Arg 130 135 140 Val He Cys Ser Asp Asn Tyr Tyr Gly Asp Asn Cys Ser Arg Leu Cys 145 150 155 160 Lys Lys Arg Asn Asp His Phe Gly His Tyr Val Cys Gln Pro Asp Gly 165 170 175 Asn Leu Ser Cys Leu Pro Gly Trp Thr Gly Glu Tyr Cys Gln Gln Pro 180 185 190 He Cys Leu Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys Pro 195 200 205 Wing Glu Cys Leu Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu 210 215 220 Cys He Pro His Asn Gly Cys Arg His Gly Thr Cys Ser Thr Pro Trp 225 230 235 240 Gln Cys Thr Cys Asp Glu Gly Trp Gly Gly Leu Phe Cys Asp Gln Asp 245 250 255 Leu Asn Tyr Cys Thr His His Ser Pro Cys Lys Asn Gly Wing Thr Cye 260 265 270 Ser Asn Ser Gly Gln Arg Ser Tyr Thr Cye Thr Cye Arg Pro Gly Tyr 275 280 285 Thr Gly Val Asp Cys Glu Leu Glu Leu Ser Glu Cys Asp Ser Asn Pro 290 295 300 Cys Arg Asn Gly Gly Ser Cye Lye Aep Gln Glu Aep Gly Tyr Hie Cys 305 310 315 320 Leu Cys Pro Pro Gly Tyr Tyr Gly Leu Hie Cye Glu Hie Ser Thr Leu 325 330 335 Ser Cys Wing Asp Ser Pro Cys Phe Asn Gly Gly Ser Cys Arg Glu Arg 340 345 350 Asn Gln Gly Wing Asn Tyr Wing Cys Glu Cys Pro Pro Asn Phe Thr Gly 355 360 365 Be Asn Cys Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro Cys Wing 370 375 380 Asn Gly Gly Gln Cys Leu Asn Arg Gly Pro Ser Arg Met Cys Arg Cys 385 390 395 400 Arg Pro Gly Phe Thr Gly Thr Tyr Cys Glu Leu His Val Ser Asp Cys 405 410 415 Wing Arg Asn Pro Cys Wing His Gly Gly Thr Cys His Asp Leu Glu Asn 420 425 430 Gly Leu Met Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg Cys Glu 435 440 445 Val Arg Thr Ser He Asp Wing Cys Wing Ser Ser Pro Cys Phe Asn Arg 450 455 460 Wing Thr Cye Tyr Thr Aep Leu Ser Thr Aep Thr Phe Val Cys Asn Cys 465 470 475 480 Pro Tyr Gly Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro 485 490 495 Pro Be Phe Pro Trp Val Wing Val Ser Leu Gly Val Gly Leu Ala Val 500 505 510 Leu Leu Val Leu Leu Gly Met Val Wing Val Wing Val Arg Gln Leu Arg 515 520 525 Leu Arg Pro Asp Asp Gly Ser Arg Glu Wing Met Asn Asn Leu Ser 530 535 540 Asp Phe Gln Lys Asp Asn Leu He Pro Wing Ala Gln Leu Lys Asn Thr 545 550 555 560 Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu Asp Lys Ser Asn 565 570 575 Cys Gly Lys Gln Gln Asn His Thr Leu Asp Tyr Asn Leu Wing Pro Gly 580 585 590 Pro Leu Gly Arg Gly Thr Met Pro Gly Lys Phe Pro His Ser Asp Lys 595 600 605 Ser Leu Gly Glu Lys Ala Pro Leu Arg Leu His Ser Glu Lys Pro Glu 610 615 620 Cys Arg He Ser Wing He Cys Ser Pro Arg Asp Ser Met Tyr Gln Ser 625 630 635 640 Val Cys Pro Glu Cys Arg He Ser Ala lie Cys Ser Pro Arg Asp Ser 645 650 655 Met Tyr Gln Ser Val Cys Leu He Ser Glu Glu Arg Asn Glu Cys Val 660 665 670 He Ala Thr Glu Val 675 < 210 > 41 < 211 > 402 < 212 > DNA < 213 > Mus musculus < 400 > 41 caccgggaga cgacctgcgg ccagagantt cgccaggaaa ctctctcatc agccaaatca 60 tcatccaagg ctctcttgct gtgggtaaga tttggcgaac agacgagcaa aatgacaccc 120 tcaccagact gagctactct taccgggtca tctgcagtga caactactat ggagagagct 180 gttctcgcct atgcaagaag cgcgatgacc acttcggaca ttatgagtgc cagccagatg 240 gcagcctgtc ctgcctgccg ggctggactg ggaagtactg tgaccagcct atatgtcttt 300 ctggctgtca tgagcagaat ggttactgca gcaagccaga tgagtgcatc tgccgtccag 360 gttggcaggg tcgcctgtgc aatgaatgta tccccccatg at 402 < 210 > 42 < 211 > 25 < 212 > DNA < 213 > Mus musculus < 400 > 42 tgctgtgggt aagatttggc gaaca 25 < 210 > 43 < 211 > 27 < 212 > DNA < 213 > Mus musculus < 400 > 43 ccatcctaat acgactcact atagggc < 210 > 44 < 211 > 2718 < 212 > DNA < 213 > Mus musculus < 400 > 44 tgctgtgggt aagatttggc gaacagacga accctcacca gcaaaatgac gactgagcta 60 gtcatctgca ctcttaccgg gtgacaacta ctatggagag agctgttctc gcctatgcaa 120 gaccacttcg gaagcgcgat gtgccagcca gacattatga gatggcagcc tgtcctgcct 180 gccgggctgg actgggaagt actgtgacca gcctatatgt ctttctggct gtcatgagca 240 gaatggttac tgcagcaagc cagatgagtg catctgccgt ccaggttggc agggtcgcct 300 gtgcaatgaa tgtatccccc acaatggctg tcgtcatggc tcccctggca acctgcagca 360 gtgtgcctgc gatgagggat ggggaggtct gttttgtgac caagatctca actactgtac 420 tcaccactct ccgtgcaaga atggatcaac gtgttccaac agtgggccaa agggttatac 480 ctgcacccgt ctcccaggct acactggtga gcactgtgag ctgggactca acaagtgtgc 540 cagcaacccc tgtcgaaatg gtggcagctg taaggaccag gagaatagct accactgcct 600 gtgtccccca ggctactatg gccagcactg tgagcatagt accttgacct gtgcggactc 660 accctgcttc tatgggggct cttgccggga gcgcaaccag gggtccagtt to gcctgcga 720 atgccccccc aactttaccg gctctaactg tgagaagaaa gtagacaggt gtaccagcaa 780 cccgtgtgcc aatggaggcc agtgcctgaa cagaggtcca agccgaacct gccgctgccg 840 gcctggattc acaggcaccc actgtgaact gcacatcagc gattgtgccc gaagtccctg 900 tgcccacggg ggcacttgcc acgatctgga gaatgggcct gtgtgcacct gccccgctgg 960 cttctctggc aggcgctgcg aggtgcggat aacccacgat gcctgtgcct ccggaccctg 1020 cttcaatggg gccacctgct acactggcct ctccccaaac aacttcgtct gcaactgtcc 1080 ttatggcttt gtgggcagcc gctgcgagtt tcccgtgggc ttgccaccca gcttcccctg 1140 ggtagctgtc tcgctgggcg tggggctagt ggtactgctg gtgctgctgg tcatggtggt 1200 agtggctgtg cggcagctgc ggcttcggag gcccgatgac aagagcaggg aagccatgaa 1260 .caatctgtca gacttccaga aggacaacct aatccctgcc gcccagctca aaaacacaaa 1320 ccagaagaag gagctggaag tggactgtgg tctggacaag tccaattgtg gcaaactgca 1380 ttggactaca gaaccacaca atctagcccc gggactccta ggacggggca gcatgcctgg 1440 cacagtgaca gaagtatcct agagcttagg agagaaggtg ccacttcggt tacacagtga 1500 gaagccagag tgtcgaatat cagccatttg ctctcccagg gactctatgt accaatcagt 1560 tcagaagaga gtgtttgata ggaacgagtg tgtgattgcc acagaggtat aaggcaggag 1620 cacccagctc cctactcaga cggcccagca gctgggcctt ccttctgcat tgtttacatt 1680 gcatccegta tgggacatct ttagtatgca cagtgctgct ctgcggagga ggagggaatg 1740 gcatgaactg aacagactgt gaacccgcca agagttgcac cggctctgca cacctccagg 1800 agtctgcctg gcttcagatg ggcagccccg ccaagggaac agagttgagg agttagagga 1860 gcatcagttg agctgatatc taaggtgcct ctcgaacttg gacttgctct gccaacagtg 1920 gtcatcatgg agctcttgac tgttctccag agagtggcag tggccctagt gggtcttggc 1980 gctgctgtag ctcctgtggg catctgtatt tccaaagtgc ctttgcccag actccatcct 2040 cacagctggg cccaaatgag aaagcagaga ggaggcttgc aaaggatagg cctcccgcag 2100 gcaga acagc cttggagttt ggcattaagc aggagctact ctgcaggtga ggaaagcccg 2160 aggaggggac acgtgtgact cctgcctcca accccagcag gtggggtgcc acctgcagcc 2220 t aggcaag agttggtcct tcccctggtc ctggtgcctc tgggctcatg tgaacagatg 2280 ggcttagggc acgccccttt tgccagccag gggtacaggc ctcactgggg agc cagggc 2340 cttcatgcta aactcccaat aagggagatg gggggaaggg ggctgtggcc taggccct c 2400 cctccctcac acccattttt gggcccttga gcctgggctc caccagtgcc cactgttgcc 2460 ccgagaccaa ccttgaagcc gattttcaaa aatcaataat atgaggtttt gttttgtagt 2520 ttattttgga atctagtatt ttgataattt aagaatcaga agcactggcc tttctacatt 2580 ttataacatt attttgtata taatgtgtat ttataatatg aaacagatgt gtacataaaa 2640 aaaaaaaaaa aaaaaaaaaa aaaaaagcga cctgcccggg cggccgctcg agccctatag 2700 tgagtcgtat taggatgg 2718 < 210 > 45 < 211 > 25 < 212 > DNA < 213 > Mus musculus < 400 > 45 ggtgagtccg cacaggtcaa ggtac 25 < 210 > 46 < 211 > 25 < 212 > DNA < 213 > Mus musculus < 400 > 46 gacaggggt gctggcacac ttgtt < 210 > 47 < 211 > 982 < 212 > DNA < 213 > Mus musculus < 400 > 47 ctcgcaggct aggaacccga ggccaagagc tgcagccaaa gtcacttggg tgcagtgtac 60 gcccgctcga tccctcacta gaccctagga tttgctccag gacacgtact tagageagee 120 accgcccagt cgccctcacc tggattacct accgaggcat cgagcagcgg agtttttgag 180 aaggcgacaa gggagcagcg tcccgagggg aatcagcttt tcaggaactc ggctggcaga 240 cgggacttgc gggagagcga catccctaac aageagatte ggagtcccgg agtggagagg 300 acaccccaag ggatgacgcc tgcgtcccgg agcgcctgtc gctgggcgct actgctgctg 360 gcggtactgt ggccgcagca gcgcgctgcg ggctccggca tcttccagct gcggctgcag 420 gagttcgtca accagcgcgg tatgctggcc aatgggcagt cctgcgaacc gggctgccgg 480 actttcttcc gcatttgcct taagcacttc caggcaacct tctccgaggg accctgcacc 540 tttggcaatg tctccacgcc ggtattgggc accaactcct tcgtcgtcag ggacaagaat 600 agcggcagtg gtcgcaaccc tctgcagttg cccttcaatt tcacctggcc gggaaccttc 660 tcactcaaca tccaagcttg gcacacaccg ggagaegace tgcggccaga gacttcgcca 720 ggaaac ctc tcatcagcca aatcatcatc caaggctctc ttgctgtggg taagatttgg 780 cgaacagacg agcaaaatga caccctcacc agactgagct actcttaccg ggtcatctgc 840 agtgacaact actatgg aga gagctgttct cgcctatgca agaagcgcga tgaccacttc 900 ggacattatg agtgccagcc agatggcagc ctgtcctgcc tgccgggctg gactgggaag 960 tactgtgacc agcctatatg te 982 < 210 > 48 < 211 > 24 < 212 > DNA < 213 > Mus musculus < 400 > 48 agccaccatg acgcctgcgt cccg 24 < 210 > 49 < 211 > 25 < 212 > DNA < 213 > Mus musculus < 400 > 49 tetattatac ctctgtggca atcac 25 < 210 > 50 < 211 > 409 < 212 > DNA < 213 > Homo sapiens < 400 > 50 cagatcagaa aagtaaagac cagttaagag gttggtgacc agataaggac aacctgattc 60 gcttaaaaac ctgccgccca acaaaccaga agaaggagct ggaagtggac tgtggcctgg 120 ctgtggcaaa acaagtecaa acacattgga cagcaaaacc etataatetg gccccagggc 180 ccctggggcg ggggaccatg ccaggaaagt ttccccacag tgacaagage ttaggagaga 240 aggcgccact gcggttacac agtgaaaagc cagagtntcg gatatcagcg atatgctccc 300 ccagggactc catgtaccag tctgtgtgtt tgatatcaga ggagaggaat gaatgtttca 360 ttnccacgga ggtataaggc aggagcctac ctgggacatc cctgctcag 409 < 210 > 51 < 211 > 25 < 212 > DNA < 213 > Homo sapiens < 400 > 51 aagaaggagc tggaagtgga ctgtg 25 < 210 > 52 < 211 > 25 < 212 > DNA < 213 > Homo sapiens < 400 > 52 atcaaacaca cagactggta catgg 25 < 210 > 53 < 211 > 2184 < 212 > DNA < 213 > Homo sapiens < 400 > 53 gcgtcctcgg cgcggtcgcc gcccagccgt agtcacctgg attacctaca gcggcagctg 60 cagcggagcc agcgagaagg ccaaagggga gcagcgtccc gagaggagcg cctcttttca 120 gggaccccgc cggctggcgg acgcgcggga aagcggcgtc gcgaacagag ccagattgag 180 ggcccgcggg tggagagagc gacgcccgag gggatggcgg cagcgtcccg gagcgcctct 240 ggctgggcgc tactgctgct ggtggcactt tggcagcagc gcgcggccgg ctccggcgtc 300 ttccagctgc agctgcagga gttcatcaac gagcgcggcg tactggccag tgggcggcct 360 tgcgagcccg gctgccggac tttcttccgc gtctgcctta agcacttcca ggcggtcgtc 420 tcgcccggac cctgcacctt cgggaccgtc tccacgccgg tattgggcac caactccttc 480 gctgtccggg acgacagtag cggcgggggg cgcaaccctc tccaactgcc cttcaatttc 540 acctggccgg gtaccttctc gctcatcatc gaagcttggc acgcgccagg agacgacctg 600 cggccagagg ccttgccacc agatgcactc tcgccatcca atcagcaaga gggctcccta 660 gctgtgggtc agaactggtt attggatgag caaaccagca ccctcacaag gctgcgctac 720 tcttaccggg tcatctgcag tgacaactac tatggagaca actgctcccg cctgtgcaag 780 aagcgcaatg accacttcgg ccactatgtg tgccagccag atggcaactt gtcctgcctg 840 cccggttgga ctgggga ata ttgccaacag cctatctgtc tttcgggctg tcatgaacag 900 aatggctact gcagcaagcc agcagagtgc ctctgccgcc caggctggca gggccggctg 960 gcatccccca tgtaacgaat .cgccacggca caatggctgt tccctggcaa cctgcagcac 1020 tgtacttgtg atgagggctg gggaggcctg 'ttttgtgacc aagatctcaa ctactgcacc 1080 caccactccc catgcaagaa tggggcaacg tgctccaaca gtgggcagcg aagctacacc 1140 tgcacctgtc gcccaggcta cactggtgtg gactgtgagc tggagctcag cgagtgtgac 1200 agcaacccct gtcgcaatgg aggcagctgt aaggaccagg aggatggcta ccactgcctg 1260 tgtcctccgg gctactatgg cctgcattgt gaacacagca ccttgagctg cgccgactcc 1320 ccctgcttca atgggggctc ctgccgggag cgcaaccagg gggccaacta tgcttgtgaa 1380 tgtcccccca acttcaccgg ctccaactgc gagaagaaag tggacaggtg caccagcaac 1440 acgggggaca ccctgtgcca gtgcctgaac cgaggtccaa gccgcatgtg ccgctgccgt 1500 cgggcaccta cctggattca ctgtgaactc cacgtcagcg actgtgcccg taaccc gc 1560 gcccacggtg gcacttgcca tgacctggag aatgggctca tgtgcacctg ccctgccggc 1620 gacgctgtga ttctctggcc ggtgcggaca tccatcgatg cctgtgcctc gagtccctgc 1680 tccaacaggg ccacctgcta cac cgacctc tccacagaca cctttgtgtg caactgccct 1740 tatggctttg tgggcagccg ctgcgagttc cccgtgggct tgccgcccag cttcccctgg 1800 gtggccgtct cgctgggtgt ggggctggca gtgctgctgg tactgctggg catggtggca 1860 gtggctgtgc ggcagctgcg gcttcgacgg ccggacgacg gcagcaggga agccatgaac 1920 aacttgtcgg acttccagaa ggacaacctg attcctgccg cccagcttaa aaacacaaac 1980 cagaagaagg agctggaagt ggactgtggc ctggacaagt ccaactgtgg caaacagcaa 2040 aaccacacat tggactataa tctggcccca gggcccctgg ggcgggggac catgccagga 2100 aagtttcccc acagtgacaa gagcttagga gagaaggcgc cactgcggtt acacagtgaa 2160 aagccagagt gtcggatatc agcg 2184 < 210 > 54 < 211 > 22 < 212 > DNA < 213 > Homo sapiens < 400 > 54 acctgattcc tgccgcccag ct 22 < 210 > 55 < 211 > 22 < 212 > DNA < 213 > Homo sapiens < 400 > 55 gatgtcccag gtaggctcct ge 22 < 210 > 56 < 211 > 349 < 212 > DNA < 213 > Homo sapiens. < 400 > 56 acctgattcc tgccgcccag cttaaaaaca caaaccagaa gaaggagctg gaagtggact 60 gtggcctgga caagtccaac fcgtggcaaac agcaaaacca cacattggac tataatctgg 120 ccccagggcc cctggggcgg gggaccatgc caggaaagtt tccccacagt gacaagagct 180 taggagagaa ggcgccactg cggttacaca gtgaaaagcc agagtgtcgg atatcagega 240 tatgctcccc cagggactcc atgtaccagt ctgtgtgttt gatatcagag gagaggaatg 300 aatgtgtcat tgccacggag gtataaggca ggagcctacc tgggacatc 349 < 210 > 57 < 211 > 17 < 212 > DNA < 213 > Mus musculus < 400 > 57 aacctggacg gcagatg 17 < 210 > 58 < 211 > 19 < 212 > DNA < 213 > Mus musculus < 400 > 58 agatttggcg aacagaega 19 < 210 > 59 < 211 > 30 < 212 > DNA < 213 > Mus musculus < 400 > 59 gaactagtcc accatgacgc ctgcgtcccg 30 < 210 > 60 < 211 > 28 < 212 > DNA < 213 > Mus musculus < 400 > 60 tcgcggccgc ggggaagctg ggtggcaa 28 < 210 > 61 < 211 > 2292 < 212 > DNA < 213 > Artificial Sequence < 220 > < 223 > Dissemination of Artificial Sequence: Hybrid of Muß musculus and Homo Sapißn. < 400 > 61 atgacgcctg cgtcccggag cgcctgtcgc tgggcgctac tgctgctggc ggtactgtgg 60 ccgcagcagc gcgctgcggg ctccggcatc ttccagctgc ggctgcagga gttcgtcaac 120 tgctggccaa cagcgcggta tgggcagtcc tgcgaaccgg gctgccggac tttcttccgc 180 atttgcctta agcacttcca ggcaaccttc tccgagggac cctgcacctt tggcaatgtc 240 tccacgccgg tat gggcac caactccttc gtcgtcaggg acaagaatag cggcagtggt 300 cgcaaccctc tgcagttgcc cttcaatttc acctggccgg gaaccttctc actcaacatc 360 caagcttggc acacaccggg agacgacctg cggccagaga cttcgccagg aaactctctc 420 tcatcatcca atcagccaaa aggctctctt gctgtgggta agatttggcg aacagacgag 480 caaaatgaca ccctcaccag actgagctac tcttaccggg tcatctgcag tgacaactac 540 tatggagaga gctgttctcg cctatgcaag aagcgcgatg accacttcgg acattatgag 600 tgccagccag atggcagcct gtcctgcctg ccgggctgga ctgggaagta ctgtgaccag 660 cct atgtc tttctggctg tcatgagcag aatggttact gcagcaagcc agatgagtgc 720 caggttggca atctgccgtc gggtcgcctg tgcaatgaat gtatccccca caa gt ggc 780 cgtcatggca cctgcagcat cccctggcag tgtgcctgcg atgagggatg gggaggtctg 840 ttttgtgacc aagatctc aa ctactgtact caccactctc cgtgcaagaa tggatcaacg 900 tccaaca tg gtgggccaaa gggttatacc tgcacctgtc tcccaggcta cactggtgag 960 cactgtgagc tgggactcag caagtgtgcc agcaacccct gtcgaaatgg tggcagctgt 1020 aaggaccagg agaatagcta ccactgcctg tgtcccccag gctactatgg ccagcactgt 1080 ccttgacctg gagcatagta tgcggactca ccctgcttca atgggggctc ttgccgggag 1140 ggtccagtta cgcaaccagg tgcctgcgaa tgccccccca actttaccgg ctctaactgt 1200 gagaagaaag tagacaggtg taccagcaac ccgtgtgcca atggaggcca gtgcctgaac 1260 agaggtccaa gccgaacctg ccgctgccgg cctggattca caggcaccca ctgtgaactg 1320 cacatcagcg attgtgcccg aagtccctgt gcccacgggg gcacttgcca cgatctggag 1380 aatgggcctg tgtgcacctg ccccgctggc ttctctggca ggtgcggata ggcgctgcga 1440 acccacgatg cctgtgcctc cggaccctgc ttcaatgggg ccacctgcta cactggcctc 1500 tccccaaaca acttcgtctg caactgtcct tatggctttg tgggcagccg ctgcgagttt 1560 cccgtgggct tgccacccag cttccccgcg gccgctgagc ccaaatcttg tgacaaaact 1620 cacacatgcc caccgtgccc agcacctgaa ctcctggggg gaccgtcagt cttcctcttc 1680 cccccaaaac ccaaggacac cctc tgatc tcccggaccc ctgaggtcac atgcgtggtg 1740 gccacaaaaa gtggacgtga ccctgaggtc aacttcaact ggtacgtgga cggcgtggag 1800 ccaagacaaa gtgcataatg gccgcgggag gageagtaca acagcacgta ccgtgtggtc 1860 ccgtcctgca agcgtcctca ccaggactgg ctgaatggca aggagtacaa gtgcaaggtc 1920 tccaacaaag ccctcccagc ceceatcgag aaaaccatct ccaaagccaa agggcagccc 1980 cgagaaccac aggtgtacac cctgccccca tcccgggatg agctgaccaa gaaccaggtc 2040 agcctgacct gcctggtcaa aggcttctat cccagcgaca tcgccgtgga gtgggagagc 2100 aatgggcagc cggagaacaa ctacaagacc acgcctcccg tgc ggactc cgacggctcc 2160 ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc 2220 tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag cctctccctg 2280 tctccgggta aa 2292 < 210 > 62 < 211 > 764 < 212 > PRT < 213 > Artificial Sequence < 220 > < 223 > Description of Artificial Sequence: Hybrid of Mus musculus and Homo Sapien. < 400 > 62 Met Thr Pro Wing Ser Arg Wing Wing Cys Arg Trp Wing Leu Leu Leu Leu 1 5 10 15 Wing Val Leu Trp Pro Gln Gln Arg Wing Wing Gly Ser Gly He Phe Gln 20 25 30 Leu Arg Leu Gln Glu Phe Val Asn Gln Arg Gly Met Leu Wing Asn Gly 35 40 45 Gln Ser Cys Glu Pro Gly Cys Arg Thr Phe Phe Arg He Cys Leu Lys 50 55 60 His Phe Gln Wing Thr Phe Ser Glu Gly Pro Cys Thr Phe Gly Asn Val 65 70 75 80 Be Thr Pro Val Leu Gly Thr Asn Ser Phe Val Val Arg Asp Lys Asn 85 90 95 Ser Gly Ser Gly Arg Asn Pro Leu Gln Leu Pro Phe Asn Phe Thr Trp 100 105 110 Pro Gly Thr Phe Ser Leu Asn He Gln Wing Trp His Thr Pro Gly Asp 115. 120 125 Asp Leu Arg Pro Glu Thr Ser Pro Gly Asn Ser Leu He Ser Gln He 130, 135 140 He He Gln Gly Ser Leu Wing Val Gly Lys He Trp Arg Thr Asp Glu 145 150 155 160 Gln Asn Asp Thr Leu Thr Arg Leu Ser Tyr Ser Tyr Arg Val He Cys 165 170 175 Being Asp Asn Tyr Tyr Gly Glu Being Cys Being Arg Leu Cys Lys Lys Arg 180 185 190 Asp Asp His Phe Gly His Tyr Glu Cys Gln Pro Asp Gly Ser Leu Ser 195 200 205 Cys Leu Pro Gly Trp Thr Gly Lys Tyr Cys Asp Gln Pro He Cys Leu 210 215 220 Ser Gly Cys His Glu Gln Asn Gly Tyr Cys Ser Lys Pro Asp Glu Cys 225 230 235 240 He Cys Arg Pro Gly Trp Gln Gly Arg Leu Cys Asn Glu Cys He Pro 245 250 255 His Asn Gly Cly Arg His Gly Thr Cys Ser He Pro Trp Gln Cye Wing 260 265 270 Cys Asp Glu Gly Trly Gly Gly Leu Phe Cys Asp Gln Asp Leu Asn Tyr 275 280 285 Cys Thr His Hxs Ser Pro Cys Lys Asn Gly Ser Thr Cys Ser Aen Ser 290 295 300 Gly Pro Lys Gly Tyr Thr Cye Thr Cys Leu Pro Gly Tyr Thr Gly Glu 305 310 315 320 His Cys Glu Leu Gly Leu Ser Lys Cys Wing Ser Asn Pro Cys Arg Asn 325 330 335 Gly Gly Ser Cys Lys Asp Gln Glu Asn Ser Tyr Hxs Cys Leu Cys Pro 340 345 - 350 Pro Gly Tyr Tyr Gly Gln His Cys Glu His Ser Thr Leu Thr Cys Ala 355 360 365 Asp Ser Pro Cys Phe Asn Gly Gly Ser Cye Arg Glu Arg Asn Gln Gly 370 375 380 Ser Ser Tyr Wing Cys Glu Cye Pro Pro Asn Phe Thr Gly Ser Asn Cys 385 390 395 400 Glu Lys Lys Val Asp Arg Cys Thr Ser Asn Pro Cys Wing Aen Gly Gly 405 410 415 Gln Cys Leu Asn Arg Gly Pro Be Arg Thr Cys Arg Cys Arg Pro Gly 420 425 430 Phe Thr Gly Thr Hxs Cys Glu Leu His He Ser Asp Cys Ala Arg Ser 435 440 445 Pro Cys Ala Hxs Gly Gly Thr Cys His Asp Leu Glu Asn Gly Pro Val 450 455 460 Cys Thr Cys Pro Wing Gly Phe Ser Gly Arg Arg Cys Glu Val Arg He 465 470 475 480 Thr Hxs Asp Wing Cys Wing Ser Gly Pro Cys Phe Asn Gly Wing Thr Cys 485 490 495 Tyr Thr Gly Leu Ser Pro Asn Asn Phe Val Cys Asn Cys Pro Tyr Gly 500 505 510 Phe Val Gly Ser Arg Cys Glu Phe Pro Val Gly Leu Pro Pro Ser Phe 515 520 525 Pro Ala Ala Ala Glu Pro Lys Ser Cys Asp Lys Thr Hxs Thr Cys Pro 530 535 540 Pro Cys Pro Pro Wing Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe 545 550 555 560 Pro Pro Lys Pro Lys Asp Thr Leu Met He Ser Arg Thr Pro Glu Val 565 570 575 Thr Cys Val Val Val Asp Val Ser Hxs Lys Asn Pro Glu Val Asn Phe 580 585 590 Asr. Trp Tyr Val Asp Gly Val Glu Val Hxs Asn Wing Lys Thr Lys Pro 595 600 605 Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr 610 615 620 Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 625 630 635 640 Be Asn Lys Ala Leu Pro Ala Pro He Glu Lys Thr He Ser Lys Ala 645 650 655 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 660 665 670 Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 675 680 685 Phe Tyr Pro Ser Asp He Wing Val Glu Trp Glu Ser Asn Gly Gln Pro 690 695 700 Glu Asn Asp Tyr Lys Thr Pro Pro Val Leu Asp Ser Asp Gly Ser 705 710 715 720 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 725 730 735 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 740 745 750 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 755 760 < 210 > 63 < 211 > 63 < 212 > DNA < 213 > Mus musculus < 400 > 63 gtctcgctgg gcgtggggct agtggtactg ctggtgctgc tggtcatggt ggtagtggct 60 gtg 63 < 210 > 64 < 211 > 22 < 12 > PRT < 213 > Mus musculus < 400 > 64 Met Thr Pro Wing Ser Arg Wing Wing Cys Arg Trp Wing Leu Leu Leu Leu 1 5 10 15 Wing Val Leu Trp Pro Gln 20 < 210 > 65 < 211 > 23 < 212 > PRT < 213 > Mus musculus < 400 > 65 Met Thr Pro Wing Ser Arg Wing Wing Cys Arg Trp Wing Leu Leu Leu Leu 1 5 10 • 15 Wing Val Leu Trp Pro Gln Gln 20 < 210 > 66 < 211 > 24 < 212 > PRT < 213 > Mus musculus < 400 > 66 Met Thr Pro Ala Ser Arg Be Ala Cys Arg Trp Ala Leu Leu Leu Leu 1 5 10 15 Wing Val Leu Trp Pro Gln Gln Arg 20 < 210 > 67 < 211 > 25 < 212 > PRT < 213 > Mus musculus < 400 > 67 Met Thr Pro Ala Ser Arg Be Ala Cys Arg Trp Ala Leu Leu Leu Leu 1 5 10. fifteen Wing Val Leu Trp Pro Gln Gln Arg Wing 20 25 < 210 > 68 < 211 > 26 < 212 > PRT < 213 > Mus musculus < 400 > 68 Met Thr Pro Wing Ser Arg Wing Wing Cys Arg Trp Wing Leu Leu Leu Leu 1 5 10 15 Wing Val Leu Trp Pro Gln Gln Arg Wing Ala 20 25 < 210 > 69 < 211 > 27 < 212 > PRT < 213 > Mus musculus < 400 > 69 Met Thr Pro Wing Ser Arg Wing Wing Cys Arg Trp Wing Leu Leu Leu Leu 1 5 10 15 Wing Val Leu Trp Pro Gln Gln Arg Wing Ala Gly 20 25 < 210 > 70 < 211 > 21 < 212 > PRT < 213 > Mus musculue < 400 > 70 Val Ser Leu Gly Val Gly Leu Val Val Leu Leu Val Val Leu Leu Val 1 5 10 15 Val Val Val Ala Val 20 < 210 > 71 < 211 > 133 < 212 > PRT < 213 > Mus musculus < 400 > 71 Arg Gln Leu Arg Leu Arg Arg Pro Asp Asp Glu Ser-Arg Glu Wing Met 1 5 10 15 Asn Asn Leu Being Asp Phe Gln Lys Asp Asn Leu He Pro Wing Wing Gln 20 25 30 Leu Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu 35 40 45 Asp Lys- Ser Asn Cys Gly Lye Leu G n Asn Hie Thr Leu Asp Tyr Asn 50 55 60 Leu Wing Pro Gly Leu Leu Gly Arg Gly 3er Met Pro Gly Lys Tyr Pro 65 70 75 80 His Ser Asp Lys Ser Leu Gly Glu Lys Val Pro Leu Arg Leu His Ser 85 90 95 Glu Lys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg Asp Ser 100 105 110 Met Tyr Gln Ser Val Cys Leu He Ser Glu Glu Arg Asn Glu Cys Val 115 120 125 He Wing Thr Glu Val 130 < 210 > 72 < 211 > 63 < 212 > DNA < 213 > Homo sapiens < 400 > 72 gtctcgctgg gtgtggggct ggcagtgctg ctggtactgc tgggcatggt ggcagtggct 60 gtg 63 < 210 > 73 < 211 > 23 < 212 > PRT < 213 > Homo sapiens < 400 > 73 Met Ala Ala Ala Ser Arg Ser Ala Ser Gly Trp Ala Leu Leu Leu Leu 1 5. 10 15 Val Ala Leu Trp Gln Gln Arg 20 < 210 > 74 < 211 > 24 < 212 > PRT < 213 > Homo sapiens < 400 > 74 Met Wing Wing Wing Being Arg Being Wing Being Gly Trp Wing Leu Leu Leu Leu 1 5 10 15 Val Wing Leu Trp Gln Gln Arg Wing 20 < 210 > 75 < 211 > 25 < 212 > PRT < 213 > Homo sapiens < 400 > 75 Met Ala Ala Ala Ser Arg Ser Ala Ser Gly Trp Ala Leu Leu Leu Leu 1 5 10 15 Val Ala Leu Trp Gln Gln Arg Ala Ala 20 25 < 210 > 76 < 211 > 26 < 212 > PRT < 213 > Homo sapiens < 400 > 76 Met Ala Ala Ala Ser Arg Ser Ala Ser Gly Trp Ala Leu Leu Leu Leu 1 5 10 15 Val Ala Leu Trp Gln Gln Arg Ala Wing Gly 20 25 < 210 > 77 < 211 > 27 < 212 > PRT < 213 > Homo sapxens < 400 > 77 Met Ala Ala Ala Ser Arg Ser Ala Ser Gly Trp Ala Leu Leu Leu Leu 1 5 10 15 Val Ala Leu Trp Gln Gln Arg Ala Wing Gly Ser 20 25 < 210 > 78 < 211 > 28 < 212 > PRT < 213 > Homo sapiens < 400 > 78 Met Ala Ala Ala Ser Arg Ser Ala Ser Gly Trp Ala Leu Leu Leu Leu 1 5 10 15 Val Ala Leu Trp Gln Gln Arg Ala Wing Gly Ser Gly 20 25 < 210 > 79 < 211 > 21 < 212 > PRT < 213 > Homo sapiens < 400 > 79 Val Ser Leu Gly Val Gly Leu Ala Val Leu Leu Val Leu Leu Gly Met 1 5 10 15 Val Ala Val Val Ala 20 < 210 > 80 < 211 > 133 < 212 > PRT < 213 > Homo sapiens < 400 > 80 Arg Gln Leu Arg Leu Arg Arg Pro Asp Asp Gly Ser Arg Glu Ala Met 1 5. 10 15 Asn Asn Leu Be Asp Phe Gln Lys Asp Asn Leu He Pro Ala Wing Gln 20 <25 30 Leu Lys Asn Thr Asn Gln Lys Lys Glu Leu Glu Val Asp Cys Gly Leu 35 40 45 Asp Lys Ser Asn Cys Gly Lys Gln Gln Asn His Thr Leu Asp Tyr Asn 50 55 60 Leu Ala Pro Gly Pro Leu Gly Arg Gly. Thr Met Pro Gly Lys Phe Pro 65 70 75 80 His Ser Asp Lys Ser Leu Gly Glu Lys Ala Pro Leu Arg Leu His Ser 85 90 95 Glu Lys Pro Glu Cys Arg He Ser Wing He Cys Ser Pro Arg Asp Ser 100 105 110 Met Tyr Gln Ser Val Cys Leu He Ser Glu Glu Arg Asn Glu Cys Val 115 120 125 He Wing Thr Glu Val 130 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (18)

Claims

1. A purified mammalian polypeptide, characterized in that it comprises an amino acid sequence selected from the group consisting of: (a) the polypeptide of SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, or SEQ ID NO: 22; (b) the polypeptide of SEQ ID NO: 4, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40; (c) a polypeptide fragment of any of the aforementioned, (d) a polypeptide analog of any of the aforementioned having at least eighty percent of the amino acid sequence identical therewith, (e) any of the aforementioned also having an N-terminal methionyl residue.

2. The polypeptide according to claim 1, characterized in that it is a human polypeptide comprising the amino acid sequence of SEQ ID NO: 26, with or without an N-terminal methionine residue.

3. The analogous polypeptide according to claim 1, characterized in that it is ninety percent or more identical in the amino acid sequence with any of (a), (b), (c), (d) or (e).

4. The polypeptide according to claims 1, 2 or 3, characterized in that it is produced by the recombinant expression.

5. A biologically active derivative of the polypeptide according to claim 1.

6. The polypeptide derived according to claim 5, characterized in that the polypeptide is linked to a synthetic water soluble polymer, a detectable marker molecule, or a polyamino acid.

7. The polypeptide derived according to claim 6, characterized in that the synthetic water-soluble polymer is polyethylene glycol or dextran.

8. The polypeptide derived according to claim 6, characterized in that it is a Fe fusion product.

9. An isolated DNA molecule encoding a polypeptide according to claim 1, characterized in that it is selected from the group consisting of: (a) the DNA molecule of SEQ ID NO: 1 or SEQ ID NO: 3, (b) a variant allelic of the DNA molecule of (a) encoding the same polypeptide, (c) the DNA molecule that selectively hybridizes to the DNA molecule of (a) or (b), and (d) the DNA molecule that, but for the degeneracy of the genetic code, it hybridizes a DNA molecule of (a), (b) or (c).

10. A biologically functional viral vector or plasmid, characterized in that it contains a DNA molecule according to claim 9.

11. A prokaryotic or eukaryotic host cell, characterized in that it contains the vector of claim 10.

12. A modified host cell, characterized in that the expression of an endogenous polypeptide having the sequence of SEQ ID NO: 2 or SEQ ID NO: 4 or a fragment or naturally occurring mutation thereof is improved or increased.

13. The host cell according to claim 12, characterized in that it is an isolated human host cell.

14. A process for the production of a polypeptide according to claim 1, characterized in that it comprises, culturing, under appropriate nutrient conditions, a host cell containing a DNA molecule encoding the polypeptide in such a manner that expression of the polypeptide occurs, obtaining the polypeptide thus produced, and optionally preparing a composition containing the polypeptide.

15. An antibody to the polypeptide of claim 1.

16. The antibody according to claim 15, characterized in that it is monoclonal.

17. A method for identifying a receptor that binds to the polypeptide according to claim 1, characterized in that it comprises the polypeptide with a receptor to identify under conditions that allow binding, and detect the presence of any linker.

18. A transgenic non-human mammal capable of expressing in any cell thereof the DNA of SEQ ID NO: 3.