US20040214202A1

US20040214202A1 - Novel human transferase proteins and polynucleotides encoding the same

Info

Publication number: US20040214202A1
Application number: US10/730,882
Authority: US
Inventors: D. Walke; C. Turner; Glenn Friedrich; Alejandro Abuin; Brian Zambrowicz; Arthur Sands
Original assignee: Individual
Current assignee: Individual
Priority date: 1999-12-13
Filing date: 2003-12-09
Publication date: 2004-10-28
Also published as: AU784376B2; US6692947B2; JP2003516154A; CA2394976A1; US20030166839A1; EP1263966A1; WO2001042477A1; AU2087601A

Abstract

Novel human polynucleotide and polypeptide sequences are disclosed that can be used in therapeutic, diagnostic, and pharmacogenomic applications.

Description

The present application claims the benefit of U.S. Provisional Application No. 60/170,408 which was filed on Dec. 13, 1999 and is herein incorporated by reference in its entirety.[0001]

1. INTRODUCTION

The present invention relates to the discovery, identification, and characterization of novel human polynucleotides encoding proteins sharing sequence similarity with mammalian glycotransferases. The invention encompasses the described polynucleotides, host cell expression systems, the encoded protein, fusion proteins, polypeptides and peptides, antibodies to the encoded proteins and peptides, and genetically engineered animals that either lack or over express the disclosed sequences, antagonists and agonists of the proteins, and other compounds that modulate the expression or activity of the proteins encoded by the disclosed polynucleotides that can be used for diagnosis, drug screening, clinical trial monitoring and the treatment of physiological disorders.

2. BACKGROUND OF THE INVENTION

Transferases covalently modify biological substrates, including protein, as part of degradation, maturation, and secretory pathways within the body. Transferases have thus been associated with, inter alia, development, protein and cellular senescence, and as cancer associated markers.

3. SUMMARY OF THE INVENTION

The present invention relates to the discovery, identification, and characterization of nucleotides that encode novel human proteins, and the corresponding amino acid sequences of these proteins. The novel human proteins (NHPs) described for the first time herein shares structural similarity with animal beta 1,4 N-acetylgalactosamine transferases.

The novel human nucleic acid (cDNA) sequences described herein, encode proteins/open reading frames (ORFs) of 506, 132, 72, 184, 124, 182, 118, 453, 393, .448, 388, .182, 122, 176, 116, 572, 512, and 566 amino acids in length (see SEQ ID NOS: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, and 36).

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

Further, the present invention also relates to processes for identifying compounds that modulate, i.e., act as agonists or antagonists, of NHP expression and/or NHP activity that utilize purified preparations of the described NHP and/or NHP product, or cells expressing the same. Such compounds can be used as therapeutic agents for the treatment of any of a wide variety of symptoms associated with biological disorders or imbalances.

4. DESCRIPTION OF THE SEQUENCE LISTING AND FIGURES

The Sequence Listing provides the sequences of the NHP ORFs encoding the described NHP amino acid sequences. SEQ ID NO: 37 describes an ORF with flanking sequences.

5. DETAILED DESCRIPTION OF THE INVENTION

The NHPs, described for the first time herein, are novel proteins that are expressed in, inter alia, human cell lines, gene trapped cells and human kidney and stomach cells. [0009]
The described sequences were compiled from gene trapped cDNAs and clones isolated from a human kidney cDNA library (Edge Biosystems, Gaithersburg, Md.). The present invention encompasses the nucleotides presented in the Sequence Listing, host cells expressing such nucleotides, the expression products of such nucleotides, and: (a) nucleotides that encode mammalian homologs of the described sequences, including the specifically described NHPs, and the NHP products; (b) nucleotides that encode one or more portions of a NHP that correspond to functional domains of the NHP, and the polypeptide products specified by such nucleotide sequences, including but not limited to the novel regions of any active domain(s); (c) isolated nucleotides that encode mutant versions, engineered or naturally occurring, of a described NHP in which all or a part of at least one domain is deleted or altered, and the polypeptide products specified by such nucleotide sequences, including but not limited to soluble proteins and peptides in which all or a portion of the signal sequence is deleted; (d) nucleotides that encode chimeric fusion proteins containing all or a portion of a coding region of a NHP, or one of its domains (e.g., a receptor or ligand binding domain, accessory protein/self-association domain, etc.) fused to another peptide or polypeptide; or (e) therapeutic or diagnostic derivatives of the described polynucleotides such as oligonucleotides, antisense polynucleotides, ribozymes, dsRNA, or gene therapy constructs comprising a sequence first disclosed in the Sequence Listing. [0010]
As discussed above, the present invention includes: (a) the human DNA sequences presented in the Sequence Listing (and vectors comprising the same) and additionally contemplates any nucleotide sequence encoding a contiguous NHP open reading frame (ORF), or a contiguous exon splice junction first described in the Sequence Listing, that hybridizes to a complement of a DNA sequence presented in the Sequence Listing under highly stringent conditions, e.g., hybridization to filter-bound DNA in 0.5 M NaHPO[0011] ₄, 7% sodium dodecyl sulfate (SDS), 1 mM EDTA at 65° C., and washing in 0.1×SSC/0.1% SDS at 68° C. (Ausubel F. M. et al., eds., 1989, Current Protocols in Molecular Biology, Vol. I, Green Publishing Associates, Inc., and John Wiley & sons, Inc., New York, at p. 2.10.3) and encodes a functionally equivalent gene product. Additionally contemplated are any nucleotide sequences that hybridize to the complement of the DNA sequence that encode and express an amino acid sequence presented in the Sequence Listing under moderately stringent conditions, e.g., washing in 0.2×SSC/0.1% SDS at 42° C. (Ausubel et al., 1989, supra), yet still encode a functionally equivalent NHP product. Functional equivalents of a NHP include naturally occurring NHPs present in other species and mutant NHPs whether naturally occurring or engineered (by site directed mutagenesis, gene shuffling, directed evolution as described in, for example, U.S. Pat. No. 5,837,458). The invention also includes degenerate nucleic acid variants of the disclosed NHP polynucleotide sequences.
Additionally contemplated are polynucleotides encoding a NHP ORF, or its functional equivalent, encoded by a polynucleotide sequence that is about 99, 95, 90, or about 85 percent similar or identical to corresponding regions of the nucleotide sequences of the Sequence Listing (as measured by BLAST sequence comparison analysis using, for example, the GCG sequence analysis package using standard default settings). [0012]
The invention also includes nucleic acid molecules, preferably DNA molecules, that hybridize to, and are therefore the complements of, the described NHP nucleotide sequences. Such hybridization conditions may be highly stringent or less highly stringent, as described above. In instances where the nucleic acid molecules are deoxyoligonucleotides (“DNA oligos”), such molecules are generally about 16 to about 100 bases long, or about 20 to about 80, or about 34 to about 45 bases long, or any variation or combination of sizes represented therein that incorporate a contiguous region of sequence first disclosed in the Sequence Listing. Such oligonucleotides can be used in conjunction with the polymerase chain reaction (PCR) to screen libraries, isolate clones, and prepare cloning and sequencing templates, etc. [0013]
Alternatively, such NHP oligonucleotides can be used as hybridization probes for screening libraries, and assessing sequence expression patterns (particularly using a micro array or high-throughput “chip” format). Additionally, a series of the described NHP oligonucleotide sequences, or the complements thereof, can be used to represent all or a portion of the described NHP sequences. An oligonucleotide or polynucleotide sequence first disclosed in at least a portion of one or more of the sequences of SEQ ID NOS: 1-37 can be used as a hybridization probe in conjunction with a solid support matrix/substrate (resins, beads, membranes, plastics, polymers, metal or metallized substrates, crystalline or polycrystalline substrates, etc.). Of particular note are spatially addressable arrays (i.e., gene chips, microtiter plates, etc.) of oligonucleotides and polynucleotides, or corresponding oligopeptides and polypeptides, wherein at least one of the biopolymers present on the spatially addressable array comprises an oligonucleotide or polynucleotide sequence first disclosed in at least one of the sequences of SEQ ID NOS: 1-37, or an amino acid sequence encoded thereby. Methods for attaching biopolymers to, or synthesizing biopolymers on, solid support matrices, and conducting binding studies thereon are disclosed in, inter alia, U.S. Pat. Nos. 5,700,637, 5,556,752, 5,744,305, 4,631,211, 5,445,934, 5,252,743, 4,713,326, 5,424,186, and 4,689,405 the disclosures of which are herein incorporated by reference in their entirety. [0014]
Addressable arrays comprising sequences first disclosed in SEQ ID NOS:1-37 can be used to identify and characterize the temporal and tissue specific expression of a sequence. These addressable arrays incorporate oligonucleotide sequences of sufficient length to confer the required specificity, yet be within the limitations of the production technology. The length of these probes is within a range of between about 8 to about 2000 nucleotides. Preferably the probes consist of 60 nucleotides and more preferably 25 nucleotides from the sequences first disclosed in SEQ ID NOS:1-37. [0015]
For example, a series of the described oligonucleotide sequences, or the complements thereof, can be used in chip format to represent all or a portion of the described sequences. The oligonucleotides, typically between about 16 to about 40 (or any whole number within the stated range) nucleotides in length can partially overlap each other and/or the sequence may be represented using oligonucleotides that do not overlap. Accordingly, the described polynucleotide sequences shall typically comprise at least about two or three distinct oligonucleotide sequences of at least about 8 nucleotides in length that are each first disclosed in the described Sequence Listing. Such oligonucleotide sequences can begin at any nucleotide present within a sequence in the Sequence Listing and proceed in either a sense (5′-to-3′) orientation vis-a-vis the described sequence or in an antisense orientation. [0016]
Microarray-based analysis allows the discovery of broad patterns of genetic activity, providing new understanding of gene functions and generating novel and unexpected insight into transcriptional processes and biological mechanisms. The use of addressable arrays comprising sequences first disclosed in SEQ ID NOS:1-37 provides detailed information about transcriptional changes involved in a specific pathway, potentially leading to the identification of novel components or gene functions that manifest themselves as novel phenotypes. [0017]
Probes consisting of sequences first disclosed in SEQ ID NOS:1-37 can also be used in the identification, selection and validation of novel molecular targets for drug discovery. The use of these unique sequences permits the direct confirmation of drug targets and recognition of drug dependent changes in gene expression that are modulated through pathways distinct from the drugs intended target. These unique sequences therefore also have utility in defining and monitoring both drug action and toxicity. [0018]
As an example of utility, the sequences first disclosed in SEQ ID NOS:1-37 can be utilized in microarrays or other assay formats, to screen collections of genetic material from patients who have a particular medical condition. These investigations can also be carried out using the sequences first disclosed in SEQ ID NOS:1-37 in silico and by comparing previously collected genetic databases and the disclosed sequences using computer software known to those in the art. [0019]
Thus the sequences first disclosed in SEQ ID NOS:1-37 can be used to identify mutations associated with a particular disease and also as a diagnostic or prognostic assay. [0020]
Although the presently described sequences have been specifically described using nucleotide sequence, it should be appreciated that each of the sequences can uniquely be described using any of a wide variety of additional structural attributes, or combinations thereof. For example, a given sequence &an be described by the net composition of the nucleotides present within a given region of the sequence in conjunction with the presence of one or more specific oligonucleotide sequence(s) first disclosed in the SEQ ID NOS: 1-37. Alternatively, a restriction map specifying the relative positions of restriction endonuclease digestion sites, or various palindromic or other specific oligonucleotide sequences can be used to structurally describe a given sequence. Such restriction maps, which are typically generated by widely available computer programs (e.g., the University of Wisconsin GCG sequence analysis package, SEQUENCHER 3.0, Gene Codes Corp., Ann Arbor, Mich., etc.), can optionally be used in conjunction with one or more discrete nucleotide sequence(s) present in the sequence that can be described by the relative position of the sequence relative to one or more additional sequence(s) or one or more restriction sites present in the disclosed sequence. [0021]
For oligonucleotide probes, highly stringent conditions may refer, for example, to washing in 6×SSC/0.05% sodium pyrophosphate at 37° C. (for 14-base oligos), 48° C. (for 17-base oligos), 55° C. (for 20-base oligos), and 60° C. (for 23-base oligos). These nucleic acid molecules may encode or act as NHP sequence antisense molecules, useful, for example, in NHP gene regulation (for and/or as antisense primers in amplification reactions of NHP nucleic acid sequences). With respect to NHP gene regulation, such techniques can be used to regulate biological functions. Further, such sequences may be used as part of ribozyme and/or triple helix sequences that are also useful for NHP gene regulation. [0022]
Inhibitory antisense or double stranded oligonucleotides can additionally comprise at least one modified base moiety which is selected from the group including but not limited to 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xantine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. [0023]
The antisense oligonucleotide can also comprise at least one modified sugar moiety selected from the group including but not limited to arabinose, 2-fluoroarabinose, xylulose, and hexose. [0024]
In yet another embodiment, the antisense oligonucleotide will comprise at least one modified phosphate backbone selected from the group consisting of a phosphorothioate, a phosphorodithioate, a phosphoramidothioate, a phosphoramidate, a phosphordiamidate, a methylphosphonate, an alkyl phosphotriester, and a formacetal or analog thereof. [0025]
In yet another embodiment, the antisense oligonucleotide is an a-anomeric oligonucleotide. An α-anomeric oligonucleotide forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual β-units, the strands run parallel to each other (Gautier et al., 1987, Nucl. Acids Res. 15:6625-6641). The oligonucleotide is a 2′-0-methylribonucleotide (Inoue et al., 1987, Nucl. Acids Res. 15:6131-6148), or a chimeric RNA-DNA analogue (Inoue et al., 1987, FEBS Lett. 215:327-330). Alternatively, double stranded RNA can be used to disrupt the expression and function of a targeted NHP. [0026]
Oligonucleotides of the invention can be synthesized by standard methods known in the art, e.g. by use of an automated DNA synthesizer (such as are commercially available from Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate oligonucleotides can be synthesized by the method of Stein et al. (1988, Nucl. Acids Res. 16:3209), and methylphosphonate oligonucleotides can be prepared by use of controlled pore glass polymer supports (Sarin et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:7448-7451), etc. [0027]
Low stringency conditions are well known to those of skill in the art, and will vary predictably depending on the specific organisms from which the library and the labeled sequences are derived. For guidance regarding such conditions see, for example, Sambrook et al., 1989, Molecular Cloning, A Laboratory Manual (and periodic updates thereof), Cold Springs Harbor Press, N.Y.; and Ausubel et al., 1989, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. [0028]
Alternatively, suitably labeled NHP nucleotide probes can be used to screen a human genomic library using appropriately stringent conditions or by PCR. The identification and characterization of human genomic clones is helpful for identifying polymorphisms (including, but not limited to, nucleotide repeats, microsatellite alleles, single nucleotide polymorphisms, or coding single nucleotide polymorphisms), determining the genomic structure of a given locus/allele, and designing diagnostic tests. For example, sequences derived from regions adjacent to the intron/exon boundaries of the human gene can be used to design primers for use in amplification assays to detect mutations within the exons, introns, splice sites (e.g., splice acceptor and/or donor sites), etc., that can be used in diagnostics and pharmacogenomics. [0029]
Further, a NHP homolog can be isolated from nucleic acid from an organism of interest by performing PCR using two degenerate or “wobble” oligonucleotide primer pools designed on the basis of amino acid sequences within the NHP products disclosed herein. The template for the reaction may be total RNA, mRNA, and/or cDNA obtained by reverse transcription of mRNA prepared from human or non-human cell lines or tissue known or suspected to express an allele of a NHP gene. [0030]
The PCR product can be subcloned and sequenced to ensure that the amplified sequences represent the sequence of the desired NHP gene. The PCR fragment can then be used to isolate a full length CDNA clone by a variety of methods. For example, the amplified fragment can be labeled and used to screen a cDNA library, such as a bacteriophage cDNA library. Alternatively, the labeled fragment can be used to isolate genomic clones via the screening of a genomic library. [0031]
PCR technology can also be used to isolate full length cDNA sequences. For example, RNA can be isolated, following standard procedures, from an appropriate cellular or tissue source (i.e., one known, or suspected, to express a NHP sequence, such as, for example, testis tissue). A reverse transcription (RT) reaction can be performed on the RNA using an oligonucleotide primer specific for the most 5′ end of the amplified fragment for the priming of first strand synthesis. The resulting RNA/DNA hybrid may then be “tailed” using a standard terminal transferase reaction, the hybrid may be digested with RNase H, and second strand synthesis may then be primed with a complementary primer. Thus, cDNA sequences upstream of the amplified fragment can be isolated. For a review of cloning strategies that can be used, see e.g., Sambrook et al., 1989, supra. [0032]
A cDNA encoding a mutant NHP sequence can be isolated, for example, by using PCR. In this case, the first cDNA strand may be synthesized by hybridizing an oligo-dT oligonucleotide to mRNA isolated from tissue known or suspected to be expressed in an individual putatively carrying a mutant NHP-allele, and by extending the new strand with reverse transcriptase. The second strand of the cDNA is then synthesized using an oligonucleotide that hybridizes specifically to the 5′ end of the normal gene. Using these two primers, the product is then amplified via PCR, optionally cloned into a suitable vector, and subjected to DNA sequence analysis through methods well known to those of skill in the art. By comparing the DNA sequence of the mutant NHP allele to that of a corresponding normal NHP allele, the mutation(s) responsible for the loss or alteration of function of the mutant NHP gene product can be ascertained. [0033]
Alternatively, a genomic library can be constructed using DNA obtained from an individual suspected of or known to carry a mutant NHP allele (e.g., a person manifesting a NHP-associated phenotype such as, for example, obesity, high blood pressure, connective tissue disorders, infertility, etc.), or a cDNA library can be constructed using RNA from a tissue known, or suspected, to express a mutant NHP allele. A normal NHP gene, or any suitable fragment thereof, can then be labeled and used as a probe to identify the corresponding mutant NHP allele in such libraries. Clones containing mutant NHP sequences can then be purified and subjected to sequence analysis according to methods well known to those skilled in the art. [0034]
Additionally, an expression library can be constructed utilizing cDNA synthesized from, for example, RNA isolated from a tissue known, or suspected, to express a mutant NHP allele in an individual suspected of or known to carry such a mutant allele. In this manner, gene products made by the putatively mutant tissue can be expressed and screened using standard antibody screening techniques in conjunction with antibodies raised against normal NHP product, as described below. (For screening techniques, see, for example, Harlow, E. and Lane, eds., 1988, “Antibodies: A Laboratory Manual”, Cold Spring Harbor Press, Cold Spring Harbor). [0035]
Additionally, screening can be accomplished by screening with labeled NHP fusion proteins, such as, for example, alkaline phosphatase-NHP or NHP-alkaline phosphatase fusion proteins. In cases where a NHP mutation results in an expressed gene product with altered function (e.g., as a result of a missense or a frameshift mutation), polyclonal antibodies to NHP are likely to cross-react with a corresponding mutant NHP gene product. Library clones detected via their reaction with such labeled antibodies can be purified and subjected to sequence analysis according to methods well known in the art. [0036]
The invention also encompasses (a) DNA vectors that contain any of the foregoing NHP coding sequences and/or their complements (i.e., antisense); (b) DNA expression vectors that contain any of the foregoing NHP coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences (for example, baculo virus as described in U.S. Pat. No. 5,869,336 herein incorporated by reference); (c) genetically engineered host cells that contain any of the foregoing NHP coding sequences operatively associated with a regulatory element that directs the expression of the coding sequences in the host cell; and (d) genetically engineered host cells that express an endogenous NHP sequence under the control of an exogenously introduced regulatory element (i.e., gene activation). As used herein, regulatory elements include, but are not limited to, inducible and non-inducible promoters, enhancers, operators and other elements known to those skilled in the art that drive and regulate expression. Such regulatory elements include but are not limited to the human cytomegalovirus (hCMV) immediate early gene, regulatable, viral elements (particularly retroviral LTR promoters), the early or late promoters of SV40 adenovirus, the lac system, the trp system, the TAC system, the TRC system, the major operator and promoter regions of phage lambda, the control regions of fd coat protein, the promoter for 3-phosphoglycerate kinase (PGK), the promoters of acid phosphatase, and the promoters of the yeast α-mating factors. [0037]
The present invention also encompasses antibodies and anti-idiotypic antibodies (including Fab fragments), antagonists and agonists of a NHP, as well as compounds or nucleotide constructs that inhibit expression of a NHP sequence (transcription factor inhibitors, antisense and ribozyme molecules, or gene or regulatory sequence replacement constructs), or promote the expression of a NHP (e.g., expression constructs in which NHP coding sequences are operatively associated with expression control elements such as promoters, promoter/enhancers, etc.). [0038]
The NHPs or NHP peptides, NHP fusion proteins, NHP nucleotide sequences, antibodies, antagonists and agonists can be useful for the detection of mutant NHPs or inappropriately expressed NHPs for the diagnosis of disease. The NHP proteins or peptides, NHP fusion proteins, NHP nucleotide sequences, host cell expression systems, antibodies, antagonists, agonists and genetically engineered cells and animals can be used for screening for drugs (or high throughput screening of combinatorial libraries) effective in the treatment of the symptomatic or phenotypic manifestations of perturbing the normal function of a NHP in the body. The use of engineered host cells and/or animals may offer an advantage in that such systems allow not only for the identification of compounds that bind to the endogenous receptor for a NHP, but can also-identify compounds that trigger NHP-mediated activities or pathways. [0039]
Finally, the NHP products can be used as therapeutics. For example, soluble derivatives such as NHP peptides/domains corresponding to NHP, NHP fusion protein products (especially NHP-Ig fusion proteins, i.e., fusions of a NHP, or a domain of a NHP, to an IgFc), NHP antibodies and anti-idiotypic antibodies (including Fab fragments), antagonists or agonists (including compounds that modulate or act on downstream targets in a NHP-mediated pathway) can be used to directly treat diseases or disorders. For instance, the administration of an effective amount of soluble NHP, or a NHP-IgFc fusion protein or an anti-idiotypic antibody (or its Fab) that mimics the NHP could activate or effectively antagonize the endogenous NHP receptor. Nucleotide constructs encoding such NHP products can be used to genetically engineer host cells to express such products in vivo; these genetically engineered cells function as “bioreactors” in the body delivering a continuous supply of a NHP, a NHP peptide, or a NHP fusion protein to the body. Nucleotide constructs encoding functional NHP, mutant NHPs, as well as antisense and ribozyme molecules can also be used in “gene therapy” approaches for the modulation of NHP expression. Thus, the invention also encompasses pharmaceutical formulations and methods for treating biological disorders. [0040]
Various aspects of the invention are described in greater detail in the subsections below. [0041]

5.1 The NHP Sequences

The cDNA sequences and the-corresponding deduced amino acid sequences of the described NHP are presented in the Sequence Listing. SEQ ID NO:37 describes the NHP ORF as well as flanking regions. The NHP nucleotides were obtained from human cDNA libraries using probes and/or primers generated from human gene trapped sequence tags. Expression analysis has provided evidence that the described NHP can be expressed a variety of human cells as well as gene trapped human cells. A silent polymorphism (C-to-T transition) was identified at, for example, base 169 of SEQ ID NO:1. [0042]

5.2 NHP and NHP Polypeptides

NHPs, polypeptides, peptide fragments, mutated, truncated, or deleted forms of the NHPs, and/or NHP fusion proteins can be prepared for a variety of uses. These uses include, but are not limited to, the generation of antibodies, as reagents in diagnostic assays, for the identification of other cellular gene products related to a NHP, as reagents in assays for screening for compounds that can be as pharmaceutical reagents useful in the therapeutic treatment of mental, biological, or medical disorders and disease. [0043]
The Sequence Listing discloses the amino acid sequence encoded by the described NHP polynucleotides. The NHPs display initiator methionines in DNA sequence contexts consistent with translation initiation sites, and apparently display a signal sequence which can indicate that the described NHP ORFs are membrane associated or possibly secreted. [0044]
The NHP amino acid sequences of the invention include the amino acid sequences presented in the Sequence Listing as well as analogues and derivatives thereof, as well as any oligopeptide sequence of at least about 10-40, generally about 12-35, or about 16-30 amino acids in length first disclosed in the Sequence Listing. Further, corresponding NHP homologues from other species are encompassed by the invention; In fact, any NHP encoded by the NHP nucleotide sequences described above are within the scope of the invention, as are any novel polynucleotide sequences encoding all or any novel portion of an amino acid sequence presented in the Sequence Listing. The degenerate nature of the genetic code is well known, and, accordingly, each amino acid presented in the Sequence Listing, is generically representative of the well known nucleic acid “triplet” codon, or in many cases codons, that can encode the amino acid. As such, as contemplated herein, the amino acid sequences presented in the Sequence Listing, when taken together with the genetic code (see, for example, Table 4-1 at page 109 of “Molecular Cell Biology”, 1986, J. Darnell et al. eds., Scientific American Books, New York, N.Y., herein incorporated by reference) are generically representative of all the various permutations and combinations of nucleic acid sequences that can encode such amino acid sequences. [0045]
The invention also encompasses proteins that are functionally equivalent to the NHPs encoded by the presently described nucleotide sequences as judged by any of a number of criteria, including, but not limited to, the ability to bind and cleave a substrate of a NHP, or the ability to effect an identical or complementary downstream pathway, or a change in cellular metabolism (e.g., proteolytic activity, ion flux, tyrosine phosphorylation, etc.). Such functionally equivalent NHP proteins include, but are not limited to, additions or substitutions of amino acid residues within the amino acid sequence encoded by the NHP nucleotide sequences described above, but which result in a silent change, thus producing a functionally equivalent gene product. Amino acid substitutions can be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved. For example, nonpolar (hydrophobic) amino acids include alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, and methionine; polar neutral amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine, and glutamine; positively charged (basic) amino acids include arginine, lysine, and histidine; and negatively charged (acidic) amino acids include aspartic acid and glutamic acid. [0046]
A variety of host-expression vector systems can be used to express the NHP nucleotide sequences of the invention. Where, as in the present instance, the NHP products or NHP polypeptides can be produced in soluble or secreted forms (by removing one or more transmembrane domains where applicable), the peptide or polypeptide can be recovered from the culture media. Such expression systems also encompass engineered host cells that express a NHP, or a functional equivalent, in situ. Purification or enrichment of NHP from such expression systems can be accomplished using appropriate detergents and lipid micelles and methods well known to those skilled in the art. However, such engineered host cells themselves may be used in situations where it is important not only to retain the structural and functional characteristics of the NHP, but to assess biological activity, e.g., in drug screening assays. [0047]
The expression systems that may be used for purposes of the invention include but are not limited to microorganisms such as bacteria (e.g., [0048] E. coli, B. subtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing NHP nucleotide sequences; yeast (e.g., Saccharomyces, Pichia) transformed with recombinant yeast expression vectors containing NHP encoding nucleotide sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing NHP sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing NHP nucleotide sequences; or mammalian cell systems (e.g., COS, CHO, BHK, 293, 3T3) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g., the adenovirus late promoter; the vaccinia virus 7.5 K promoter).
In bacterial systems, a number of expression vectors may be advantageously selected depending upon the use intended for the NHP product being expressed. For example, when a large quantity of such a protein is to be produced for the generation of pharmaceutical compositions of or containing NHP, or for raising antibodies to a NHP, vectors that direct the expression of high levels of fusion protein products that are readily purified may be desirable. Such vectors include, but are not limited, to the [0049] E. coli expression vector pUR278 (Ruther et al., 1983, EMBO J. 2:1791), in which a NHP coding sequence may be ligated individually into the vector in frame with the lacZ coding region so that a fusion protein is produced; pIN vectors (Inouye & Inouye, 1985, Nucleic Acids Res. 13:3101-3109; Van Heeke & Schuster, 1989, J. Biol. Chem. 264:5503-5509); and the like. pGEX vectors (Pharmacia or American Type Culture Collection) can also be used to express foreign polypeptides as fusion proteins with glutathione S-transferase (GST). In general, such fusion proteins are soluble and can easily be purified from lysed cells by adsorption to glutathione-agarose beads followed by elution in the presence of free glutathione. The PGEX-vectors are designed to include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.
In an insect system, [0050] Autographa californica nuclear polyhidrosis virus (AcNPV) is used as a vector to express foreign sequences. The virus grows in Spodoptera frugiperda cells. A NHP coding sequence can be cloned individually into non-essential regions (for example the polyhedrin gene) of the virus and placed under control of an AcNPV promoter (for example the polyhedrin promoter). Successful insertion of NHP coding sequence will result in inactivation of the polyhedrin gene and production of non-occluded recombinant virus (i.e., virus lacking the proteinaceous coat coded for by the polyhedrin gene). These recombinant viruses are then used to infect Spodoptera frugiperda cells in which the inserted sequence is expressed (e.g., see Smith et al., 1983, J. Virol. 46: 584; Smith, U.S. Pat. No. 4,215,051).
In mammalian host cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, the NHP nucleotide sequence of interest may be ligated to an adenovirus transcription/translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene may then be inserted in the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., region E1 or E3) will result in a recombinant virus that is viable and capable of expressing a NHP product in infected hosts (e.g., See Logan & Shenk, 1984, Proc. Natl. Acad. Sci. USA 81:3655-3659). Specific initiation signals may also be required for efficient translation of inserted NHP nucleotide sequences. These signals include the ATG initiation codon and adjacent sequences. In cases where an entire NHP gene or cDNA, including its own initiation codon and adjacent sequences, is inserted into the appropriate expression vector, no additional translational control signals may be needed. However, in cases where only a portion of a NHP coding sequence is inserted, exogenous translational control signals, including, perhaps, the ATG initiation codon, must be provided. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (See Bittner et al., 1987, Methods in Enzymol. 153:516-544). [0051]
In addition, a host cell strain may be chosen that modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. Appropriate cell lines or host systems can be chosen to ensure the correct modification and processing of the foreign protein expressed. To this end, eukaryotic host cells which possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include, but are not limited to, CHO, VERO, BHK, HeLa, COS, Md.CK, 293, 3T3, WI38, and in particular, human cell lines. [0052]
For long-term, high-yield production of recombinant proteins, stable expression is preferred. For example, cell lines which stably express the NHP sequences described above can be engineered. Rather than using expression vectors which contain viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoter, enhancer sequences, transcription terminators, polyadenylation sites, etc.), and a selectable marker. Following the introduction of the foreign DNA, engineered cells may be allowed to grow for 1-2 days in an enriched media, and then are switched to a selective media. The selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci which in turn can be cloned and expanded into cell lines. This method may advantageously be used to engineer cell lines which express the NHP product. Such engineered cell lines may be particularly useful in screening and evaluation of compounds that affect the endogenous activity of the NHP product. [0053]
A number of selection systems may be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler, et al., 1977, Cell 11:223), hypoxanthine-guanine phosphoribosyltransferase (Szybalska & Szybalski, 1962, Proc. Natl. Acad. Sci. USA 48:2026), and adenine phosphoribosyltransferase (Lowy, et al., 1980, Cell 22:817) genes can be-employed in tk[0054] ⁻, hgprt⁻ or aprt⁻ cells, respectively. Also, antimetabolite resistance can be used as the basis of selection for the following genes: dhfr, which confers resistance to methotrexate (Wigler, et al., 1980, Natl. Acad. Sci. USA 77:3567; O'Hare, et al., 1981, Proc. Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance to mycophenolic acid (Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA 78:2072); neo, which confers resistance to the aminoglycoside G-418 (Colberre-Garapin, et al., 1981, J. Mol. Biol. 150:1); and hygro, which confers resistance to hygromycin (Santerre, et al., 1984, Gene 30:147).
Alternatively, any fusion protein can be readily purified by utilizing an antibody specific for the fusion protein being expressed. For example, a system described by Janknecht et al. allows for the ready purification of non-denatured fusion proteins expressed in human cell lines (Janknecht, et al., 1991, Proc. Natl. Acad. Sci. USA 88:8972-8976). In this system, the sequence of interest is subcloned into a vaccinia recombination plasmid such that the sequence's open reading frame is translationally fused to an amino-terminal tag consisting of six histidine residues. Extracts from cells infected with recombinant vaccinia virus are loaded onto Ni[0055] ²⁺-nitriloacetic acid-agarose columns and histidine-tagged proteins are selectively eluted with imidazole-containing buffers.
Also encompassed by the present invention are novel protein constructs engineered in such a way that they facilitate transport of the NHP td the target site, to the desired organ, across the cell membrane and/or to the nucleus where the NHP can exert its function activity. This goal may be achieved by coupling of the NHP to a cytokine or other ligand that would direct the NHP to the target organ and facilitate receptor mediated transport across the membrane into the cytosol. Conjugation of NHPs to antibody molecules or their Fab fragments could be used to target cells bearing a particular epitope. Attaching the appropriate signal sequence to the NHP would also transport the NHP to the desired location within the cell. Alternatively targeting of NHP or its nucleic acid sequence might be achieved using liposome or lipid complex based delivery systems. Such technologies are described in [0056] Lilosomes:A Practical Aoproach, New RRC ed., Oxford University Press, New York and in U.S. Pat. Nos. 4,594,595, 5,459,127, 5,948,767 and 6,110,490 and their respective disclosures which are herein incorporated by reference in their entirety.

5.3 Antibodies to NHP Products

Antibodies that specifically recognize one or more epitopes of a NHP, or epitopes of conserved variants of a NHP, or peptide fragments of a NHP are also encompassed by the invention. Such antibodies include but are not limited to polyclonal antibodies, monoclonal antibodies (mAbs), humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab′)[0057] ₂fragments, fragments produced by a Fab expression library, anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above.
The antibodies of the invention may be used, for example, in the detection of NHP in a biological sample and may, therefore, be utilized as part of a diagnostic or prognostic technique whereby patients may be tested for abnormal amounts of NHP. Such antibodies may also be utilized in conjunction with, for example, compound screening schemes for the evaluation of the effect of test compounds on expression and/or activity of a NHP gene product. Additionally, such antibodies can be used in conjunction gene therapy to, for example, evaluate the normal and/or engineered NHP-expressing cells prior to their introduction into the patient. Such antibodies may additionally be used as a method for the inhibition of abnormal NHP activity. Thus, such antibodies may, therefore, be utilized as part of treatment methods. [0058]
For the production of antibodies, various host animals may be immunized by injection with the NHP, an NHP peptide (e.g., one corresponding to a functional domain of an NHP), truncated NHP polypeptides (NHP in which one or more domains have been deleted), functional equivalents of the NHP or mutated variant of the NHP. Such host animals may include but are not limited to pigs, rabbits, mice, goats, and rats, to name but a few. Various adjuvants may be used to increase the immunological response, depending on the host species, including but not limited to Freund's adjuvant (complete and incomplete), mineral salts such as aluminum hydroxide or aluminum phosphate, surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, and potentially useful human adjuvants such as BCG (bacille Calmette-Guerin) and [0059] Corynebacterium parvum. Alternatively, the immune response could be enhanced by combination and or coupling with molecules such as keyhole limpet hemocyanin, tetanus toxoid, diptheria toxoid, ovalbumin, cholera toxin or fragments thereof. Polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of the immunized animals.
Monoclonal antibodies, which are homogeneous populations of antibodies to a particular antigen, can be obtained by any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique of Kohler and Milstein, (1975, Nature 256:495-497; and U.S. Pat. No. 4,376,110), the human B-cell hybridoma technique (Kosbor et al., 1983, Immunology Today 4:72; Cole et al., 1983, Proc. Natl. Acad. Sci. USA 80:2026-2030), and the EBV-hybridoma technique (Cole et al., 1985, Monoclonal Antibodies And Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Such antibodies may be of any immunoglobulin class including IgG, IgM, IgE, IgA, IgD and any subclass thereof. The hybridoma producing the mAb of this invention may be cultivated in vitro or in vivo. Production of high titers of mAbs in vivo makes this the presently preferred method of production. [0060]
In addition, techniques developed for the production of “chimeric antibodies” (Morrison et al., 1984, Proc. Natl. Acad. Sci., 81:6851-6855; Neuberger et al., 1984, Nature, 312:604-608; Takeda et al., 1985, Nature, 314:452-454) by splicing the sequences from a mouse antibody molecule of appropriate antigen specificity together with sequences from a human antibody molecule of appropriate biological activity;can be used. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine mAb and a human immunoglobulin constant region. Such technologies are described in U.S. Pat. Nos. 6,075,181 and 5,877,397 and their respective disclosures which are herein incorporated by reference in their entirety. [0061]
Alternatively, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,946,778; Bird, 1988, Science 242:423-426; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; and Ward et al., 1989, Nature 334:544-546) can be adapted to produce single chain antibodies against NHP gene products. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide. [0062]
Antibody fragments which recognize specific epitopes may be generated by known techniques. For example, such fragments include, but are hot limited to: the F(ab′)[0063] ₂fragments which can be produced by pepsin digestion of the antibody molecule and the Fab fragments which can be generated by reducing the disulfide bridges of the F(ab′)₂fragments. Alternatively, Fab expression libraries may be constructed (Huse et al., 1989, Science, 246:1275-1281) to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.
Antibodies to a NHP can, in turn, be utilized to generate anti-idiotype antibodies that “mimic” a given NHP, using techniques well known to those skilled in the art. (See, e.g., Greenspan & Bona, 1993, FASEB J 7(5):437-444; and Nissinoff, 1991, J. Immunol. 147(8):2429-2438). For example antibodies which bind to a NHP domain and competitively inhibit the binding of NHP to its cognate receptor can be used to generate anti-idiotypes that “mimic” the NHP and, therefore, bind and activate or neutralize a receptor. Such anti-idiotypic antibodies or Fab fragments of such anti-idiotypes can be used in therapeutic regimens involving a NHP signaling pathway. [0064]
The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention, and functionally equivalent methods and components are within the scope of the invention. Indeed, various modifications of the invention, in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. All cited publications, patents, and patent applications are herein incorporated by reference in their entirety. [0065]
1 37 1 1521 DNA Homo sapiens 1 atgacttcgg gcggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 60 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 120 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 180 cgtctcagga acctcttttc ctacgatgga atctggctgt tcccgaaaaa tcagtgcaaa 240 tgtgaagcca acaaagagca gggaggttac aactttcagg atgcctatgg ccagagcgac 300 ctcccagcgg tgaaagcgag gagacaggct gaatttgaac actttcagag gagagaaggg 360 ctgccccgcc cactgcccct gctggtccag cccaacctcc cctttgggta cccagtccac 420 ggagtggagg tgatgcccct gcacacggtt cccatcccag gcctccagtt tgaaggaccc 480 gatgcccccg tctatgaggt caccctgaca gcttctctgg ggacactgaa cacccttgct 540 gatgtcccag acagtgtggt gcagggcaga ggccagaagc agctgatcat ttctaccagt 600 gaccggaagc tgttgaagtt cattcttcag cacgtgacat acaccagcac ggggtaccag 660 caccagaagg tagacatagt gagtctggag tccaggtcct cagtggccaa gtttccagtg 720 accatccgcc atcctgtcat acccaagcta tacgaccctg gaccagagag gaagctcaga 780 aacctggtta ccattgctac caagactttc ctccgccccc acaagctcat gatcatgctc 840 cggagtattc gagagtatta cccagacttg accgtaatag tggctgatga cagccagaag 900 cccctggaaa ttaaagacaa ccacgtggag tattacacta tgccctttgg gaagggttgg 960 tttgctggta ggaacctggc catatctcag gtcaccacca aatacgttct ctgggtggac 1020 gatgattttc tcttcaacga ggagaccaag attgaggtgc tggtggatgt cctggagaaa 1080 acagaactgg acgtggtagg cggcagtgtg ctgggaaatg tgttccagtt taagttgttg 1140 ctggaacaga gtgagaatgg ggcctgcctt cacaagagga tgggattttt ccaacccctg 1200 gatggcttcc ccagctgcgt ggtgaccagt ggcgtggtca acttcttcct ggcccacacg 1260 gagcgactcc aaagagttgg ctttgatccc cgcctgcaac gagtggctca ctcagaattc 1320 ttcattgatg ggctagggac cctactcgtg gggtcatgcc cagaagtgat tataggtcac 1380 cagtctcggt ctccagtggt ggactcagaa ctggctgccc tagagaagac ctacaataca 1440 taccggtcca acaccctcac ccgggtccag ttcaagctgg cccttcacta cttcaagaac 1500 catctccaat gtgccgcata a 1521 2 506 PRT Homo sapiens 2 Met Thr Ser Gly Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 1 5 10 15 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 20 25 30 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 35 40 45 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 50 55 60 Leu Phe Ser Tyr Asp Gly Ile Trp Leu Phe Pro Lys Asn Gln Cys Lys 65 70 75 80 Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp Ala Tyr 85 90 95 Gly Gln Ser Asp Leu Pro Ala Val Lys Ala Arg Arg Gln Ala Glu Phe 100 105 110 Glu His Phe Gln Arg Arg Glu Gly Leu Pro Arg Pro Leu Pro Leu Leu 115 120 125 Val Gln Pro Asn Leu Pro Phe Gly Tyr Pro Val His Gly Val Glu Val 130 135 140 Met Pro Leu His Thr Val Pro Ile Pro Gly Leu Gln Phe Glu Gly Pro 145 150 155 160 Asp Ala Pro Val Tyr Glu Val Thr Leu Thr Ala Ser Leu Gly Thr Leu 165 170 175 Asn Thr Leu Ala Asp Val Pro Asp Ser Val Val Gln Gly Arg Gly Gln 180 185 190 Lys Gln Leu Ile Ile Ser Thr Ser Asp Arg Lys Leu Leu Lys Phe Ile 195 200 205 Leu Gln His Val Thr Tyr Thr Ser Thr Gly Tyr Gln His Gln Lys Val 210 215 220 Asp Ile Val Ser Leu Glu Ser Arg Ser Ser Val Ala Lys Phe Pro Val 225 230 235 240 Thr Ile Arg His Pro Val Ile Pro Lys Leu Tyr Asp Pro Gly Pro Glu 245 250 255 Arg Lys Leu Arg Asn Leu Val Thr Ile Ala Thr Lys Thr Phe Leu Arg 260 265 270 Pro His Lys Leu Met Ile Met Leu Arg Ser Ile Arg Glu Tyr Tyr Pro 275 280 285 Asp Leu Thr Val Ile Val Ala Asp Asp Ser Gln Lys Pro Leu Glu Ile 290 295 300 Lys Asp Asn His Val Glu Tyr Tyr Thr Met Pro Phe Gly Lys Gly Trp 305 310 315 320 Phe Ala Gly Arg Asn Leu Ala Ile Ser Gln Val Thr Thr Lys Tyr Val 325 330 335 Leu Trp Val Asp Asp Asp Phe Leu Phe Asn Glu Glu Thr Lys Ile Glu 340 345 350 Val Leu Val Asp Val Leu Glu Lys Thr Glu Leu Asp Val Val Gly Gly 355 360 365 Ser Val Leu Gly Asn Val Phe Gln Phe Lys Leu Leu Leu Glu Gln Ser 370 375 380 Glu Asn Gly Ala Cys Leu His Lys Arg Met Gly Phe Phe Gln Pro Leu 385 390 395 400 Asp Gly Phe Pro Ser Cys Val Val Thr Ser Gly Val Val Asn Phe Phe 405 410 415 Leu Ala His Thr Glu Arg Leu Gln Arg Val Gly Phe Asp Pro Arg Leu 420 425 430 Gln Arg Val Ala His Ser Glu Phe Phe Ile Asp Gly Leu Gly Thr Leu 435 440 445 Leu Val Gly Ser Cys Pro Glu Val Ile Ile Gly His Gln Ser Arg Ser 450 455 460 Pro Val Val Asp Ser Glu Leu Ala Ala Leu Glu Lys Thr Tyr Asn Thr 465 470 475 480 Tyr Arg Ser Asn Thr Leu Thr Arg Val Gln Phe Lys Leu Ala Leu His 485 490 495 Tyr Phe Lys Asn His Leu Gln Cys Ala Ala 500 505 3 399 DNA Homo sapiens 3 atggggagcg ctggcttttc cgtgggaaaa ttccacgtgg aggtggcctc tcgcggccgg 60 gaatgtgtct cggggacgcc cgagtgtggg aatcggctcg ggagtgcggg cttcggggat 120 ctctgcttgg aactcagagg cgctgaccca gcctggggcc cgtttgctgc ccacgggagg 180 agccgccgtc agggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 240 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 300 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 360 cgtctcagga acctcttttc ctacgatgga atctggtga 399 4 132 PRT Homo sapiens 4 Met Gly Ser Ala Gly Phe Ser Val Gly Lys Phe His Val Glu Val Ala 1 5 10 15 Ser Arg Gly Arg Glu Cys Val Ser Gly Thr Pro Glu Cys Gly Asn Arg 20 25 30 Leu Gly Ser Ala Gly Phe Gly Asp Leu Cys Leu Glu Leu Arg Gly Ala 35 40 45 Asp Pro Ala Trp Gly Pro Phe Ala Ala His Gly Arg Ser Arg Arg Gln 50 55 60 Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val Ile Ile Leu Val 65 70 75 80 Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe Leu Gln Ala Val 85 90 95 Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala Pro Gly Val Gln 100 105 110 Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn Leu Phe Ser Tyr 115 120 125 Asp Gly Ile Trp 130 5 219 DNA Homo sapiens 5 atgacttcgg gcggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 60 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 120 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 180 cgtctcagga acctcttttc ctacgatgga atctggtga 219 6 72 PRT Homo sapiens 6 Met Thr Ser Gly Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 1 5 10 15 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 20 25 30 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 35 40 45 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 50 55 60 Leu Phe Ser Tyr Asp Gly Ile Trp 65 70 7 555 DNA Homo sapiens 7 atggggagcg ctggcttttc cgtgggaaaa ttccacgtgg aggtggcctc tcgcggccgg 60 gaatgtgtct cggggacgcc cgagtgtggg aatcggctcg ggagtgcggg cttcggggat 120 ctctgcttgg aactcagagg cgctgaccca gcctggggcc cgtttgctgc ccacgggagg 180 agccgccgtc agggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 240 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 300 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 360 cgtctcagga acctcttttc ctacgatgga atctgtcctc ttgcttgttt caggctgttc 420 ccgaaaaatc agtgcaaatg tgaagccaac aaagagcagg gaggttacaa ctttcaggat 480 gcctatggcc agagcgacct cccagcggtg aaagcgagga gacaggctga atttgaacac 540 tttcagagga ggtaa 555 8 184 PRT Homo sapiens 8 Met Gly Ser Ala Gly Phe Ser Val Gly Lys Phe His Val Glu Val Ala 1 5 10 15 Ser Arg Gly Arg Glu Cys Val Ser Gly Thr Pro Glu Cys Gly Asn Arg 20 25 30 Leu Gly Ser Ala Gly Phe Gly Asp Leu Cys Leu Glu Leu Arg Gly Ala 35 40 45 Asp Pro Ala Trp Gly Pro Phe Ala Ala His Gly Arg Ser Arg Arg Gln 50 55 60 Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val Ile Ile Leu Val 65 70 75 80 Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe Leu Gln Ala Val 85 90 95 Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala Pro Gly Val Gln 100 105 110 Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn Leu Phe Ser Tyr 115 120 125 Asp Gly Ile Cys Pro Leu Ala Cys Phe Arg Leu Phe Pro Lys Asn Gln 130 135 140 Cys Lys Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp 145 150 155 160 Ala Tyr Gly Gln Ser Asp Leu Pro Ala Val Lys Ala Arg Arg Gln Ala 165 170 175 Glu Phe Glu His Phe Gln Arg Arg 180 9 372 DNA Homo sapiens 9 atgacttcgg gcggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 60 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 120 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 180 cgtctcagga acctcttttc ctacgatgga atctgtcctc ttgcttgttt caggctgttc 240 ccgaaaaatc agtgcaaatg tgaagccaac aaagagcagg gaggttacaa ctttcaggat 300 gcctatggcc agagcgacct cccagcggtg aaagcgagga gacaggctga atttgaacac 360 tttcagagga gg 372 10 124 PRT Homo sapiens 10 Met Thr Ser Gly Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 1 5 10 15 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 20 25 30 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 35 40 45 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 50 55 60 Leu Phe Ser Tyr Asp Gly Ile Cys Pro Leu Ala Cys Phe Arg Leu Phe 65 70 75 80 Pro Lys Asn Gln Cys Lys Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr 85 90 95 Asn Phe Gln Asp Ala Tyr Gly Gln Ser Asp Leu Pro Ala Val Lys Ala 100 105 110 Arg Arg Gln Ala Glu Phe Glu His Phe Gln Arg Arg 115 120 11 537 DNA Homo sapiens 11 atggggagcg ctggcttttc cgtgggaaaa ttccacgtgg aggtggcctc tcgcggccgg 60 gaatgtgtct cggggacgcc cgagtgtggg aatcggctcg ggagtgcggg cttcggggat 120 ctctgcttgg aactcagagg cgctgaccca gcctggggcc cgtttgctgc ccacgggagg 180 agccgccgtc agggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 240 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 300 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 360 cgtctcagga acctcttttc ctacgatgga atctggctgt tcccgaaaaa tcagtgcaaa 420 tgtgaagcca acaaagagca gggaggttac aactttcagg atgcctatgg ccagagcgac 480 ctcccagcgg tgaaagcgag gagacaggct gaatttgaac actttcagag gaggtaa 537 12 182 PRT Homo sapiens 12 Arg Arg Thr Asn Met Gly Ser Ala Gly Phe Ser Val Gly Lys Phe His 1 5 10 15 Val Glu Val Ala Ser Arg Gly Arg Glu Cys Val Ser Gly Thr Pro Glu 20 25 30 Cys Gly Asn Arg Leu Gly Ser Ala Gly Phe Gly Asp Leu Cys Leu Glu 35 40 45 Leu Arg Gly Ala Asp Pro Ala Trp Gly Pro Phe Ala Ala His Gly Arg 50 55 60 Ser Arg Arg Gln Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 65 70 75 80 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 85 90 95 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 100 105 110 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 115 120 125 Leu Phe Ser Tyr Asp Gly Ile Trp Leu Phe Pro Lys Asn Gln Cys Lys 130 135 140 Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp Ala Tyr 145 150 155 160 Gly Gln Ser Asp Leu Pro Ala Val Lys Ala Arg Arg Gln Ala Glu Phe 165 170 175 Glu His Phe Gln Arg Arg 180 13 357 DNA Homo sapiens 13 atgacttcgg gcggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 60 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 120 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 180 cgtctcagga acctcttttc ctacgatgga atctggctgt tcccgaaaaa tcagtgcaaa 240 tgtgaagcca acaaagagca gggaggttac aactttcagg atgcctatgg ccagagcgac 300 ctcccagcgg tgaaagcgag gagacaggct gaatttgaac actttcagag gaggtaa 357 14 118 PRT Homo sapiens 14 Met Thr Ser Gly Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 1 5 10 15 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 20 25 30 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 35 40 45 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 50 55 60 Leu Phe Ser Tyr Asp Gly Ile Trp Leu Phe Pro Lys Asn Gln Cys Lys 65 70 75 80 Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp Ala Tyr 85 90 95 Gly Gln Ser Asp Leu Pro Ala Val Lys Ala Arg Arg Gln Ala Glu Phe 100 105 110 Glu His Phe Gln Arg Arg 115 15 1361 DNA Homo sapiens 15 atggggagcg ctggcttttc cgtgggaaaa ttccacgtgg aggtggcctc tcgcggccgg 60 gaatgtgtct cggggacgcc cgagtgtggg aatcggctcg ggagtgcggg cttcggggat 120 ctctgcttgg aactcagagg cgctgaccca gcctggggcc cgtttgctgc ccacgggagg 180 agccgccgtc agggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 240 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 300 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 360 cgtctcagga acctcttttc ctacgatgga atctgtcctc ttgcttgttt caggctgttc 420 ccgaaaaatc agtgcaaatg tgaagccaac aaagagcagg gaggttacaa ctttcaggat 480 gcctatggcc agagcgacct cccagcggtg aaagcgagga gacaggctga atttgaacac 540 tttcagagga gagaagggct gccccgccca ctgcccctgc tggtccagcc caacctcccc 600 tttgggtacc cagtccacgg agtggaggtg atgcccctgc acacggttcc catcccaggc 660 ctccagtttg aaggacccga tgcccccgtc tatgaggtca ccctgacagc ttctctgggg 720 acactgaaca cccttgctga tgtcccagac agtgtggtgc agggcagagg ccagaagcag 780 ctgatcattt ctaccagtga ccggaagctg ttgaagttca ttcttcagca cgtgacatac 840 accagcacgg ggtaccagca ccagaaggta gacatagtga gtctggagtc caggtcctca 900 gtggccaagt ttccagtgac catccgccat cctgtcatac ccaagctata cgaccctgga 960 ccagagagga agctcagaaa cctggttacc attgctacca agactttcct ccgcccccac 1020 aagctcatga tcatgctccg gagtattcga gagtattacc cagacttgac cgtaatagtg 1080 gctgatgaca gccagaagcc cctggaaatt aaagacaacc acgtggagta ttacactatg 1140 ccctttggga agggttggtt tgctggtagg aacctggcca tatctcaggt caccaccaaa 1200 tacgttctct gggtggacga tgattttctc ttcaacgagg agaccaagat tgaggtgctg 1260 gtggatgtcc tggagaaaac agaactggac gtggtaaggg acagttgcca gtttcaccca 1320 gccacaatct gtagagatgg agaagagggg agaagagagc g 1361 16 453 PRT Homo sapiens 16 Met Gly Ser Ala Gly Phe Ser Val Gly Lys Phe His Val Glu Val Ala 1 5 10 15 Ser Arg Gly Arg Glu Cys Val Ser Gly Thr Pro Glu Cys Gly Asn Arg 20 25 30 Leu Gly Ser Ala Gly Phe Gly Asp Leu Cys Leu Glu Leu Arg Gly Ala 35 40 45 Asp Pro Ala Trp Gly Pro Phe Ala Ala His Gly Arg Ser Arg Arg Gln 50 55 60 Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val Ile Ile Leu Val 65 70 75 80 Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe Leu Gln Ala Val 85 90 95 Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala Pro Gly Val Gln 100 105 110 Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn Leu Phe Ser Tyr 115 120 125 Asp Gly Ile Cys Pro Leu Ala Cys Phe Arg Leu Phe Pro Lys Asn Gln 130 135 140 Cys Lys Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp 145 150 155 160 Ala Tyr Gly Gln Ser Asp Leu Pro Ala Val Lys Ala Arg Arg Gln Ala 165 170 175 Glu Phe Glu His Phe Gln Arg Arg Glu Gly Leu Pro Arg Pro Leu Pro 180 185 190 Leu Leu Val Gln Pro Asn Leu Pro Phe Gly Tyr Pro Val His Gly Val 195 200 205 Glu Val Met Pro Leu His Thr Val Pro Ile Pro Gly Leu Gln Phe Glu 210 215 220 Gly Pro Asp Ala Pro Val Tyr Glu Val Thr Leu Thr Ala Ser Leu Gly 225 230 235 240 Thr Leu Asn Thr Leu Ala Asp Val Pro Asp Ser Val Val Gln Gly Arg 245 250 255 Gly Gln Lys Gln Leu Ile Ile Ser Thr Ser Asp Arg Lys Leu Leu Lys 260 265 270 Phe Ile Leu Gln His Val Thr Tyr Thr Ser Thr Gly Tyr Gln His Gln 275 280 285 Lys Val Asp Ile Val Ser Leu Glu Ser Arg Ser Ser Val Ala Lys Phe 290 295 300 Pro Val Thr Ile Arg His Pro Val Ile Pro Lys Leu Tyr Asp Pro Gly 305 310 315 320 Pro Glu Arg Lys Leu Arg Asn Leu Val Thr Ile Ala Thr Lys Thr Phe 325 330 335 Leu Arg Pro His Lys Leu Met Ile Met Leu Arg Ser Ile Arg Glu Tyr 340 345 350 Tyr Pro Asp Leu Thr Val Ile Val Ala Asp Asp Ser Gln Lys Pro Leu 355 360 365 Glu Ile Lys Asp Asn His Val Glu Tyr Tyr Thr Met Pro Phe Gly Lys 370 375 380 Gly Trp Phe Ala Gly Arg Asn Leu Ala Ile Ser Gln Val Thr Thr Lys 385 390 395 400 Tyr Val Leu Trp Val Asp Asp Asp Phe Leu Phe Asn Glu Glu Thr Lys 405 410 415 Ile Glu Val Leu Val Asp Val Leu Glu Lys Thr Glu Leu Asp Val Val 420 425 430 Arg Asp Ser Cys Gln Phe His Pro Ala Thr Ile Cys Arg Asp Gly Glu 435 440 445 Glu Gly Arg Arg Glu 450 17 1181 DNA Homo sapiens 17 atgacttcgg gcggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 60 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 120 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 180 cgtctcagga acctcttttc ctacgatgga atctgtcctc ttgcttgttt caggctgttc 240 ccgaaaaatc agtgcaaatg tgaagccaac aaagagcagg gaggttacaa ctttcaggat 300 gcctatggcc agagcgacct cccagcggtg aaagcgagga gacaggctga atttgaacac 360 tttcagagga gagaagggct gccccgccca ctgcccctgc tggtccagcc caacctcccc 420 tttgggtacc cagtccacgg agtggaggtg atgcccctgc acacggttcc catcccaggc 480 ctccagtttg aaggacccga tgcccccgtc tatgaggtca ccctgacagc ttctctgggg 540 acactgaaca cccttgctga tgtcccagac agtgtggtgc agggcagagg ccagaagcag 600 ctgatcattt ctaccagtga ccggaagctg ttgaagttca ttcttcagca cgtgacatac 660 accagcacgg ggtaccagca ccagaaggta gacatagtga gtctggagtc caggtcctca 720 gtggccaagt ttccagtgac catccgccat cctgtcatac ccaagctata cgaccctgga 780 ccagagagga agctcagaaa cctggttacc attgctacca agactttcct ccgcccccac 840 aagctcatga tcatgctccg gagtattcga gagtattacc cagacttgac cgtaatagtg 900 gctgatgaca gccagaagcc cctggaaatt aaagacaacc acgtggagta ttacactatg 960 ccctttggga agggttggtt tgctggtagg aacctggcca tatctcaggt caccaccaaa 1020 tacgttctct gggtggacga tgattttctc ttcaacgagg agaccaagat tgaggtgctg 1080 gtggatgtcc tggagaaaac agaactggac gtggtaaggg acagttgcca gtttcaccca 1140 gccacaatct gtagagatgg agaagagggg agaagagagc g 1181 18 393 PRT Homo sapiens 18 Met Thr Ser Gly Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 1 5 10 15 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 20 25 30 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 35 40 45 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 50 55 60 Leu Phe Ser Tyr Asp Gly Ile Cys Pro Leu Ala Cys Phe Arg Leu Phe 65 70 75 80 Pro Lys Asn Gln Cys Lys Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr 85 90 95 Asn Phe Gln Asp Ala Tyr Gly Gln Ser Asp Leu Pro Ala Val Lys Ala 100 105 110 Arg Arg Gln Ala Glu Phe Glu His Phe Gln Arg Arg Glu Gly Leu Pro 115 120 125 Arg Pro Leu Pro Leu Leu Val Gln Pro Asn Leu Pro Phe Gly Tyr Pro 130 135 140 Val His Gly Val Glu Val Met Pro Leu His Thr Val Pro Ile Pro Gly 145 150 155 160 Leu Gln Phe Glu Gly Pro Asp Ala Pro Val Tyr Glu Val Thr Leu Thr 165 170 175 Ala Ser Leu Gly Thr Leu Asn Thr Leu Ala Asp Val Pro Asp Ser Val 180 185 190 Val Gln Gly Arg Gly Gln Lys Gln Leu Ile Ile Ser Thr Ser Asp Arg 195 200 205 Lys Leu Leu Lys Phe Ile Leu Gln His Val Thr Tyr Thr Ser Thr Gly 210 215 220 Tyr Gln His Gln Lys Val Asp Ile Val Ser Leu Glu Ser Arg Ser Ser 225 230 235 240 Val Ala Lys Phe Pro Val Thr Ile Arg His Pro Val Ile Pro Lys Leu 245 250 255 Tyr Asp Pro Gly Pro Glu Arg Lys Leu Arg Asn Leu Val Thr Ile Ala 260 265 270 Thr Lys Thr Phe Leu Arg Pro His Lys Leu Met Ile Met Leu Arg Ser 275 280 285 Ile Arg Glu Tyr Tyr Pro Asp Leu Thr Val Ile Val Ala Asp Asp Ser 290 295 300 Gln Lys Pro Leu Glu Ile Lys Asp Asn His Val Glu Tyr Tyr Thr Met 305 310 315 320 Pro Phe Gly Lys Gly Trp Phe Ala Gly Arg Asn Leu Ala Ile Ser Gln 325 330 335 Val Thr Thr Lys Tyr Val Leu Trp Val Asp Asp Asp Phe Leu Phe Asn 340 345 350 Glu Glu Thr Lys Ile Glu Val Leu Val Asp Val Leu Glu Lys Thr Glu 355 360 365 Leu Asp Val Val Arg Asp Ser Cys Gln Phe His Pro Ala Thr Ile Cys 370 375 380 Arg Asp Gly Glu Glu Gly Arg Arg Glu 385 390 19 1344 DNA Homo sapiens 19 atggggagcg ctggcttttc cgtgggaaaa ttccacgtgg aggtggcctc tcgcggccgg 60 gaatgtgtct cggggacgcc cgagtgtggg aatcggctcg ggagtgcggg cttcggggat 120 ctctgcttgg aactcagagg cgctgaccca gcctggggcc cgtttgctgc ccacgggagg 180 agccgccgtc agggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 240 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 300 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 360 cgtctcagga acctcttttc ctacgatgga atctggctgt tcccgaaaaa tcagtgcaaa 420 tgtgaagcca acaaagagca gggaggttac aactttcagg atgcctatgg ccagagcgac 480 ctcccagcgg tgaaagcgag gagacaggct gaatttgaac actttcagag gagagaaggg 540 ctgccccgcc cactgcccct gctggtccag cccaacctcc cctttgggta cccagtccac 600 ggagtggagg tgatgcccct gcacacggtt cccatcccag gcctccagtt tgaaggaccc 660 gatgcccccg tctatgaggt caccctgaca gcttctctgg ggacactgaa cacccttgct 720 gatgtcccag acagtgtggt gcagggcaga ggccagaagc agctgatcat ttctaccagt 780 gaccggaagc tgttgaagtt cattcttcag cacgtgacat acaccagcac ggggtaccag 840 caccagaagg tagacatagt gagtctggag tccaggtcct cagtggccaa gtttccagtg 900 accatccgcc atcctgtcat acccaagcta tacgaccctg gaccagagag gaagctcaga 960 aacctggtta ccattgctac caagactttc ctccgccccc acaagctcat gatcatgctc 1020 cggagtattc gagagtatta cccagacttg accgtaatag tggctgatga cagccagaag 1080 cccctggaaa ttaaagacaa ccacgtggag tattacacta tgccctttgg gaagggttgg 1140 tttgctggta ggaacctggc catatctcag gtcaccacca aatacgttct ctgggtggac 1200 gatgattttc tcttcaacga ggagaccaag attgaggtgc tggtggatgt cctggagaaa 1260 acagaactgg acgtggtaag ggacagttgc cagtttcacc cagccacaat ctgtagagat 1320 ggagaagagg ggagaagaga gcga 1344 20 448 PRT Homo sapiens 20 Met Gly Ser Ala Gly Phe Ser Val Gly Lys Phe His Val Glu Val Ala 1 5 10 15 Ser Arg Gly Arg Glu Cys Val Ser Gly Thr Pro Glu Cys Gly Asn Arg 20 25 30 Leu Gly Ser Ala Gly Phe Gly Asp Leu Cys Leu Glu Leu Arg Gly Ala 35 40 45 Asp Pro Ala Trp Gly Pro Phe Ala Ala His Gly Arg Ser Arg Arg Gln 50 55 60 Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val Ile Ile Leu Val 65 70 75 80 Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe Leu Gln Ala Val 85 90 95 Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala Pro Gly Val Gln 100 105 110 Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn Leu Phe Ser Tyr 115 120 125 Asp Gly Ile Trp Leu Phe Pro Lys Asn Gln Cys Lys Cys Glu Ala Asn 130 135 140 Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp Ala Tyr Gly Gln Ser Asp 145 150 155 160 Leu Pro Ala Val Lys Ala Arg Arg Gln Ala Glu Phe Glu His Phe Gln 165 170 175 Arg Arg Glu Gly Leu Pro Arg Pro Leu Pro Leu Leu Val Gln Pro Asn 180 185 190 Leu Pro Phe Gly Tyr Pro Val His Gly Val Glu Val Met Pro Leu His 195 200 205 Thr Val Pro Ile Pro Gly Leu Gln Phe Glu Gly Pro Asp Ala Pro Val 210 215 220 Tyr Glu Val Thr Leu Thr Ala Ser Leu Gly Thr Leu Asn Thr Leu Ala 225 230 235 240 Asp Val Pro Asp Ser Val Val Gln Gly Arg Gly Gln Lys Gln Leu Ile 245 250 255 Ile Ser Thr Ser Asp Arg Lys Leu Leu Lys Phe Ile Leu Gln His Val 260 265 270 Thr Tyr Thr Ser Thr Gly Tyr Gln His Gln Lys Val Asp Ile Val Ser 275 280 285 Leu Glu Ser Arg Ser Ser Val Ala Lys Phe Pro Val Thr Ile Arg His 290 295 300 Pro Val Ile Pro Lys Leu Tyr Asp Pro Gly Pro Glu Arg Lys Leu Arg 305 310 315 320 Asn Leu Val Thr Ile Ala Thr Lys Thr Phe Leu Arg Pro His Lys Leu 325 330 335 Met Ile Met Leu Arg Ser Ile Arg Glu Tyr Tyr Pro Asp Leu Thr Val 340 345 350 Ile Val Ala Asp Asp Ser Gln Lys Pro Leu Glu Ile Lys Asp Asn His 355 360 365 Val Glu Tyr Tyr Thr Met Pro Phe Gly Lys Gly Trp Phe Ala Gly Arg 370 375 380 Asn Leu Ala Ile Ser Gln Val Thr Thr Lys Tyr Val Leu Trp Val Asp 385 390 395 400 Asp Asp Phe Leu Phe Asn Glu Glu Thr Lys Ile Glu Val Leu Val Asp 405 410 415 Val Leu Glu Lys Thr Glu Leu Asp Val Val Arg Asp Ser Cys Gln Phe 420 425 430 His Pro Ala Thr Ile Cys Arg Asp Gly Glu Glu Gly Arg Arg Glu Arg 435 440 445 21 1164 DNA Homo sapiens 21 atgacttcgg gcggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 60 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 120 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 180 cgtctcagga acctcttttc ctacgatgga atctggctgt tcccgaaaaa tcagtgcaaa 240 tgtgaagcca acaaagagca gggaggttac aactttcagg atgcctatgg ccagagcgac 300 ctcccagcgg tgaaagcgag gagacaggct gaatttgaac actttcagag gagagaaggg 360 ctgccccgcc cactgcccct gctggtccag cccaacctcc cctttgggta cccagtccac 420 ggagtggagg tgatgcccct gcacacggtt cccatcccag gcctccagtt tgaaggaccc 480 gatgcccccg tctatgaggt caccctgaca gcttctctgg ggacactgaa cacccttgct 540 gatgtcccag acagtgtggt gcagggcaga ggccagaagc agctgatcat ttctaccagt 600 gaccggaagc tgttgaagtt cattcttcag cacgtgacat acaccagcac ggggtaccag 660 caccagaagg tagacatagt gagtctggag tccaggtcct cagtggccaa gtttccagtg 720 accatccgcc atcctgtcat acccaagcta tacgaccctg gaccagagag gaagctcaga 780 aacctggtta ccattgctac caagactttc ctccgccccc acaagctcat gatcatgctc 840 cggagtattc gagagtatta cccagacttg accgtaatag tggctgatga cagccagaag 900 cccctggaaa ttaaagacaa ccacgtggag tattacacta tgccctttgg gaagggttgg 960 tttgctggta ggaacctggc catatctcag gtcaccacca aatacgttct ctgggtggac 1020 gatgattttc tcttcaacga ggagaccaag attgaggtgc tggtggatgt cctggagaaa 1080 acagaactgg acgtggtaag ggacagttgc cagtttcacc cagccacaat ctgtagagat 1140 ggagaagagg ggagaagaga gcga 1164 22 388 PRT Homo sapiens 22 Met Thr Ser Gly Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 1 5 10 15 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 20 25 30 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 35 40 45 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 50 55 60 Leu Phe Ser Tyr Asp Gly Ile Trp Leu Phe Pro Lys Asn Gln Cys Lys 65 70 75 80 Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp Ala Tyr 85 90 95 Gly Gln Ser Asp Leu Pro Ala Val Lys Ala Arg Arg Gln Ala Glu Phe 100 105 110 Glu His Phe Gln Arg Arg Glu Gly Leu Pro Arg Pro Leu Pro Leu Leu 115 120 125 Val Gln Pro Asn Leu Pro Phe Gly Tyr Pro Val His Gly Val Glu Val 130 135 140 Met Pro Leu His Thr Val Pro Ile Pro Gly Leu Gln Phe Glu Gly Pro 145 150 155 160 Asp Ala Pro Val Tyr Glu Val Thr Leu Thr Ala Ser Leu Gly Thr Leu 165 170 175 Asn Thr Leu Ala Asp Val Pro Asp Ser Val Val Gln Gly Arg Gly Gln 180 185 190 Lys Gln Leu Ile Ile Ser Thr Ser Asp Arg Lys Leu Leu Lys Phe Ile 195 200 205 Leu Gln His Val Thr Tyr Thr Ser Thr Gly Tyr Gln His Gln Lys Val 210 215 220 Asp Ile Val Ser Leu Glu Ser Arg Ser Ser Val Ala Lys Phe Pro Val 225 230 235 240 Thr Ile Arg His Pro Val Ile Pro Lys Leu Tyr Asp Pro Gly Pro Glu 245 250 255 Arg Lys Leu Arg Asn Leu Val Thr Ile Ala Thr Lys Thr Phe Leu Arg 260 265 270 Pro His Lys Leu Met Ile Met Leu Arg Ser Ile Arg Glu Tyr Tyr Pro 275 280 285 Asp Leu Thr Val Ile Val Ala Asp Asp Ser Gln Lys Pro Leu Glu Ile 290 295 300 Lys Asp Asn His Val Glu Tyr Tyr Thr Met Pro Phe Gly Lys Gly Trp 305 310 315 320 Phe Ala Gly Arg Asn Leu Ala Ile Ser Gln Val Thr Thr Lys Tyr Val 325 330 335 Leu Trp Val Asp Asp Asp Phe Leu Phe Asn Glu Glu Thr Lys Ile Glu 340 345 350 Val Leu Val Asp Val Leu Glu Lys Thr Glu Leu Asp Val Val Arg Asp 355 360 365 Ser Cys Gln Phe His Pro Ala Thr Ile Cys Arg Asp Gly Glu Glu Gly 370 375 380 Arg Arg Glu Arg 385 23 549 DNA Homo sapiens 23 atggggagcg ctggcttttc cgtgggaaaa ttccacgtgg aggtggcctc tcgcggccgg 60 gaatgtgtct cggggacgcc cgagtgtggg aatcggctcg ggagtgcggg cttcggggat 120 ctctgcttgg aactcagagg cgctgaccca gcctggggcc cgtttgctgc ccacgggagg 180 agccgccgtc agggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 240 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 300 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 360 cgtctcagga acctcttttc ctacgatgga atctgtcctc ttgcttgttt caggctgttc 420 ccgaaaaatc agtgcaaatg tgaagccaac aaagagcagg gaggttacaa ctttcaggat 480 gcctatggcc agagcgacct cccagcggtg aaagcgagga gacaggctga atttgaacac 540 ccttgctga 549 24 182 PRT Homo sapiens 24 Met Gly Ser Ala Gly Phe Ser Val Gly Lys Phe His Val Glu Val Ala 1 5 10 15 Ser Arg Gly Arg Glu Cys Val Ser Gly Thr Pro Glu Cys Gly Asn Arg 20 25 30 Leu Gly Ser Ala Gly Phe Gly Asp Leu Cys Leu Glu Leu Arg Gly Ala 35 40 45 Asp Pro Ala Trp Gly Pro Phe Ala Ala His Gly Arg Ser Arg Arg Gln 50 55 60 Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val Ile Ile Leu Val 65 70 75 80 Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe Leu Gln Ala Val 85 90 95 Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala Pro Gly Val Gln 100 105 110 Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn Leu Phe Ser Tyr 115 120 125 Asp Gly Ile Cys Pro Leu Ala Cys Phe Arg Leu Phe Pro Lys Asn Gln 130 135 140 Cys Lys Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp 145 150 155 160 Ala Tyr Gly Gln Ser Asp Leu Pro Ala Val Lys Ala Arg Arg Gln Ala 165 170 175 Glu Phe Glu His Pro Cys 180 25 369 DNA Homo sapiens 25 atgacttcgg gcggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 60 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 120 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 180 cgtctcagga acctcttttc ctacgatgga atctgtcctc ttgcttgttt caggctgttc 240 ccgaaaaatc agtgcaaatg tgaagccaac aaagagcagg gaggttacaa ctttcaggat 300 gcctatggcc agagcgacct cccagcggtg aaagcgagga gacaggctga atttgaacac 360 ccttgctga 369 26 122 PRT Homo sapiens 26 Met Thr Ser Gly Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 1 5 10 15 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 20 25 30 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 35 40 45 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 50 55 60 Leu Phe Ser Tyr Asp Gly Ile Cys Pro Leu Ala Cys Phe Arg Leu Phe 65 70 75 80 Pro Lys Asn Gln Cys Lys Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr 85 90 95 Asn Phe Gln Asp Ala Tyr Gly Gln Ser Asp Leu Pro Ala Val Lys Ala 100 105 110 Arg Arg Gln Ala Glu Phe Glu His Pro Cys 115 120 27 531 DNA Homo sapiens 27 atggggagcg ctggcttttc cgtgggaaaa ttccacgtgg aggtggcctc tcgcggccgg 60 gaatgtgtct cggggacgcc cgagtgtggg aatcggctcg ggagtgcggg cttcggggat 120 ctctgcttgg aactcagagg cgctgaccca gcctggggcc cgtttgctgc ccacgggagg 180 agccgccgtc agggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 240 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 300 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 360 cgtctcagga acctcttttc ctacgatgga atctggctgt tcccgaaaaa tcagtgcaaa 420 tgtgaagcca acaaagagca gggaggttac aactttcagg atgcctatgg ccagagcgac 480 ctcccagcgg tgaaagcgag gagacaggct gaatttgaac acccttgctg a 531 28 176 PRT Homo sapiens 28 Met Gly Ser Ala Gly Phe Ser Val Gly Lys Phe His Val Glu Val Ala 1 5 10 15 Ser Arg Gly Arg Glu Cys Val Ser Gly Thr Pro Glu Cys Gly Asn Arg 20 25 30 Leu Gly Ser Ala Gly Phe Gly Asp Leu Cys Leu Glu Leu Arg Gly Ala 35 40 45 Asp Pro Ala Trp Gly Pro Phe Ala Ala His Gly Arg Ser Arg Arg Gln 50 55 60 Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val Ile Ile Leu Val 65 70 75 80 Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe Leu Gln Ala Val 85 90 95 Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala Pro Gly Val Gln 100 105 110 Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn Leu Phe Ser Tyr 115 120 125 Asp Gly Ile Trp Leu Phe Pro Lys Asn Gln Cys Lys Cys Glu Ala Asn 130 135 140 Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp Ala Tyr Gly Gln Ser Asp 145 150 155 160 Leu Pro Ala Val Lys Ala Arg Arg Gln Ala Glu Phe Glu His Pro Cys 165 170 175 29 351 DNA Homo sapiens 29 atgacttcgg gcggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 60 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 120 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 180 cgtctcagga acctcttttc ctacgatgga atctggctgt tcccgaaaaa tcagtgcaaa 240 tgtgaagcca acaaagagca gggaggttac aactttcagg atgcctatgg ccagagcgac 300 ctcccagcgg tgaaagcgag gagacaggct gaatttgaac acccttgctg a 351 30 116 PRT Homo sapiens 30 Met Thr Ser Gly Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 1 5 10 15 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 20 25 30 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 35 40 45 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 50 55 60 Leu Phe Ser Tyr Asp Gly Ile Trp Leu Phe Pro Lys Asn Gln Cys Lys 65 70 75 80 Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp Ala Tyr 85 90 95 Gly Gln Ser Asp Leu Pro Ala Val Lys Ala Arg Arg Gln Ala Glu Phe 100 105 110 Glu His Pro Cys 115 31 1719 DNA Homo sapiens 31 atggggagcg ctggcttttc cgtgggaaaa ttccacgtgg aggtggcctc tcgcggccgg 60 gaatgtgtct cggggacgcc cgagtgtggg aatcggctcg ggagtgcggg cttcggggat 120 ctctgcttgg aactcagagg cgctgaccca gcctggggcc cgtttgctgc ccacgggagg 180 agccgccgtc agggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 240 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 300 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 360 cgtctcagga acctcttttc ctacgatgga atctgtcctc ttgcttgttt caggctgttc 420 ccgaaaaatc agtgcaaatg tgaagccaac aaagagcagg gaggttacaa ctttcaggat 480 gcctatggcc agagcgacct cccagcggtg aaagcgagga gacaggctga atttgaacac 540 tttcagagga gagaagggct gccccgccca ctgcccctgc tggtccagcc caacctcccc 600 tttgggtacc cagtccacgg agtggaggtg atgcccctgc acacggttcc catcccaggc 660 ctccagtttg aaggacccga tgcccccgtc tatgaggtca ccctgacagc ttctctgggg 720 acactgaaca cccttgctga tgtcccagac agtgtggtgc agggcagagg ccagaagcag 780 ctgatcattt ctaccagtga ccggaagctg ttgaagttca ttcttcagca cgtgacatac 840 accagcacgg ggtaccagca ccagaaggta gacatagtga gtctggagtc caggtcctca 900 gtggccaagt ttccagtgac catccgccat cctgtcatac ccaagctata cgaccctgga 960 ccagagagga agctcagaaa cctggttacc attgctacca agactttcct ccgcccccac 1020 aagctcatga tcatgctccg gagtattcga gagtattacc cagacttgac cgtaatagtg 1080 gctgatgaca gccagaagcc cctggaaatt aaagacaacc acgtggagta ttacactatg 1140 ccctttggga agggttggtt tgctggtagg aacctggcca tatctcaggt caccaccaaa 1200 tacgttctct gggtggacga tgattttctc ttcaacgagg agaccaagat tgaggtgctg 1260 gtggatgtcc tggagaaaac agaactggac gtggtaggcg gcagtgtgct gggaaatgtg 1320 ttccagttta agttgttgct ggaacagagt gagaatgggg cctgccttca caagaggatg 1380 ggatttttcc aacccctgga tggcttcccc agctgcgtgg tgaccagtgg cgtggtcaac 1440 ttcttcctgg cccacacgga gcgactccaa agagttggct ttgatccccg cctgcaacga 1500 gtggctcact cagaattctt cattgatggg ctagggaccc tactcgtggg gtcatgccca 1560 gaagtgatta taggtcacca gtctcggtct ccagtggtgg actcagaact ggctgcccta 1620 gagaagacct acaatacata ccggtccaac accctcaccc gggtccagtt caagctggcc 1680 cttcactact tcaagaacca tctccaatgt gccgcataa 1719 32 572 PRT Homo sapiens 32 Met Gly Ser Ala Gly Phe Ser Val Gly Lys Phe His Val Glu Val Ala 1 5 10 15 Ser Arg Gly Arg Glu Cys Val Ser Gly Thr Pro Glu Cys Gly Asn Arg 20 25 30 Leu Gly Ser Ala Gly Phe Gly Asp Leu Cys Leu Glu Leu Arg Gly Ala 35 40 45 Asp Pro Ala Trp Gly Pro Phe Ala Ala His Gly Arg Ser Arg Arg Gln 50 55 60 Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val Ile Ile Leu Val 65 70 75 80 Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe Leu Gln Ala Val 85 90 95 Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala Pro Gly Val Gln 100 105 110 Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn Leu Phe Ser Tyr 115 120 125 Asp Gly Ile Cys Pro Leu Ala Cys Phe Arg Leu Phe Pro Lys Asn Gln 130 135 140 Cys Lys Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp 145 150 155 160 Ala Tyr Gly Gln Ser Asp Leu Pro Ala Val Lys Ala Arg Arg Gln Ala 165 170 175 Glu Phe Glu His Phe Gln Arg Arg Glu Gly Leu Pro Arg Pro Leu Pro 180 185 190 Leu Leu Val Gln Pro Asn Leu Pro Phe Gly Tyr Pro Val His Gly Val 195 200 205 Glu Val Met Pro Leu His Thr Val Pro Ile Pro Gly Leu Gln Phe Glu 210 215 220 Gly Pro Asp Ala Pro Val Tyr Glu Val Thr Leu Thr Ala Ser Leu Gly 225 230 235 240 Thr Leu Asn Thr Leu Ala Asp Val Pro Asp Ser Val Val Gln Gly Arg 245 250 255 Gly Gln Lys Gln Leu Ile Ile Ser Thr Ser Asp Arg Lys Leu Leu Lys 260 265 270 Phe Ile Leu Gln His Val Thr Tyr Thr Ser Thr Gly Tyr Gln His Gln 275 280 285 Lys Val Asp Ile Val Ser Leu Glu Ser Arg Ser Ser Val Ala Lys Phe 290 295 300 Pro Val Thr Ile Arg His Pro Val Ile Pro Lys Leu Tyr Asp Pro Gly 305 310 315 320 Pro Glu Arg Lys Leu Arg Asn Leu Val Thr Ile Ala Thr Lys Thr Phe 325 330 335 Leu Arg Pro His Lys Leu Met Ile Met Leu Arg Ser Ile Arg Glu Tyr 340 345 350 Tyr Pro Asp Leu Thr Val Ile Val Ala Asp Asp Ser Gln Lys Pro Leu 355 360 365 Glu Ile Lys Asp Asn His Val Glu Tyr Tyr Thr Met Pro Phe Gly Lys 370 375 380 Gly Trp Phe Ala Gly Arg Asn Leu Ala Ile Ser Gln Val Thr Thr Lys 385 390 395 400 Tyr Val Leu Trp Val Asp Asp Asp Phe Leu Phe Asn Glu Glu Thr Lys 405 410 415 Ile Glu Val Leu Val Asp Val Leu Glu Lys Thr Glu Leu Asp Val Val 420 425 430 Gly Gly Ser Val Leu Gly Asn Val Phe Gln Phe Lys Leu Leu Leu Glu 435 440 445 Gln Ser Glu Asn Gly Ala Cys Leu His Lys Arg Met Gly Phe Phe Gln 450 455 460 Pro Leu Asp Gly Phe Pro Ser Cys Val Val Thr Ser Gly Val Val Asn 465 470 475 480 Phe Phe Leu Ala His Thr Glu Arg Leu Gln Arg Val Gly Phe Asp Pro 485 490 495 Arg Leu Gln Arg Val Ala His Ser Glu Phe Phe Ile Asp Gly Leu Gly 500 505 510 Thr Leu Leu Val Gly Ser Cys Pro Glu Val Ile Ile Gly His Gln Ser 515 520 525 Arg Ser Pro Val Val Asp Ser Glu Leu Ala Ala Leu Glu Lys Thr Tyr 530 535 540 Asn Thr Tyr Arg Ser Asn Thr Leu Thr Arg Val Gln Phe Lys Leu Ala 545 550 555 560 Leu His Tyr Phe Lys Asn His Leu Gln Cys Ala Ala 565 570 33 1539 DNA Homo sapiens 33 atgacttcgg gcggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 60 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 120 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 180 cgtctcagga acctcttttc ctacgatgga atctgtcctc ttgcttgttt caggctgttc 240 ccgaaaaatc agtgcaaatg tgaagccaac aaagagcagg gaggttacaa ctttcaggat 300 gcctatggcc agagcgacct cccagcggtg aaagcgagga gacaggctga atttgaacac 360 tttcagagga gagaagggct gccccgccca ctgcccctgc tggtccagcc caacctcccc 420 tttgggtacc cagtccacgg agtggaggtg atgcccctgc acacggttcc catcccaggc 480 ctccagtttg aaggacccga tgcccccgtc tatgaggtca ccctgacagc ttctctgggg 540 acactgaaca cccttgctga tgtcccagac agtgtggtgc agggcagagg ccagaagcag 600 ctgatcattt ctaccagtga ccggaagctg ttgaagttca ttcttcagca cgtgacatac 660 accagcacgg ggtaccagca ccagaaggta gacatagtga gtctggagtc caggtcctca 720 gtggccaagt ttccagtgac catccgccat cctgtcatac ccaagctata cgaccctgga 780 ccagagagga agctcagaaa cctggttacc attgctacca agactttcct ccgcccccac 840 aagctcatga tcatgctccg gagtattcga gagtattacc cagacttgac cgtaatagtg 900 gctgatgaca gccagaagcc cctggaaatt aaagacaacc acgtggagta ttacactatg 960 ccctttggga agggttggtt tgctggtagg aacctggcca tatctcaggt caccaccaaa 1020 tacgttctct gggtggacga tgattttctc ttcaacgagg agaccaagat tgaggtgctg 1080 gtggatgtcc tggagaaaac agaactggac gtggtaggcg gcagtgtgct gggaaatgtg 1140 ttccagttta agttgttgct ggaacagagt gagaatgggg cctgccttca caagaggatg 1200 ggatttttcc aacccctgga tggcttcccc agctgcgtgg tgaccagtgg cgtggtcaac 1260 ttcttcctgg cccacacgga gcgactccaa agagttggct ttgatccccg cctgcaacga 1320 gtggctcact cagaattctt cattgatggg ctagggaccc tactcgtggg gtcatgccca 1380 gaagtgatta taggtcacca gtctcggtct ccagtggtgg actcagaact ggctgcccta 1440 gagaagacct acaatacata ccggtccaac accctcaccc gggtccagtt caagctggcc 1500 cttcactact tcaagaacca tctccaatgt gccgcataa 1539 34 512 PRT Homo sapiens 34 Met Thr Ser Gly Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val 1 5 10 15 Ile Ile Leu Val Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe 20 25 30 Leu Gln Ala Val Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala 35 40 45 Pro Gly Val Gln Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn 50 55 60 Leu Phe Ser Tyr Asp Gly Ile Cys Pro Leu Ala Cys Phe Arg Leu Phe 65 70 75 80 Pro Lys Asn Gln Cys Lys Cys Glu Ala Asn Lys Glu Gln Gly Gly Tyr 85 90 95 Asn Phe Gln Asp Ala Tyr Gly Gln Ser Asp Leu Pro Ala Val Lys Ala 100 105 110 Arg Arg Gln Ala Glu Phe Glu His Phe Gln Arg Arg Glu Gly Leu Pro 115 120 125 Arg Pro Leu Pro Leu Leu Val Gln Pro Asn Leu Pro Phe Gly Tyr Pro 130 135 140 Val His Gly Val Glu Val Met Pro Leu His Thr Val Pro Ile Pro Gly 145 150 155 160 Leu Gln Phe Glu Gly Pro Asp Ala Pro Val Tyr Glu Val Thr Leu Thr 165 170 175 Ala Ser Leu Gly Thr Leu Asn Thr Leu Ala Asp Val Pro Asp Ser Val 180 185 190 Val Gln Gly Arg Gly Gln Lys Gln Leu Ile Ile Ser Thr Ser Asp Arg 195 200 205 Lys Leu Leu Lys Phe Ile Leu Gln His Val Thr Tyr Thr Ser Thr Gly 210 215 220 Tyr Gln His Gln Lys Val Asp Ile Val Ser Leu Glu Ser Arg Ser Ser 225 230 235 240 Val Ala Lys Phe Pro Val Thr Ile Arg His Pro Val Ile Pro Lys Leu 245 250 255 Tyr Asp Pro Gly Pro Glu Arg Lys Leu Arg Asn Leu Val Thr Ile Ala 260 265 270 Thr Lys Thr Phe Leu Arg Pro His Lys Leu Met Ile Met Leu Arg Ser 275 280 285 Ile Arg Glu Tyr Tyr Pro Asp Leu Thr Val Ile Val Ala Asp Asp Ser 290 295 300 Gln Lys Pro Leu Glu Ile Lys Asp Asn His Val Glu Tyr Tyr Thr Met 305 310 315 320 Pro Phe Gly Lys Gly Trp Phe Ala Gly Arg Asn Leu Ala Ile Ser Gln 325 330 335 Val Thr Thr Lys Tyr Val Leu Trp Val Asp Asp Asp Phe Leu Phe Asn 340 345 350 Glu Glu Thr Lys Ile Glu Val Leu Val Asp Val Leu Glu Lys Thr Glu 355 360 365 Leu Asp Val Val Gly Gly Ser Val Leu Gly Asn Val Phe Gln Phe Lys 370 375 380 Leu Leu Leu Glu Gln Ser Glu Asn Gly Ala Cys Leu His Lys Arg Met 385 390 395 400 Gly Phe Phe Gln Pro Leu Asp Gly Phe Pro Ser Cys Val Val Thr Ser 405 410 415 Gly Val Val Asn Phe Phe Leu Ala His Thr Glu Arg Leu Gln Arg Val 420 425 430 Gly Phe Asp Pro Arg Leu Gln Arg Val Ala His Ser Glu Phe Phe Ile 435 440 445 Asp Gly Leu Gly Thr Leu Leu Val Gly Ser Cys Pro Glu Val Ile Ile 450 455 460 Gly His Gln Ser Arg Ser Pro Val Val Asp Ser Glu Leu Ala Ala Leu 465 470 475 480 Glu Lys Thr Tyr Asn Thr Tyr Arg Ser Asn Thr Leu Thr Arg Val Gln 485 490 495 Phe Lys Leu Ala Leu His Tyr Phe Lys Asn His Leu Gln Cys Ala Ala 500 505 510 35 1701 DNA Homo sapiens 35 atggggagcg ctggcttttc cgtgggaaaa ttccacgtgg aggtggcctc tcgcggccgg 60 gaatgtgtct cggggacgcc cgagtgtggg aatcggctcg ggagtgcggg cttcggggat 120 ctctgcttgg aactcagagg cgctgaccca gcctggggcc cgtttgctgc ccacgggagg 180 agccgccgtc agggctcgag atttctgtgg ctcctcaaga tattggtcat aatcctggta 240 cttggcattg ttggatttat gttcggaagc atgttccttc aagcagtgtt cagcagcccc 300 aagccagaac tcccaagtcc tgccccgggt gtccagaagc tgaagcttct gcctgaggaa 360 cgtctcagga acctcttttc ctacgatgga atctggctgt tcccgaaaaa tcagtgcaaa 420 tgtgaagcca acaaagagca gggaggttac aactttcagg atgcctatgg ccagagcgac 480 ctcccagcgg tgaaagcgag gagacaggct gaatttgaac actttcagag gagagaaggg 540 ctgccccgcc cactgcccct gctggtccag cccaacctcc cctttgggta cccagtccac 600 ggagtggagg tgatgcccct gcacacggtt cccatcccag gcctccagtt tgaaggaccc 660 gatgcccccg tctatgaggt caccctgaca gcttctctgg ggacactgaa cacccttgct 720 gatgtcccag acagtgtggt gcagggcaga ggccagaagc agctgatcat ttctaccagt 780 gaccggaagc tgttgaagtt cattcttcag cacgtgacat acaccagcac ggggtaccag 840 caccagaagg tagacatagt gagtctggag tccaggtcct cagtggccaa gtttccagtg 900 accatccgcc atcctgtcat acccaagcta tacgaccctg gaccagagag gaagctcaga 960 aacctggtta ccattgctac caagactttc ctccgccccc acaagctcat gatcatgctc 1020 cggagtattc gagagtatta cccagacttg accgtaatag tggctgatga cagccagaag 1080 cccctggaaa ttaaagacaa ccacgtggag tattacacta tgccctttgg gaagggttgg 1140 tttgctggta ggaacctggc catatctcag gtcaccacca aatacgttct ctgggtggac 1200 gatgattttc tcttcaacga ggagaccaag attgaggtgc tggtggatgt cctggagaaa 1260 acagaactgg acgtggtagg cggcagtgtg ctgggaaatg tgttccagtt taagttgttg 1320 ctggaacaga gtgagaatgg ggcctgcctt cacaagagga tgggattttt ccaacccctg 1380 gatggcttcc ccagctgcgt ggtgaccagt ggcgtggtca acttcttcct ggcccacacg 1440 gagcgactcc aaagagttgg ctttgatccc cgcctgcaac gagtggctca ctcagaattc 1500 ttcattgatg ggctagggac cctactcgtg gggtcatgcc cagaagtgat tataggtcac 1560 cagtctcggt ctccagtggt ggactcagaa ctggctgccc tagagaagac ctacaataca 1620 taccggtcca acaccctcac ccgggtccag ttcaagctgg cccttcacta cttcaagaac 1680 catctccaat gtgccgcata a 1701 36 566 PRT Homo sapiens 36 Met Gly Ser Ala Gly Phe Ser Val Gly Lys Phe His Val Glu Val Ala 1 5 10 15 Ser Arg Gly Arg Glu Cys Val Ser Gly Thr Pro Glu Cys Gly Asn Arg 20 25 30 Leu Gly Ser Ala Gly Phe Gly Asp Leu Cys Leu Glu Leu Arg Gly Ala 35 40 45 Asp Pro Ala Trp Gly Pro Phe Ala Ala His Gly Arg Ser Arg Arg Gln 50 55 60 Gly Ser Arg Phe Leu Trp Leu Leu Lys Ile Leu Val Ile Ile Leu Val 65 70 75 80 Leu Gly Ile Val Gly Phe Met Phe Gly Ser Met Phe Leu Gln Ala Val 85 90 95 Phe Ser Ser Pro Lys Pro Glu Leu Pro Ser Pro Ala Pro Gly Val Gln 100 105 110 Lys Leu Lys Leu Leu Pro Glu Glu Arg Leu Arg Asn Leu Phe Ser Tyr 115 120 125 Asp Gly Ile Trp Leu Phe Pro Lys Asn Gln Cys Lys Cys Glu Ala Asn 130 135 140 Lys Glu Gln Gly Gly Tyr Asn Phe Gln Asp Ala Tyr Gly Gln Ser Asp 145 150 155 160 Leu Pro Ala Val Lys Ala Arg Arg Gln Ala Glu Phe Glu His Phe Gln 165 170 175 Arg Arg Glu Gly Leu Pro Arg Pro Leu Pro Leu Leu Val Gln Pro Asn 180 185 190 Leu Pro Phe Gly Tyr Pro Val His Gly Val Glu Val Met Pro Leu His 195 200 205 Thr Val Pro Ile Pro Gly Leu Gln Phe Glu Gly Pro Asp Ala Pro Val 210 215 220 Tyr Glu Val Thr Leu Thr Ala Ser Leu Gly Thr Leu Asn Thr Leu Ala 225 230 235 240 Asp Val Pro Asp Ser Val Val Gln Gly Arg Gly Gln Lys Gln Leu Ile 245 250 255 Ile Ser Thr Ser Asp Arg Lys Leu Leu Lys Phe Ile Leu Gln His Val 260 265 270 Thr Tyr Thr Ser Thr Gly Tyr Gln His Gln Lys Val Asp Ile Val Ser 275 280 285 Leu Glu Ser Arg Ser Ser Val Ala Lys Phe Pro Val Thr Ile Arg His 290 295 300 Pro Val Ile Pro Lys Leu Tyr Asp Pro Gly Pro Glu Arg Lys Leu Arg 305 310 315 320 Asn Leu Val Thr Ile Ala Thr Lys Thr Phe Leu Arg Pro His Lys Leu 325 330 335 Met Ile Met Leu Arg Ser Ile Arg Glu Tyr Tyr Pro Asp Leu Thr Val 340 345 350 Ile Val Ala Asp Asp Ser Gln Lys Pro Leu Glu Ile Lys Asp Asn His 355 360 365 Val Glu Tyr Tyr Thr Met Pro Phe Gly Lys Gly Trp Phe Ala Gly Arg 370 375 380 Asn Leu Ala Ile Ser Gln Val Thr Thr Lys Tyr Val Leu Trp Val Asp 385 390 395 400 Asp Asp Phe Leu Phe Asn Glu Glu Thr Lys Ile Glu Val Leu Val Asp 405 410 415 Val Leu Glu Lys Thr Glu Leu Asp Val Val Gly Gly Ser Val Leu Gly 420 425 430 Asn Val Phe Gln Phe Lys Leu Leu Leu Glu Gln Ser Glu Asn Gly Ala 435 440 445 Cys Leu His Lys Arg Met Gly Phe Phe Gln Pro Leu Asp Gly Phe Pro 450 455 460 Ser Cys Val Val Thr Ser Gly Val Val Asn Phe Phe Leu Ala His Thr 465 470 475 480 Glu Arg Leu Gln Arg Val Gly Phe Asp Pro Arg Leu Gln Arg Val Ala 485 490 495 His Ser Glu Phe Phe Ile Asp Gly Leu Gly Thr Leu Leu Val Gly Ser 500 505 510 Cys Pro Glu Val Ile Ile Gly His Gln Ser Arg Ser Pro Val Val Asp 515 520 525 Ser Glu Leu Ala Ala Leu Glu Lys Thr Tyr Asn Thr Tyr Arg Ser Asn 530 535 540 Thr Leu Thr Arg Val Gln Phe Lys Leu Ala Leu His Tyr Phe Lys Asn 545 550 555 560 His Leu Gln Cys Ala Ala 565 37 3244 DNA Homo sapiens 37 ggcggcctgg ctgctaggct ccgtgacatc cggcagtctg agggcggcgg gattcgggat 60 gacttcgggc gggtgagtgt cctcggggca gagcaaaagc gagaggtgaa acttcgggag 120 cagggagcgc cgcgggtcct ttctggcgtc tgcagagcgg gcaggtgctg gggacgcaga 180 cgccggagcc agggagcggg cggttggagt cttaagtcca accggttccc cgcataggtg 240 gctgcagagg cgaggtgacg gcgcgtgcgg aacgaactct gcacccccag gaatggggag 300 cgctggcttt tccgtgggaa aattccacgt ggaggtggcc tctcgcggcc gggaatgtgt 360 ctcggggacg cccgagtgtg ggaatcggct cgggagtgcg ggcttcgggg atctctgctt 420 ggaactcaga ggcgctgacc cagcctgggg cccgtttgct gcccacggga ggagccgccg 480 tcagggctcg agatttctgt ggctcctcaa gatattggtc ataatcctgg tacttggcat 540 tgttggattt atgttcggaa gcatgttcct tcaagcagtg ttcagcagcc ccaagccaga 600 actcccaagt cctgccccgg gtgtccagaa gctgaagctt ctgcctgagg aacgtctcag 660 gaacctcttt tcctacgatg gaatctggtg agagactgcg tgttctttct ttcaccttaa 720 tgcacacatc ttccttgctc ctcctcaagt accatgccct actgtgccca ttgtaccgat 780 ggttcccttg ctttcctaag cctgtgctga atgcacaagt gactgcaagc caggatgggg 840 cttggtctgt acgatccagt ctatgttctc tatagcatcc agcaaaatcc cttaaaactt 900 tcgagagcat gtagtttttt tttatcaaaa ctgcagaaaa gatgctgctt ctctgtctct 960 ctgccctcct tttatggtgg ggtgagatac aactgacagt cacgtggctc tcagatttaa 1020 agaagttagg tgcaggggac aattcaagag aggaaaagtc ttcagccttc ctctgtccct 1080 gcttccctcc ctttgtcccc ttgtctctgt gaggggccag tgcaagggac tccagggtct 1140 catcatctca gaacagttgg gtgtaggaaa gaagattttc agggtaaact acacactggt 1200 cctcttgctt gtttcaggct gttcccgaaa aatcagtgca aatgtgaagc caacaaagag 1260 cagggaggtt acaactttca ggatgcctat ggccagagcg acctcccagc ggtgaaagcg 1320 aggagacagg ctgaatttga acactttcag aggaggtaat gcgggtcatg aaggcccttg 1380 ggttctgaga tggaacaaaa gccctcccta tgtcctgagg ttgtgaatct taagagaaaa 1440 agcaggaagg aattctctct cttgcaaggg tccctgggag gaactattag gaatgaaaca 1500 aagaaggaat cgaggaaatc atccttaaat gaagatttac aaaactttgt atgtacaaaa 1560 catttcataa caacaacaac aacaacaaaa agctgggatt ggtgacacat gtctgtcatt 1620 ctagcacttt gggaggtcaa gatgggagga tagcttgagc ccaggagttt gagaccagct 1680 tgggcaatat agtgagaccc ccatcttcta caaaacattt ttaaaattag ccaggcatga 1740 tggtacatgc ctgtagtccc agctactcag taggctgaag tgagaggatc acttgagccc 1800 agaagttgaa gctgcatgag ccaggatcac accactgcac tccagcttga gaagggctgc 1860 cccgcccact gcccctgctg gtccagccca acctcccctt tgggtaccca gtccacggag 1920 tggaggtgat gcccctgcac acggttccca tcccaggcct ccagtttgaa ggacccgatg 1980 cccccgtcta tgaggtcacc ctgacagctt ctctggggac actgaacacc cttgctgatg 2040 tcccagacag tgtggtgcag ggcagaggcc agaagcagct gatcatttct accagtgacc 2100 ggaagctgtt gaagttcatt cttcagcacg tgacatacac cagcacgggg taccagcacc 2160 agaaggtaga catagtgagt ctggagtcca ggtcctcagt ggccaagttt ccagtgacca 2220 tccgccatcc tgtcataccc aagctatacg accctggacc agagaggaag ctcagaaacc 2280 tggttaccat tgctaccaag actttcctcc gcccccacaa gctcatgatc atgctccgga 2340 gtattcgaga gtattaccca gacttgaccg taatagtggc tgatgacagc cagaagcccc 2400 tggaaattaa agacaaccac gtggagtatt acactatgcc ctttgggaag ggttggtttg 2460 ctggtaggaa cctggccata tctcaggtca ccaccaaata cgttctctgg gtggacgatg 2520 attttctctt caacgaggag accaagattg aggtgctggt ggatgtcctg gagaaaacag 2580 aactggacgt ggtaagggac agttgccagt ttcacccagc cacaatctgt agagatggag 2640 aagaggggag aagagagcga ggcggcagtg tgctgggaaa tgtgttccag tttaagttgt 2700 tgctggaaca gagtgagaat ggggcctgcc ttcacaagag gatgggattt ttccaacccc 2760 tggatggctt ccccagctgc gtggtgacca gtggcgtggt caacttcttc ctggcccaca 2820 cggagcgact ccaaagagtt ggctttgatc cccgcctgca acgagtggct cactcagaat 2880 tcttcattga tgggctaggg accctactcg tggggtcatg cccagaagtg attataggtc 2940 accagtctcg gtctccagtg gtggactcag aactggctgc cctagagaag acctacaata 3000 cataccggtc caacaccctc acccgggtcc agttcaagct ggcccttcac tacttcaaga 3060 accatctcca atgtgccgca taaaggtgtg agggcataga gaaacactag gctggctggt 3120 atggtatcta tagcagccac caaaactgga ctctgatagg tgaacgttgt accaaccagc 3180 tgtggtaggg aaaagggaaa tggctcaagt tactggaagt accaatcaaa ggtgaagggt 3240 cact 3244

Claims

What is claimed is:

1. An isolated nucleic acid molecule comprising at least 24 contiguous bases of nucleotide sequence first disclosed in the NHP polynucleotide described in SEQ ID NO: 1.

2. An isolated nucleic acid molecule comprising a nucleotide sequence that:

(a) encodes the amino acid sequence shown in SEQ ID NO: 2; and

(b) hybridizes under stringent conditions to the nucleotide sequence of SEQ ID NO: 1 or the complement thereof.

3. An isolated nucleic acid molecule encoding the amino acid sequence described in SEQ ID NO: 2.

4. An isolated oligopeptide comprising a least about 12 amino acids in a sequence first disclosed in SEQ ID NO: 2.