Novel G protein-coupled receptor family members, human thioredoxin family members, human leucine-rich repeat family members, and human ringfinger family member (24-Jul-2003)

RELATED APPLICATIONS

[0001] This application is a continuation-in-part and claims priority to U.S. application Ser. No. 09/796,338, filed Feb. 28, 2001 and International Application Serial No. PCT/US01/06543, filed Feb. 28, 2001, which claim the benefit of U.S. Provisional Application Serial No. 60/186,059, filed Feb. 29, 2000; and U.S. application Ser. No. (not available), filed Apr. 30, 2002, which is a continuation of U.S. application Ser. No. 09/514,214, filed on Feb. 25, 2000 and International Application Serial No. PCT/US01/06057, filed Feb. 23, 2001; and U.S. application Ser. No. 09/911,005, filed Jul. 23, 2001 and International Application Serial No. PCT/US01/23152, filed Jul. 23, 2001, which claim the benefit of U.S. Provisional Application Serial No. 60/220,042, filed Jul. 21, 2000; and International Application Serial No. PCT/US01/40476, filed Apr. 9, 2001, which claims the benefit of U.S. application Ser. No. 09/551,288, filed Apr. 18, 2000; and U.S. application Ser. No. 09/801,260, filed Mar. 6, 2001 and International Application Serial No. PCT/US01/07139, filed Mar. 5, 2001, which claim the benefit of U.S. Provisional Application Serial No. 60/187,447, filed Mar. 7, 2000; and U.S. application Ser. No. 09/882,835, filed Jun. 15, 2001 and International Application Serial No. PCT/US01/19544, filed Jun. 15, 2001, which claim the benefit of U.S. Provisional Application Serial No. 60/211,673, filed Jun. 15, 2000; and U.S. application Ser. No. 09/963,339, filed Sep. 25, 2001 and International Application Serial No. PCT/US01/29967, filed Sep. 25, 2001, which claim the benefit of U.S. Provisional Application Serial No. 60/235,049, filed Sep. 25, 2000; and U.S. application Ser. No. 09/815,626, filed Mar. 23, 2001 and International Application Serial No. PCT/US01/09470, filed Mar. 23, 2001, which claim the benefit of U.S. Provisional Application Serial No. 60/191,863, filed Mar. 24, 2000; and U.S. application Ser. No. 09/822,687, filed Mar. 30, 2001 and International Application Serial No. PCT/US01/10380, filed Mar. 30, 2001, which claim the benefit of U.S. Provisional Application Serial No. 60/193,919, filed Mar. 31, 2000; and U.S. application Ser. No. 09/964,012, filed Sep. 25, 2001 and International Application Serial No. PCT/US01/29968, filed Sep. 25, 2001, which claim the benefit of U.S. Provisional Application Serial No. 60/235,032, filed Sep. 25, 2000, the contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION FOR 1983, 52881, 2398, 45449, 50289 or 52872

[0002] G-protein coupled receptors (GPCRs) are seven transmembrane domain proteins that mediate signal transduction of a diverse number of ligands through heterotrimeric G proteins (Strader, C. D. et al. (1994) Annu. Rev. Biochem. 63: 101-132). G protein-coupled receptors (GPCRs), along with G-proteins and effector proteins (e.g., intracellular enzymes and channels), are the components of a modular signaling system. Upon ligand binding to an extracellular portion of a GPCR, different G proteins are activated, which in turn modulate the activity of different intracellular effector enzymes and ion channels (Gutkind, J. S. (1998) J. Biol. Chem. 273: 1839-1842; Selbie, L. A. and Hill, S. J. (1998) Trends Pharmacol. Sci. 19:87-93).

[0003] G proteins represent a family of heterotrimeric proteins composed of α, β and γ subunits, which bind guanine nucleotides. These proteins are usually linked to cell surface receptors (e.g., a GPCR). Following ligand binding to a GPCR, a conformational change is transmitted to the G protein, which causes the α-subunit to exchange a bound GDP molecule for a GTP molecule and to dissociate from the βγ-subunits. The GTP-bound form of the α-subunit typically functions as an effector-modulating moiety, leading to the production of second messengers, such as cyclic AMP (e.g., by activation of adenylate cyclase), diacylglycerol or inositol phosphates. Over 20 different types of α-subunits are known in man, which associate with a smaller pool of β and γ subunits. Examples of mammalian G proteins include G_i, G_o, G_q, G_s and G_t (Lodish H. et al. Molecular Cell Biology, Scientific American Books Inc., New York, N.Y., 1995).

[0004] One subfamily of seven transmembrane receptors is the rhodopsin family. Proteins of this family can be expressed in photoreceptor cells. They generally contain a prosthetic group, 11-cis-retinal. Absorption of light by retinal causes an isomerization in the molecule and consequently a conformational change in the rhodopsin protein. This structural change is transmitted to a signaling cascade by means of the coupled G protein.

[0005] GPCRs are of critical importance to several systems including the endocrine system, the central nervous system and peripheral physiological processes. The GPCR genes and gene-products are also believed to be causative agents of disease (Spiegel et al. (1993) J. Clin. Invest. 92:1119-1125); McKusick and Amberger (1993) J. Med. Genet. 30:1-26). Given the important biological roles and properties of GPCRs, there exists a need for the identification of novel genes encoding such proteins as well as for the discovery of modulators of such molecules for use in regulating a variety of normal and/or pathological cellular processes.

SUMMARY OF THE INVENTION FOR 1983, 52881, 2398, 45449, 50289 or 52872

[0006] The present invention is based, in part, on the discovery of novel G-protein coupled receptors and nucleic acids encoding these receptors, referred to herein collectively as “GPCRs,” or by the individual clone name “1983, 52881, 2398, 45449, 50289, and 52872.” The nucleotide sequence of a cDNA encoding 1983 is shown in SEQ ID NO: 1, and the amino acid sequence of a 1983 polypeptide is shown in SEQ ID NO: 2. In addition, the nucleotide sequence of the coding region of a 1983 polypeptide is depicted in SEQ ID NO: 3. The nucleotide sequence of a cDNA encoding a 52881 polypeptide is shown in SEQ ID NO: 4, and the amino acid sequence of a 52881 polypeptide is shown in SEQ ID NO: 5. In addition, the nucleotide sequence of the coding region of a 52881 polypeptide is depicted in SEQ ID NO: 6. The nucleotide sequence of a cDNA encoding 2398 polypeptide is shown in SEQ ID NO: 7, and the amino acid sequence of a 2398 polypeptide is shown in SEQ ID NO: 8. In addition, the nucleotide sequence of the coding region of a 2398 polypeptide is depicted in SEQ ID NO: 9. The nucleotide sequence of a cDNA encoding a 45449 polypeptide is shown in SEQ ID NO: 10, and the amino acid sequence of a 45449 polypeptide is shown in SEQ ID NO: 11. In addition, the nucleotide sequence of the coding region of a 45449 polypeptide is depicted in SEQ ID NO: 12. The nucleotide sequence of a cDNA encoding a 50289 polypeptide is shown in SEQ ID NO: 13, and the amino acid sequence of a 50289 polypeptide is shown in SEQ ID NO: 14. In addition, the nucleotide sequence of the coding region of a 50289 polypeptide is depicted in SEQ ID NO: 15. The nucleotide sequence of a cDNA encoding a 52872 polypeptide is shown in SEQ ID NO: 16, and the amino acid sequence of a 52872 polypeptide is shown in SEQ ID NO: 17. In addition, the nucleotide sequence of the coding region of a 52872 polypeptide is depicted in SEQ ID NO: 18.

[0007] Accordingly, in one aspect, the invention features a nucleic acid molecule which encodes a 1983, 52881, 2398, 45449, 50289, or 52872 protein or polypeptide, e.g., a biologically active portion of the 1983, 52881, 2398, 45449, 50289, or 52872 protein. In a preferred embodiment the isolated nucleic acid molecule encodes a polypeptide having the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17. In other embodiments, the invention provides isolated 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid molecules having the nucleotide sequence shown in SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, or the sequence of the DNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______. In still other embodiments, the invention provides nucleic acid molecules that are substantially identical (e.g., naturally occurring allelic variants) to the nucleotide sequence shown in SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, or the sequence of the DNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ___, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______. In other embodiments, the invention provides a nucleic acid molecule which hybridizes under a stringent hybridization condition described herein to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, or the sequence of the DNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______, wherein the nucleic acid encodes a full length 1983, 52881, 2398, 45449, 50289, or 52872 protein or an active fragment thereof.

[0008] In a preferred embodiment, the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid has a nucleotide sequence identical to, or substantially identical to, SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, or the sequence of the DNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______. In other embodiments, the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid is a fragment of at least 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or more contiguous nucleotides of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, or the sequence of the DNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______.

[0009] In a related aspect, the invention further provides nucleic acid constructs which include a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid molecule described herein. In certain embodiments, the nucleic acid molecules of the invention are operatively linked to native or heterologous regulatory sequences. Also included, are vectors and host cells containing the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid molecules of the invention e.g., vectors and host cells suitable for producing 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid molecules and polypeptides.

[0010] In another related aspect, the invention provides nucleic acid fragments suitable as primers or hybridization probes for the detection of 1983, 52881, 2398, 45449, 50289, or 52872-encoding nucleic acids.

[0011] In still another related aspect, isolated nucleic acid molecules that are antisense to a 1983, 52881, 2398, 45449, 50289, or 52872 encoding nucleic acid molecule are provided.

[0012] In another aspect, the invention features, 1983, 52881, 2398, 45449, 50289, or 52872 polypeptides, and biologically active or antigenic fragments thereof that are useful, e.g., as reagents or targets in assays applicable to treatment and diagnosis of 1983, 52881, 2398, 45449, 50289, or 52872-mediated or 1983, 52881, 2398, 45449, 50289, or 52872-related disorders. In another embodiment, the invention provides 1983, 52881, 2398, 45449, 50289, or 52872 polypeptides having a 1983, 52881, 2398, 45449, 50289, or 52872 activity. Preferred polypeptides are 1983, 52881, 2398, 45449, 50289, or 52872 proteins including at least one seven transmembrane domain domain or at least one ANF receptor ligand binding domain, and, preferably, having a 1983, 52881, 2398, 45449, 50289, or 52872 activity, e.g., a 1983, 52881, 2398, 45449, 50289, or 52872 activity as described herein.

[0013] In other embodiments, the invention provides 1983, 52881, 2398, 45449, 50289, or 52872 polypeptides, e.g., a 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide having the amino acid sequence shown in SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, or an amino acid sequence encoded by the cDNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______; an amino acid sequence that is substantially identical to the amino acid sequence shown in SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17, or an amino acid sequence encoded by the cDNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______; or an amino acid sequence encoded by a nucleic acid molecule having a nucleotide sequence which hybridizes under a stringent hybridization condition described herein to a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 18, or the sequence of the DNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______, wherein the nucleic acid encodes a full length 1983, 52881, 2398, 45449, 50289, or 52872 protein or an active fragment thereof.

[0014] In a preferred embodiment, the 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide has an amino acid sequence identical to, or substantially identical to, SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17; or an amino acid sequence encoded by the cDNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______. In other embodiments, the 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide is a fragment of at least 15, 20, 50, 100, 150, 200, 250, 300 or more contiguous amino acids of SEQ ID NO: 2, SEQ ID NO: 5, SEQ ID NO: 8, SEQ ID NO: 11, SEQ ID NO: 14, SEQ ID NO: 17; or an amino acid sequence encoded by the cDNA insert of the plasmid deposited with ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, ATCC Accession Number ______, or ATCC Accession Number ______.

[0015] In a related aspect, the invention further provides nucleic acid constructs which include a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid molecule described herein.

[0016] In a related aspect, the invention provides 1983, 52881, 2398, 45449, 50289, or 52872 polypeptides or fragments operatively linked to non-52881 polypeptides to form fusion proteins.

[0017] In another aspect, the invention features antibodies and antigen-binding fragments thereof, that react with, or more preferably specifically bind 1983, 52881, 2398, 45449, 50289, or 52872 polypeptides.

[0018] In another aspect, the invention provides methods of screening for compounds that modulate the expression or activity of the 1983, 52881, 2398, 45449, 50289, or 52872 polypeptides or nucleic acids.

[0019] In still another aspect, the invention provides a process for modulating 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide or nucleic acid expression or activity, e.g. using the screened compounds. In certain embodiments, the methods involve treatment of conditions related to activity or expression of the 1983, 52881, 2398, 45449, 50289, or 52872 polypeptides or nucleic acids, such as cardiovascular disorders, angiogenesis-related disorders, neural disorders, conditions involving pain response, aberrant or altered pain responses, pain related disorders, or inflammatory responses.

[0020] Examples of cardiovascular disorders include e.g., atherosclerosis, thrombosis, heart failure, ischemic heart disease, angina pectoris, myocardial infarction, sudden cardiac death, hypertensive heart disease; non-coronary vessel disease, such as arteriolosclerosis, small vessel disease, nephropathy, hypertriglyceridemia, hypercholesterolemia, hyperlipidemia, xanthomatosis, asthma, hypertension, emphysema and chronic pulmonary disease; or a cardiovascular condition associated with interventional procedures (“procedural vascular trauma”), such as restenosis following angioplasty, placement of a shunt, stet, stent, synthetic or natural excision grafts, indwelling catheter, valve or other implantable devices.

[0021] In one embodiment, the cardiovascular disorder is caused by aberrant fatty acid metabolism. Examples of disorders involving aberrant fatty acid metabolism include, but are not limited to, atherosclerosis, arteriolosclerosis, hypertriglyceridemia, obesity, diabetes, hypercholesterolemia, xanthomatosis, and hyperlipidemia. Most preferable, the disorder is atherosclerosis.

[0022] In the cardiovascular applications, an agent is administered alone or in combination with a cholesterol-lowering agent. Examples of cholesterol lowering agents include bile acid sequestering resins (e.g. colestipol hydrochloride or cholestyramine), fibric acid derivatives (e.g. clofibrate, fenofibrate, or gemfibrozil), thiazolidenediones (e.g. troglitazone), or hydroxymethylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitors (e.g. statins, such as fluvastatin sodium, lovastatin, pravastatin sodium, or simvastatin), an ApoAII-lowering agent, a VLDL lowering agent, an ApoAI-stimulating agent, as well as inhibitors of, nicotinic acid, niacin, or probucol. Preferred cholesterol lowering agents include inhibitors of HMG-CoA reductase (e.g., statins), nicotinic acid, and niacin.

[0023] The cholesterol-lowering agent can be administered prior to, at the same time, or after administration of the agent, in single or multiple administration schedules. For example, the cholesterol lowering agent and the agents of the invention can be administered continually over a preselected period of time, or administered in a series of spaced doses, i.e., intermittently, for a period of time.

[0024] In preferred embodiments, the agent, alone or in combination with, the cholesterol lowering agent, inhibit (block or reduce) atherosclerotic lesion formation or development, e.g., so as to inhibit lipid accumulation, increase plaque stability or promote lesion regression.

[0025] In a preferred embodiment, the agent, administered alone or in combination with the cholesterol lowering agent, results in a favorable plasma lipid profile (e.g., increased HDL and/or reduced LDL).

[0026] In a preferred embodiment, the agent modulates (e.g., decreases or increases) the activity or expression of a 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide or nucleic acid.

[0027] In a preferred embodiment, the agent modulates (e.g., increases or decreases) expression of the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid by, e.g., modulating transcription, mRNA stability, etc.

[0028] In preferred embodiments, the agent is a peptide, a phosphopeptide, a small molecule, e.g., a member of a combinatorial or natural product library, or an antibody, or any combination thereof.

[0029] In additional preferred embodiments, the agent is an antisense, a ribozyme, or a triple helix molecule, or a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or a fragment thereof, or any combination thereof.

[0030] In a preferred embodiment, the subject is a patient undergoing a therapeutic or prophylactic protocol. Preferably, the subject is a human suffering from, or at risk of a cardiovascular disease, e.g., atherosclerosis, thrombosis, heart failure, ischemic heart disease, angina pectoris, myocardial infarction, sudden cardiac death, hypertensive heart disease; non-coronary vessel disease, such as arteriolosclerosis, small vessel disease, nephropathy, hypertriglyceridemia, obesity, diabetes, hypercholesterolemia, hyperlipidemia, xanthomatosis, asthma, hypertension, emphysema and chronic pulmonary disease; or a cardiovascular condition associated with interventional procedures (“procedural vascular trauma”), such as restenosis following angioplasty, placement of a shunt, stet, stent, synthetic or natural excision grafts, indwelling catheter, valve or other implantable devices.

[0031] In a preferred embodiment, the subject is a human suffering from, or at risk of a disorder involving aberrant fatty acid metabolism. Examples of such disorders include, but are not limited to, atherosclerosis, arteriolosclerosis, hypertriglyceridemia, obesity, diabetes, hypercholesterolemia, xanthomatosis and hyperlipidemia. Most preferable, the disorder is atherosclerosis.

[0032] In other embodiments, the subject is a non-human animal, e.g., an experimental animal.

[0033] In yet another aspect, the invention features a method of treating or preventing a cardiovascular disorder (e.g., atherosclerosis), in a subject. The method includes administering to the subject an agent that modulates the activity or expression of a 1983, 52881, 2398, or 45449 polypeptide or nucleic acid, in an amount effective to treat or prevent the cardiovascular disorder.

[0034] In yet another aspect, the invention features a method of treating or preventing a disease related to angiogenesis or neovascularization in a subject. The method includes administering to the subject an agent that modulates the activity or expression of a 1983, 52881, 2398, or 45449, 50289, or 52872 polypeptide or nucleic acid, in an amount effective to treat or prevent the disorder. Diseases in which angiogenesis or neovascularization play a role include neoplastic disease, retinopathy (e.g., diabetic retinopathy), and macular degeneration.

[0035] The invention also features a method of diagnosing a disorder, e.g., a cardiovascular disorder (e.g., atherosclerosis) or angiogenesis-related disorder, in a subject. The method includes evaluating the expression or activity of a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or a 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide, such that, a difference in the level of 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide relative to a normal subject or a cohort of normal subjects is indicative of the disorder.

[0036] In a preferred embodiment, the subject is a human.

[0037] In a preferred embodiment, the evaluating step occurs in vitro or ex vivo. For example, a sample, e.g., a blood sample, is obtained from the subject.

[0038] In a preferred embodiment, the evaluating step occurs in vivo. For example, by administering to the subject a detectably labeled agent that interacts with the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or polypeptide, such that a signal is generated relative to the level of activity or expression of the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or polypeptide.

[0039] In a preferred embodiment, the disorder is a cardiovascular disorder, e.g., a cardiovascular disorder as described herein.

[0040] In a preferred embodiment, the disorder is atherosclerosis.

[0041] The invention also provides assays for determining the activity of or the presence or absence of 1983, 52881, 2398, 45449, 50289, or 52872 polypeptides or nucleic acid molecules in a biological sample, including for disease diagnosis.

[0042] In a further aspect, the invention provides assays for determining the presence or absence of a genetic alteration in a 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide or nucleic acid molecule, including for disease diagnosis.

[0043] In yet another aspect, the invention features a method for identifying an agent, e.g., a compound, which modulates the activity of a 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide, e.g., a 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide as described herein, or the expression of a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid, e.g., a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid as described herein, including contacting the 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide or nucleic acid with a test agent (e.g., a test compound); and determining the effect of the test compound on the activity of the polypeptide or nucleic acid to thereby identify a compound which modulates the activity of the polypeptide or nucleic acid. Such agents are useful for treating or preventing a 1983, 52881, 2398, 45449, 50289, or 52872-mediated disorders, e.g., cardiovascular disorders (e.g., atherosclerosis).

[0044] In a preferred embodiment, the contacting step occurs in vitro or ex vivo. For example, a sample, e.g., a blood sample, is obtained from the subject.

[0045] In a preferred embodiment, the contacting step occurs in vivo. For example, by administering to the subject a detectably labeled agent that interacts with the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or polypeptide, such that a signal is generated relative to the level of activity or expression of the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or polypeptide.

[0046] In a preferred embodiment, the agent is an inhibitor (partial or complete inhibitor) of 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide activity or expression. For example, inhibiting 1983, 52881, 2398, 45449, 50289, or 52872 expression and/or activity may promote the growth of blood vessels through the process of angiogenesis.

[0047] In a preferred embodiment, the agent is an agonist of 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide activity or expression. For example, increasing 1983, 52881, 2398, 45449, 50289, or 52872 expression and/or activity may inhibit the process of angiogenesis. Such an agent would be particularly useful in inhibiting unwanted angiogenesis, e.g., angiogenesis associated with tumor growth.

[0048] In preferred embodiments, the agent is a peptide, a phosphopeptide, a small molecule, e.g., a member of a combinatorial library, or an antibody, or any combination thereof.

[0049] In additional preferred embodiments, the agent is an antisense, a ribozyme, a triple helix molecule, or a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid, or any combination thereof.

[0050] In still another aspect, the invention features a method of modulating (e.g., enhancing or inhibiting) a pain response or an inflammatory response. The method includes contacting a cell with an agent that modulates the activity or expression of a 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide or nucleic acid, in an amount effective to modulate the pain response or inflammatory response.

[0051] In a preferred embodiment, the agent modulates (e.g., increases or decreases) signaling through a pain associated receptor, e.g., a 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide described herein.

[0052] In a preferred embodiment, the agent modulates (e.g., increases or decreases) expression of the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid by, e.g., modulating transcription, mRNA stability, etc.

[0053] In preferred embodiments, the agent is a peptide, a phosphopeptide, a small molecule, e.g., a member of a combinatorial library, or an antibody, or any combination thereof. The antibody can be conjugated to a therapeutic moiety selected from the group consisting of a cytotoxin, a cytotoxic agent and a radioactive metal ion.

[0054] In additional preferred embodiments, the agent is an antisense molecule, a ribozyme, a triple helix molecule, or a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid, or any combination thereof.

[0055] In a preferred embodiment, the agent is administered in combination with a cytotoxic agent.

[0056] In a preferred embodiment, the cell, e.g., the 1983, 52881, 2398, 45449, 50289, or 52872-expressing cell, is a neural cell, e.g., central or peripheral nervous system cell (e.g., a cell in an area involved in pain control, e.g., a cell in the substantia gelatinosa of the spinal cord, or a cell in the periaqueductal gray matter).

[0057] In a preferred embodiment, the agent and the 1983, 52881, 2398, 45449, 50289, or 52872-polypeptide or nucleic acid are contacted in vitro or ex vivo.

[0058] In a preferred embodiment, the contacting step is effected in vivo in a subject, e.g., as part of a therapeutic or prophylactic protocol. Preferably, the subject is a human, e.g., a patient with pain or a pain-associated disorder disclosed herein. For example, the subject can be a patient with pain elicited from tissue injury, e.g., inflammation, infection, ischemia; pain associated with musculoskeletal disorders, e.g., joint pain; tooth pain; headaches, e.g., migrane; pain associated with surgery; pain related to inflammation, e.g., irritable bowel syndrome; or chest pain. The subject can be a patient with complex regional pain syndrome (CRPS), reflex sympathetic dystrophy (RSD), causalgia, neuralgia, central pain and dysesthesia syndrome, carotidynia, neurogenic pain, refractory cervicobrachial pain syndrome, myofascial pain syndrome, craniomandibular pain dysfunction syndrome, chronic idiopathic pain syndrome, Costen's pain-dysfunction, acute chest pain syndrome, gynecologic pain syndrome, patellofemoral pain syndrome, anterior knee pain syndrome, recurrent abdominal pain in children, colic, low back pain syndrome, neuropathic pain, phantom pain from amputation, phantom tooth pain, or pain asymbolia. The subject can be a cancer patient, e.g., a patient with brain cancer, bone cancer, or prostate cancer. In other embodiments, the subject is a non-human animal, e.g., an experimental animal, e.g., an arthritic rat model of chronic pain, a chronic constriction injury (CCI) rat model of neuropathic pain, or a rat model of unilateral inflammatory pain by intraplantar injection of complete Freund's adjuvant (CFA).

[0059] The contacting step(s) can be repeated.

[0060] In preferred embodiments, the agent is a peptide, a phosphopeptide, a small molecule, e.g., a member of a combinatorial library, or an antibody, or any combination thereof. The antibody can be conjugated to a therapeutic moiety selected from the group consisting of a cytotoxin, a cytotoxic agent and a radioactive metal ion.

[0061] In additional preferred embodiments, the agent is an antisense, a ribozyme, or a triple helix molecule, or a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid, or any combination thereof.

[0062] In a preferred embodiment, the agent is administered in combination with a cytotoxic agent.

[0063] The administration of the agent and/or protein can be repeated.

[0064] In still another aspect, the invention features a method for evaluating the efficacy of a treatment of a disorder, e.g., a disorder disclosed herein, in a subject. The method includes treating a subject with a protocol under evaluation; assessing the expression of a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide, such that a change in the level of 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide after treatment, relative to the level before treatment, is indicative of the efficacy of the treatment of the disorder.

[0065] In a preferred embodiment, the disorder is pain or a pain related disorder.

[0066] In a preferred embodiment, the subject is a human.

[0067] The invention also features a method of diagnosing a disorder, e.g., a disorder disclosed herein, in a subject. The method includes evaluating the expression or activity of a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or a 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide, such that, a difference in the level of 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or 1983, 52881, 2398, 45449, 50289, or 52872 polypeptide relative to a normal subject or a cohort of normal subjects is indicative of the disorder.

[0068] In a preferred embodiment, the disorder is a neurological disorder.

[0069] In a preferred embodiment, the disorder is pain or a pain related disorder.

[0070] In a preferred embodiment, the subject is a human.

[0071] In a preferred embodiment, the evaluating step occurs in vitro or ex vivo. For example, a sample, e.g., a blood sample, is obtained from the subject.

[0072] In a preferred embodiment, the evaluating step occurs in vivo. For example, by administering to the subject a detectably labeled agent that interacts with the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or polypeptide, such that a signal is generated relative to the level of activity or expression of the 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid or polypeptide.

[0073] In another aspect, the invention features a two dimensional array having a plurality of addresses, each address of the plurality being positionally distinguishable from each other address of the plurality, and each address of the plurality having a unique capture probe, e.g., a nucleic acid or peptide sequence. At least one address of the plurality has a capture probe that recognizes a 1983, 52881, 2398, 45449, 50289, or 52872 molecule. In one embodiment, the capture probe is a nucleic acid, e.g., a probe complementary to a 1983, 52881, 2398, 45449, 50289, or 52872 nucleic acid sequence. In another embodiment, the capture probe is a polypeptide, e.g., an antibody specific for 1983, 52881, 2398, 45449, 50289, or 52872 polypeptides. Also featured is a method of analyzing a sample by contacting the sample to the aforementioned array and detecting binding of the sample to the array.

[0074] Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0075] FIGS. 1A-1D depict a cDNA sequence (SEQ ID NO: 1) and predicted amino acid sequence (SEQ ID NO: 2) of human 1983. The methionine-initiated open reading frame of human 1983 (without the 5′ and 3′ untranslated regions) is shown as coding sequence SEQ ID NO: 3.

[0076] FIG. 2 depicts a hydropathy plot of human 1983 receptor. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The location of the transmembrane domains is also indicated. The cysteine residues (cys) and N-glycosylation sites (Ngly) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 1983 receptor are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 210-220, from about 290-300, and from about 365-375 of SEQ ID NO: 2; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 15-35, from about 195-205, and from about 275-285 of SEQ ID NO: 2; a sequence which includes a Cys, or a glycosylation site.

[0077] FIG. 3 depicts an alignment of the seven transmembrane (7 tm) domain of human 1983 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 19), while the lower amino acid sequence corresponds to amino acids 379 to 626 of SEQ ID NO: 2.

[0078] FIG. 4 depicts an alignment of the EGF-like domain of human 1983 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 20), while the lower amino acid sequence corresponds to amino acids 17 to 54 of SEQ ID NO: 2.

[0079] FIG. 5 depicts an alignment of the latrophilin/CL-1-like GPS domain of human 1983 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 21), while the lower amino acid sequence corresponds to amino acids 321 to 373 of SEQ ID NO: 2.

[0080] FIGS. 6A-6D depict a cDNA sequence (SEQ ID NO: 4) and predicted amino acid sequence (SEQ ID NO: 5) of human 52881. The methionine-initiated open reading frame of human 52881 (without the 5′ and 3′ untranslated regions) is shown as coding sequence SEQ ID NO: 6.

[0081] FIG. 7 depicts a hydropathy plot of human 52881. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The location of the transmembrane domains is also indicated. The cysteine residues (cys) and N-glycosylation sites (Ngly) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 52881 receptor are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 280-300, from about 420-430, and from about 495-505 of SEQ ID NO: 5; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 225-240, from about 475-490, and from about 540-555 of SEQ ID NO: 5; a sequence which includes a Cys, or a glycosylation site.

[0082] FIG. 8 depicts an alignment of the seven transmembrane (7 tm) domain of human 52881 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 22), while the lower amino acid sequence corresponds to amino acids 80 to 154 of SEQ ID NO: 5.

[0083] FIGS. 9A-9B depict a cDNA sequence (SEQ ID NO: 7) and predicted amino acid sequence (SEQ ID NO: 8) of human 2398. The methionine-initiated open reading frame of human 2398 (without the 5′ and 3′ untranslated regions) is shown as coding sequence SEQ ID NO: 9.

[0084] FIG. 10 depicts a hydropathy plot of human 2398. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The location of the transmembrane domains is also indicated. The cysteine residues (cys) and N-glycosylation sites (Ngly) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 2398 receptor are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 265-275 and from about 285-295 of SEQ ID NO: 8; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 1-25, from about 70-80, and from about 320-330 of SEQ ID NO: 8; a sequence which includes a Cys, or a glycosylation site.

[0085] FIG. 11 depicts an alignment of the seven transmembrane (7 tm) domain of human 2398 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 23), while the lower amino acid sequence corresponds to amino acids 58 to 303 of SEQ ID NO: 8.

[0086] FIGS. 12A-12B depict a cDNA sequence (SEQ ID NO: 10) and predicted amino acid sequence (SEQ ID NO: 11) of human 45449. The methionine-initiated open reading frame of human 45449 (without the 5′ and 3′ untranslated regions) is shown as coding sequence SEQ ID NO: 12.

[0087] FIG. 13 depicts a hydropathy plot of human 45449. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The location of the transmembrane domains are also indicated. The cysteine residues (cys) and N-glycosylation sites (Ngly) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 45449 receptor are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 160-170 of SEQ ID NO: 11; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 100-110 and from about 195-205 of SEQ ID NO: 11; a sequence which includes a Cys, or a glycosylation site.

[0088] FIG. 14 depicts an alignment of the seven transmembrane (7 tm) domain of human 45449 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 24), while the lower amino acid sequence corresponds to amino acids 1 to 176 of SEQ ID NO: 11.

[0089] FIGS. 15A-15E depict a cDNA sequence (SEQ ID NO: 13) and predicted amino acid sequence (SEQ ID NO: 14) of human 50289. The methionine-initiated open reading frame of human 50289 (without the 5′ and 3′ untranslated regions) is shown as coding sequence SEQ ID NO: 15.

[0090] FIG. 16 depicts a hydropathy plot of human 50289. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The location of the transmembrane domains is also indicated. The cysteine residues (cys) and N-glycosylation sites (Ngly) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 50289 receptor are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 70-80, from about 150-165, and from about 220-240 of SEQ ID NO: 14; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 50-60, from about 480-510, and from about 545-560 of SEQ ID NO: 14; a sequence which includes a Cys, or a glycosylation site.

[0091] FIG. 17 depicts an alignment of the ANF receptor ligand binding domain of human 50289 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 25), while the lower amino acid sequence corresponds to amino acids 61 to 470 of SEQ ID NO: 14.

[0092] FIGS. 18A-18B depict a cDNA sequence (SEQ ID NO: 16) and predicted amino acid sequence (SEQ ID NO: 17) of human 52872. The methionine-initiated open reading frame of human 52872 (without the 5′ and 3′ untranslated regions) is shown as coding sequence SEQ ID NO: 18.

[0093] FIG. 19 depicts a hydropathy plot of human 52872. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The cysteine residues (cys) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 52872 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 45-65, from about 165-180, and from about 210-225 of SEQ ID NO: 17; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 295-300, from about 345-360, and from about 370-380 of SEQ ID NO: 17; a sequence which includes a Cys, or a glycosylation site.

[0094] FIG. 20 depicts an alignment of the seven transmembrane receptor domain of human 52872 with a consensus amino acid sequence derived from a hidden Markov model (HMM) from PFAM. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 23), while the lower amino acid sequence corresponds to amino acids 59 to 323 of SEQ ID NO: 17.

[0095] FIG. 21 depicts relative 52872 mRNA levels in tissue samples derived from human adrenal gland, brain, heart, kidney, liver, lung, mammary gland, placenta, prostate, pituitary gland, muscle, small intestine, spleen, stomach, testes, thymus, trachea, uterus, spinal cord, skin, and dorsal root ganglion (DRG).

[0096] FIG. 22 depicts relative 52872 mRNA levels in tissue samples derived from human brain, spinal cord, heart, kidney, liver, lung, DRG, spinal cord, and skin.

[0097] FIG. 23 depicts relative 52872 mRNA levels in monkey tissue samples (cortex, DRG, spinal cord, sciatic nerve, kidney, hairy skin, heart, and liver) and in human tissue samples (brain, spinal cord, heart, kidney, liver, and lung).

[0098] FIG. 24 depicts the expression of 52872 in DRG following CFA injection, axotomy, and CCI at various days (D) following the treatment.

[0099] FIG. 25 depicts the expression of 52872 in spinal cord following CFA injection, axotomy, and CCI at various days (D) following the treatment.

[0100] FIG. 26 is a bar graph depicting relative 52881 expression as determined by hybridization on mRNA derived from the 293 cell line 293 (lane 1) and human umbilical vein endothelial cells (HUVEC) treated with: no added growth factors (lane 2); IL-1β (lane 3); or VEGF (lane 4). In lanes 5-7, HUVEC were plated and grown on Matrigel and expression was determined 2 hours after plating (lane 5), 6 hours after plating (lane 6), and 16 hours after plating (lane 7).

[0101] FIG. 27 depicts relative 1983 mRNA levels in normal and diseased tissue samples.

[0102] FIG. 28 depicts relative 1983 mRNA levels in normal human tissues.

[0103] FIG. 29 depicts relative 1983 mRNA levels in tissues and cell samples.

[0104] FIG. 30 depicts relative 1983 mRNA levels in mouse angiogenic tissues.

[0105] FIG. 31 depicts relative 1983 mRNA levels in an angiogenesis panel.

[0106] FIG. 32 depicts relative 1983 mRNA levels in the mouse hindlimb.

[0107] FIG. 33 depicts relative 2398 mRNA levels in tissues and cell samples.

[0108] FIG. 34 depicts relative 2398 mRNA levels in tissues and cell samples.

[0109] FIG. 35 depicts relative 45449 mRNA levels in tissues and cell samples.

[0110] FIG. 36 depicts relative 50289 mRNA levels in tissues and cell samples.

[0111] FIG. 37 depicts relative 50289 mRNA levels in tissues and cell samples.

[0112] FIG. 38 depicts relative 50289 mRNA levels in tissues and cell samples.

[0113] FIGS. 39A and 39B depicts a cDNA sequence (SEQ ID NO: 27) and predicted amino acid sequence (SEQ ID NO: 28) of human 44576 receptor. The methionine-initiated open reading frame of human 44576 (without the 5′ and 3′ untranslated regions) starts at nucleotide 316 until nucleotide 1437 of SEQ ID NO: 27 (shown also as coding sequence (SEQ ID NO: 29)

[0114] FIG. 40 depicts a hydropathy plot of human 44576 receptor. Relative hydrophobic residues are shown above the dashed horizontal line. The hydrophobic portions correspond to predicted transmembrane domains located at about 46 to 63, 79 to 102, 123 to 142, 151 to 173, 193 to 211, 230 to 254, and 264 to 280 of SEQ ID NO: 28. The relative hydrophilic residues are shown below the dashed horizontal line, e.g., about amino acids 210 to 230 and 300 to 310 of SEQ ID NO: 28. The location of the extracellular domain (e.g., about amino acids 1-45 of SEQ ID NO: 28), extracellular loops (e.g., about amino acids 103 to 122, 174 to 192, and 255 to 263 of SEQ ID NO: 28), intracellular (cytoplasmic) loops (e.g., about amino acids 64 to 78, 143 to 150, 212 to 229 of SEQ ID NO: 28), and the cytoplasmic domain (e.g., about amino acids 281 to 374 of SEQ ID NO: 28) is also indicated. The cysteine residues (cys) and N-glycosylation sites (Ngly) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 44576 receptor are indicated.

[0115] FIGS. 41A-41B are bar graphs depicting the expression of 44576 RNA relative to the indicated reference sample in a panel of human tissues or cells, including bone cells, fetal liver, bone marrow, trachea, skin, skeletal muscle, testis, detected using Taq Man analysis.

[0116] FIG. 42 depicts a hydropathy plot of human 65494. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. Numbers corresponding to positions in the amino acid sequence of human 65494 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 17 to 41, from about 51 to 75, and from about 126 to 146 of SEQ ID NO: 31; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 42 to 47, from about 76 to 80, and from about 305 to 310 of SEQ ID NO: 31.

[0117] FIG. 43 depicts an alignment of the transmembrane receptor (7 tm_—1) domain of human 65494 with a consensus amino acid sequence derived from a hidden Markov model (HMM) from PFAM. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 33), while the lower amino acid sequence corresponds to amino acids 31 to 250 of SEQ ID NO: 31.

[0118] FIGS. 44A-44C depicts a cDNA sequence (SEQ ID NO: 34) and predicted amino acid sequence (SEQ ID NO: 35) of human 20716. The methionine-initiated open reading frame of human 20716 (without the 5′ and 3′ untranslated regions) starts at nucleotide 89 of SEQ ID NO: 34 through nucleotide 1036 of SEQ ID NO: 34 (coding sequence is also shown in SEQ ID NO: 36).

[0119] FIG. 45 depicts a hydropathy plot of human 20716. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The cysteine residues (cys) are indicated by short vertical lines below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 20716 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence of residues 22-87 or 200-230 of SEQ ID NO: 35; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of residues 87-93 or 230-240 of SEQ ID NO: 35; a sequence which includes a Cys; or a glycosylation site.

[0120] FIG. 46 depicts an alignment of a seven transmembrane (7 tm) domain of human 20716 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 38), while the lower amino acid sequence corresponds to amino acids 42-293 of SEQ ID NO: 35 (SEQ ID NO: 37).

[0121] FIG. 47 depicts bar graphs demonstrating the expression of 20716 RNA relative to the indicated reference sample, detected using Taq Man analysis, in a panel of human tissues or cells, including peripheral blood mononuclear cells (PBMC), CD14⁺-expressing cells, (mobilized) peripheral blood leukocytes (mPB CD34⁺-expressing cells), bone marrow mononuclear cells (BM MNC), neutrophils, (normal) bone marrow (NBM) CD 15⁺/CD14⁻-expressing cells, (mobilized) bone marrow CD15⁺/CD11b⁻-expressing cells); and to a lesser extent, cells derived from the lung, kidney, brain, spleen, fetal liver, fibrotic liver (LF) and lymph nodes.

[0122] FIGS. 48A-48E depict a cDNA sequence (SEQ ID NO: 40) and predicted amino acid sequence (SEQ ID NO: 41) of human 22105. The methionine-initiated open reading frame of human 22105 (without the 5′ and 3′ untranslated regions) extends from nucleotide position 150 to position 3026 of SEQ ID NO: 40 (coding sequence shown in SEQ ID NO: 42).

[0123] FIG. 49 depicts a hydropathy plot of human 22105. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The cysteine residues (cys) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 22105 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 347 to 357, from about 585 to 595, and from about 755 to 765 of SEQ ID NO: 41; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 165 to 175, from about 830 to 850, and from about 920 to 930 of SEQ ID NO: 41; a sequence which includes a Cys, or a glycosylation site.

[0124] FIG. 50A depicts an alignment of the first thioredoxin domain of 22105 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 43), while the lower amino acid sequence corresponds to amino acids 119 to 165 of SEQ ID NO: 41.

[0125] FIG. 50B depicts an alignment of the second thioredoxin domain of 22105 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 44), while the lower amino acid sequence corresponds to amino acids 662 to 695 of SEQ ID NO: 41.

[0126] FIG. 51 depicts a hydropathy plot of human 22109. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. Numbers corresponding to positions in the amino acid sequence of human 22109 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 281 to 291 of SEQ ID NO: 46; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 90 to 120 of SEQ ID NO: 46.

[0127] FIG. 52A depicts an alignment of the DnaJ domain of human 22109 with a consensus amino acid sequence derived from a hidden Markov model (HMM) from PFAM. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 48), while the lower amino acid sequence corresponds to amino acids 35 to 100 of SEQ ID NO: 46.

[0128] FIG. 52B depicts an alignment of the thioredoxin domain of human 22109 with a consensus amino acid sequence derived from a hidden Markov model (HMM) from PFAM. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 49), while the lower amino acid sequence corresponds to amino acids 128 to 234 of SEQ ID NO: 46.

[0129] FIG. 53 depicts a hydropathy plot of human 22108. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The cysteine residues (Cys) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 22108 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 171 to 185 and from about 375 to 395 of SEQ ID NO: 51; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 31 to 45 and from about 275 to 295 of SEQ ID NO: 51; a sequence which includes a Cys, or a glycosylation site.

[0130] FIG. 54 depicts an alignment of the thioredoxin domain of human 22108 with a consensus amino acid sequence derived from a hidden Markov model (HMM) from PFAM. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 56), while the lower amino acid sequence corresponds to amino acids 24 to 131 of SEQ ID NO: 51.

[0131] FIG. 55 depicts a hydropathy plot of human 47916. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The cysteine residues (Cys) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 47916 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 450 to 460 of SEQ ID NO: 54; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 10 to 90, from about 110 to 140, and from about 280 to 320 of SEQ ID NO: 54; a sequence which includes a Cys, or a glycosylation site.

[0132] FIG. 56 depicts an alignment of the thioredoxin domain of human 47916 with a consensus amino acid sequence derived from a hidden Markov model (HMM) from PFAM. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 57), while the lower amino acid sequence corresponds to amino acids 381 to 484 of SEQ ID NO: 54.

[0133] FIGS. 57A and 57B depicts a cDNA sequence (SEQ ID NO: 60) and predicted amino acid sequence (SEQ ID NO: 61) of human 33395. The methionine-initiated open reading frame of human 33395 (without the 5′ and 3′ untranslated regions) until the end of SEQ ID NO: 60 is shown also as coding sequence SEQ ID NO: 62.

[0134] FIG. 58 depicts a hydropathy plot of human 33395. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The cysteine residues (cys) are indicated by short vertical lines just below the hydropathy trace. The numbers corresponding to the amino acid sequence of human 33395 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about residue 40 to about residue 60 of SEQ ID NO: 61, or from about residue 535 to about residue 559 of SEQ ID NO: 61; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about 370 to about 400; other fragments include a sequence which includes a Cys, or a glycosylation site.

[0135] FIGS. 59A, 59B-1, and 59B-2 depict an alignment of the LRR domains, N-terminal LRR (LRRNT) domain, and C-terminal LRR (LRRCT) domain of human 33395 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequences are the consensus amino acid sequence (SEQ ID NOs: 65-71), while the lower amino acid sequence corresponds to amino acids 27-58, 60-83, 84-107, 108-131, 132-155, 157-180, 181-204, 205-228 or 249-294 of SEQ ID NO: 61.

[0136] FIGS. 60A and 60B depict an alignment of the immunoglobulin (Ig) domain of human 33395 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NOs: 72-74), while the lower amino acid sequence corresponds to amino acids 310-368 of SEQ ID NO: 61.

[0137] FIGS. 61A and 61B depict an alignment of the fibronectin III (fn3) domain of human 33395 with a consensus amino acid sequence derived from a hidden Markov model. The upper sequence is the consensus amino acid sequence (SEQ ID NOs: 75-76), while the lower amino acid sequence corresponds to amino acids 425-505 of SEQ ID NO: 61.

[0138] FIG. 62 depicts a series of plots summarizing an analysis of the primary and secondary protein structure of human 33395. The particular algorithm used for each plot is indicated at the right hand side of each plot. The following plots are depicted: Gamier-Robson plots providing the predicted location of alpha-, beta-, turn and coil regions (Gamier et al. (1978) J. Mol. Biol. 120:97); Chou-Fasman plots providing the predicted location of alpha-, beta-, turn and coil regions (Chou and Fasman (1978) Adv. In Enzymol. Mol. 47:45-148); Kyte-Doolittle hydrophilicity/hydrophobicity plots (Kyte and Doolittle (1982) J. Mol. Biol. 157:105-132); Eisenberg plots providing the predicted location of alpha- and beta-amphipathic regions (Eisenberg et al. (1982) Nature 299:371-374); a Karplus-Schultz plot providing the predicted location of flexible regions (Karplus and Schulz (1985) Naturwissens-Chafen 72:212-213); a plot of the antigenic index (Jameson-Wolf) (Jameson and Wolf (1988) CABIOS 4:121-136); and a surface probability plot (Emini algorithm) (Emini et al. (1985) J. Virol. 55:836-839). The numbers corresponding to the amino acid sequence of human 33395 are indicated. Polypeptide fragments of the invention include polypeptides which have all or part of any of the regions described in this figure. Also included are variants having a mutation in a selected region shown in this figure.

[0139] FIG. 63 is a bar graph of 33395 expression in (1) Prostate, (2) Osteoclasts, (3) Liver, (4) Liver, (5) Breast, (6) Breast, (7) Skeletal. Muscle, (8) Skeletal. Muscle, (9) Brain, (10) Brain, (11) Colon, (12) Colon, (13) Heart, (14) Heart, (15) Ovary, (16) Ovary, (17) Kidney, (18) Kidney, (19) Lung, (20) Lung, (21) Vein, (22) Vein, (23) Trachea, (24) Adipose, (25) Adipose, (26) Small Intestine, (27) Thyroid, (28) Thyroid, (29) Skin, (30) Skin, (31) Testis, (32) Placenta, (33) Fetal liver, (34) Fetal Liver, (35) Fetal Heart, (36) Fetal Heart, (37) Undifferentiated Osteoblasts, (38) Differentiated Osteoblasts, (39) Primary Culture Osteoblasts, (40) Fetal Spin Cord, (41) Cervix, (42) Spleen, (43) Spinal Cord, (44) Thymus, (45) Tonsil, and (46) Lymph node. For example, 33395 mRNA is particularly abundant in skeletal muscle, brain, trachea, testes, fetal liver, and undifferentiated osteoblasts.

[0140] FIG. 64 is a bar graph of 33395 expression in human and monkey cardiovascular tissues: (1-3) monkey normal aorta; (4) human diseased aorta; (5) human normal aorta cell line; (6) monkey aorta normal; (7-8) human; (9) monkey normal coronary artery; (10) human normal coronary artery; (11-12) monkey saph. vein; and (13-16) human normal saph. vein.

[0141] FIGS. 65A-65D depict a cDNA sequence (SEQ ID NO: 77) and predicted amino acid sequence (SEQ ID NO: 78) of human 31939. The methionine-initiated open reading frame of human 31939 (without the 5′ and 3′ untranslated regions) starts at nucleotide 187 and goes to nucleotide 2328 of SEQ ID NO: 77 (shown also as coding sequence SEQ ID NO: 79.

[0142] FIG. 66 depicts a hydropathy plot of human 31939. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. The numbers corresponding to the amino acid sequence of human 31939 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about residue 19 to 38, 570 to 595, and 624 to 644 of SEQ ID NO: 78; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about residue 19 to 38, 570 to 595, and 624 to 644 of SEQ ID NO: 78.

[0143] FIG. 67 depicts an alignment of the LRR domains, N-terminal LRR (LRRNT) domain, and C-terminal LRR (LRRCT) domain of human 31939 with consensus amino acid sequenced derived from a Hidden Markov Models (PFAM Accession PF01462; PFAM Accession PF00560; and PFAM Accession PF01463). The upper sequences are the consensus amino acid sequences (SEQ ID NO: 80 for LRRNT, SEQ ID NO: 81 for LRR, and SEQ ID NO: 82 for LRRCT, while the lower amino acid sequence corresponds to amino acids 56 to 85, 87 to 110, 111 to 134, 135 to 158, 159 to 182, 183 to 207, 208 to 229, 230 to 253, 254 to 277, 278 to 301, and 311 to 362 of SEQ ID NO: 78.

[0144] FIGS. 68A and 68B depict an alignment of the immunoglobulin (Ig) domain of human 31939 with a consensus amino acid sequence derived from a Hidden Markov Model (see, e.g., PFAM Accession PF00047 for FIG. 68A). The upper sequence is the consensus amino acid sequence (in FIG. 68A, SEQ ID NO: 83; in FIG. 68B, SEQ ID NO: 84 for igv1_—8, SEQ ID NO: 85 for igc2_—5, and SEQ ID NO: 86 for IG_—3c), while the lower amino acid sequence corresponds to amino acids 378 to 438 of SEQ ID NO: 78 (FIG. 68A), 380-438, 376 to 443, and 370 to 454 of SEQ ID NO: 78 (FIG. 68B alignments, respectively).

[0145] FIG. 69 depicts a hydropathy plot of human 84241. Relative hydrophobic residues are shown above the dashed horizontal line, and relative hydrophilic residues are below the dashed horizontal line. Numbers corresponding to positions in the amino acid sequence of human 84241 are indicated. Polypeptides of the invention include fragments which include: all or part of a hydrophobic sequence, i.e., a sequence above the dashed line, e.g., the sequence from about amino acid 69 to 75, from about 96 to 103, and from about 138 to 144, of SEQ ID NO: 88; all or part of a hydrophilic sequence, i.e., a sequence below the dashed line, e.g., the sequence of from about amino acid 17 to 27, from about 38 to 46, and from about 156 to 166, of SEQ ID NO: 88; a sequence which includes a Cys, or a glycosylation site.

[0146] FIG. 70 depicts an alignment of the IBR domain domain of human 84241 with a consensus amino acid sequence derived from a hidden Markov model (HMM) from PFAM. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 90), while the lower amino acid sequence corresponds to amino acids 148 to 213 of SEQ ID NO: 88.

[0147] FIG. 71A depicts an alignment of the first RING finger domain of human 84241 with a consensus amino acid sequence derived from a hidden Markov model (HMM) from SMART. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 91), while the lower amino acid sequence corresponds to amino acids 77 to 126 of SEQ ID NO: 88.

[0148] FIG. 71B depicts an alignment of the second RING finger domain of human 84241 with a consensus amino acid sequence derived from a hidden Markov model (HMM) from SMART. The upper sequence is the consensus amino acid sequence (SEQ ID NO: 91), while the lower amino acid sequence corresponds to amino acids 177 to 243 of SEQ ID NO: 88.

DETAILED DESCRIPTION OF THE INVENTION FOR 1983, 52881, 2398, 45449, 50289 OR 52872 HUMAN 1983

[0149] The human 1983 nucleotide sequence (FIGS. 1A-1D; SEQ ID NO: 1), which is approximately 3127 nucleotides long including untranslated regions, contains a predicted methionine-initiated coding sequence of about 1938 nucleotides, including the termination codon (nucleotides indicated as coding of SEQ ID NO: 1 in FIGS. 1A-1D; SEQ ID NO: 3). The coding sequence encodes a 645 amino acid protein (FIG. 2; SEQ ID NO: 2).

[0150] The human 1983 protein contains a predicted seven transmembrane (7 TM) domain located at about amino acids 379 to 626 of SEQ ID NO: 2 (FIG. 3). Human 1983 additionally includes a predicted extracellular domain which extends from about amino acid 1 to about amino acid 387 of SEQ ID NO: 2. The extracellular domain of the 1983 protein includes an EGF-like domain located at about amino acids 17-54 of SEQ ID NO: 2 (FIG. 4). The extracellular domain of the 1983 protein additionally includes a latrophilin CL-1-like GPS domain located at about amino acids 321-373 of SEQ ID NO: 2 (FIG. 5).

[0151] The seven transmembrane domain of the 1983 protein shows homology to members of the secretin family. Predicted transmembrane domains extend from about amino acid 388 (extracellular end) to about amino acid 407 (cytoplasmic end) of SEQ ID NO: 2; from about amino acid 420 (cytoplasmic end) to about amino acid 436 (extracellular end) of SEQ ID NO: 2; from about amino acid 455 (extracellular end) to about amino acid 479 (cytoplasmic end) of SEQ ID NO: 2; from about amino acid 488 (cytoplasmic end) to about amino acid 508 (extracellular end) of SEQ ID NO: 2; from about amino acid 525 (extracellular end) to about amino acid 549 (cytoplasmic end) of SEQ ID NO: 2; from about amino acid 574 (cytoplasmic end) to about amino acid 591 (extracellular end) of SEQ ID NO: 2; and from about amino acid 598 (extracellular end) to about amino acid 622 (cytoplasmic end) of SEQ ID NO: 2; three cytoplasmic loops are located at about amino acids 408-419, 480-487 and 550-573 of SEQ ID NO: 2; three extracellular loops are located at about amino acid 437-454, 509-524 and 590-597 of SEQ ID NO: 2; and a C-terminal cytoplasmic domain is located at about amino acid residues 623-645 of SEQ ID NO: 2.

[0152] The 1983 receptor protein additionally contains one predicted EF-hand calcium binding domain (PS00018) from about amino acids 108-120 of SEQ ID NO: 2; ten predicted protein kinase C phosphorylation sites (PS00005) from about amino acids 90-92, 136-138, 188-190, 313-315, 318-320, 355-357, 412-414, 440-442, 513-515, and 623-625 of SEQ ID NO: 2; fifteen predicted casein kinase II phosphorylation sites (PS00006) from about amino acids acids 9-12, 23-26, 31-34, 49-52, 90-93, 105-108, 110-113, 116-119, 136-139, 145-148, 199-202, 265-268, 280-283, 301-304, and 563-566 of SEQ ID NO: 2; seven predicted N-myristoylation sites (PS00008) from about amino acids 5-10, 35-40, 337-342, 343-348, 389-394, 435-440, and 476-481 of SEQ ID NO: 2; eight predicted N-glycosylation sites (PS00001) from about amino acids 19-22, 29-32, 82-85, 132-135, 143-146, 204-207, 336-339, and 350-353 of SEQ ID NO: 2; one predicted glycosaminoglycan attachment site (PS00002) from about amino acid 4-7 of SEQ ID NO: 2; one predicted cAMP/cGMP phosporylation site (PS00004) located at about amino acid 315-318 of SEQ ID NO: 2; one tyrosine kinase phosphorylation site (PS00007) located at about amino acid 624-631 of SEQ ID NO: 2; and one aspartic acid and asparagine hydroxylation site (PS00010) located at about amino acid 30-41 of SEQ ID NO: 2.

[0153] A plasmid containing the nucleotide sequence encoding human 1983 (clone Fbh1983FL) was deposited with American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Va. 20110-2209, on ______ and assigned Accession Number ______. This deposit will be maintained under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. This deposit was made merely as a convenience for those of skill in the art and is not an admission that a deposit is required under 35 U.S.C. §112.

[0154] For general information regarding PFAM identifiers, PS prefix and PF prefix domain identification numbers, refer to Sonnhammer et al. (1997) Protein 28:405-420 and http://www.psc.edu/general/software/packages/pfam/pfam.html.

[0155] Human 52881

[0156] The human 52881 sequence (FIGS. 6A-6D; SEQ ID NO: 4), which is approximately 4238 nucleotides long including untranslated regions, contains a predicted methionine-initiated coding sequence of about 1830 nucleotides, including the termination codon (nucleotides indicated as coding of SEQ ID NO: 4 in FIGS. 6A-6D; SEQ ID NO: 6). The coding sequence encodes a 609 amino acid protein (FIG. 7; SEQ ID NO: 5).

[0157] The 52881 protein contains a predicted seven transmembrane (7 TM) domain located at about amino acids 80 to 154 of SEQ ID NO: 5 (FIG. 8). The seven transmembrane domain shows homology to members of the rhodopsin family. Predicted transmembrane domains extend from about amino acids 11-34, 44-67, 85-106, 127-149, 172-196, and 245-269 of SEQ ID NO: 5 (FIG. 2). Predicted non-transmembrane domains extend from about amino acids 1-10, 35-43, 68-84, 107-126, 150-171, 197-244, and 270-609 of SEQ ID NO: 5.

[0158] The 52881 protein additionally contains: four predicted cAMP/cGMP phosporylation sites (PS00004) located at about amino acids 225-228, 393-396, 436-439, and 453-456 of SEQ ID NO: 5; six predicted protein kinase C phosphorylation sites (PS00005) located at about amino acids 153-155, 268-270, 392-394, 462-464, 482-484, and 560-562 of SEQ ID NO: 5; 10 predicted casein kinase II phosphorylation sites (PS00006) located at about amino acids 228-231, 324-327, 328-331, 364-367, 396-399, 417-420, 466-469, 506-509, 568-571, and 590-593 of SEQ ID NO: 5; one predicted tyrosine kinase phosphorylation site (PS00007) located at about amino acids 342-348 of SEQ ID NO: 5; 10 predicted N-myristoylation sites (PS00008) located at about amino acids 9-14, 169-174, 181-186, 187-192, 232-237, 244-249, 531-536, 564-569, 573-578 and 579-584 of SEQ ID NO: 5; and one predicted amidation site (PS00009) from about amino acids 223-226 of SEQ ID NO: 5.

[0159] A plasmid containing the nucleotide sequence encoding human 52881 (clone Fbh52881FL) was deposited with American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Va. 20110-2209, on ______ and assigned Accession Number ______. This deposit will be maintained under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. This deposit was made merely as a convenience for those of skill in the art and is not an admission that a deposit is required under 35 U.S.C. §112.

[0160] Human 2398

[0161] The human 2398 nucleotide sequence (FIGS. 9A-9B; SEQ ID NO: 7), which is approximately 1113 nucleotides long including untranslated regions, contains a predicted methionine-initiated coding sequence of about 1053 nucleotides, including the termination codon (nucleotides indicated as coding of SEQ ID NO: 7 in FIGS. 9A-9B; SEQ ID NO: 9). The coding sequence encodes a 350 amino acid protein (FIG. 10; SEQ ID NO: 8). The 2398 protein contains a G-protein receptor signature (PS00237) located at about amino acids 125-141 of SEQ ID NO: 8. The 2398 protein also includes a predicted seven transmembrane (7 TM) domain located at about amino acids 58 to 303 of SEQ ID NO: 8 (FIG. 11). The seven transmembrane domain shows homology to members of the rhodopsin family. An extracellular domain extends from about amino acids 1-41 of SEQ ID NO: 8. Predicted transmembrane domains (FIG. 10) extend from about amino acid 42 (extracellular end) to about amino acid 66 (cytoplasmic end) of SEQ ID NO: 8; from about amino acid 78 (cytoplasmic end) to about amino acid 99 (extracellular end) of SEQ ID NO: 8; from about amino acid 114 (extracellular end) to about amino acid 135 (cytoplasmic end) of SEQ ID NO: 8; from about amino acid 154 (cytoplasmic end) to about amino acid 176 (extracellular end) of SEQ ID NO: 8; from about amino acid 202 (extracellular end) to about amino acid 224 (cytoplasmic end) of SEQ ID NO: 8; from about amino acid 241 (cytoplasmic end) to about amino acid 259 (extracellular end) of SEQ ID NO: 8; and from about amino acid 291 (extracellular end) to about amino acid 310 (cytoplasmic end) of SEQ ID NO: 8; three cytoplasmic loops are located at about amino acids 67-77, 136-153, and 225-240 of SEQ ID NO: 8; three extracellular loops are located at about amino acid 100-113, 177-201, and 260-290 of SEQ ID NO: 8; and a C-terminal cytoplasmic domain is located at about amino acid residues 311-350 of SEQ ID NO: 8.

[0162] The 2398 receptor protein additionally contains five predicted protein kinase C phosphorylation sites (PS00005) from about amino acids 195-197, 223-225, 278-280, 309-311 and 323-325 of SEQ ID NO: 8; four predicted casein kinase II phosphorylation sites (PS00006) from about amino acids 25-28, 74-77, 177-180, and 330-333 of SEQ ID NO: 8; one predicted glycosaminoglycan attachment site (PS00002) located at about amino acids 148-151 of SEQ ID NO: 8; one predicted N-myristoylation site (PS00008) from about amino acids 55-60 of SEQ ID NO: 8; and one tyrosine kinase phosphorylation site (PS00007) located at about amino acid 263-269 of SEQ ID NO: 8.

[0163] A plasmid containing the nucleotide sequence encoding human 2398 (clone Fbh2398FL) was deposited with American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Va. 20110-2209, on ______ and assigned Accession Number ______. This deposit will be maintained under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. This deposit was made merely as a convenience for those of skill in the art and is not an admission that a deposit is required under 35 U.S.C. §112.

[0164] Human 45449

[0165] The human 45449 nucleotide sequence (FIGS. 12A-12B; SEQ ID NO: 10), which is approximately 1109 nucleotides long including untranslated regions, contains a predicted methionine-initiated coding sequence of about 672 nucleotides, including the termination codon (nucleotides indicated as coding of SEQ ID NO: 10 in FIGS. 12A-12B; SEQ ID NO: 12). The coding sequence encodes a 223 amino acid protein (FIG. 13; SEQ ID NO: 11).

[0166] The 45449 protein contains a predicted seven transmembrane (7 TM) domain located at about amino acids 1 to 176 of SEQ ID NO: 11 (FIG. 14). The seven transmembrane domain shows homology to members of the rhodopsin family. An N-terminal domain extends from about amino acids 1-11 of SEQ ID NO: 11. Predicted transmembrane domains (FIG. 13) extend from about amino acid 12-33, 68-90, and 123-147 of SEQ ID NO: 11. Predicted non-transmembrane domains extend from about amino acids 91-122 and 34-67 of SEQ ID NO: 11. A C-terminal domain is located at about amino acid residues 148-324 of SEQ ID NO: 11.

[0167] The 45449 receptor protein additionally contains: one predicted opsin retinal binding site located at about amino acids 165-183 of SEQ ID NO: 11; three predicted protein kinase C phosphorylation sites (PS00005) from about amino acids 99-101, 194-196, and 209-211 of SEQ ID NO: 11; one predicted casein kinase II phosphorylation sites (PS00006) from about amino acid 99-102 of SEQ ID NO: 11; two predicted N-myristoylation sites (PS00008) from about amino acids 50-55 and 189-194 of SEQ ID NO: 11; and two predicted cAMP/cGMP dependent protein kinase phosphorylation site located at about amino acids 195-198 and 211-214 of SEQ ID NO: 11.

[0168] A plasmid containing the nucleotide sequence encoding human 45449 (clone Fbh45449FL) was deposited with American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Va. 20110-2209, on ______ and assigned Accession Number ______. This deposit will be maintained under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. This deposit was made merely as a convenience for those of skill in the art and is not an admission that a deposit is required under 35 U.S.C. §112.

[0169] Human 50289

[0170] The human 50289 nucleotide sequence (FIGS. 15A-15E; SEQ ID NO: 13), which is approximately 3489 nucleotides long including untranslated regions, contains a predicted methionine-initiated coding sequence of about 2559 nucleotides, including the termination codon (nucleotides indicated as coding of SEQ ID NO: 13 in FIGS. 15A-15E; SEQ ID NO: 15). The coding sequence encodes a 852 amino acid protein (FIG. 16; SEQ ID NO: 14).

[0171] The mature protein is approximately 832 amino acid residues in length (from about amino acid 21 to amino acid 852 of SEQ ID NO: 14). The mature 50289 protein contains a natriuretic peptide (ANF) ligand binding domain located at about amino acids 61 to 470 of SEQ ID NO: 14 (FIG. 17). The ANF domain is located at the extracellular domain of the human 50289, which extends from about amino acid 1-546 of SEQ ID NO: 14. Predicted transmembrane domains (FIG. 16) extend from about amino acid 567 (extracellular end) to about amino acid 590 (cytoplasmic end) of SEQ ID NO: 14; from about amino acid 600 (cytoplasmic end) to about amino acid 623 (extracellular end) of SEQ ID NO: 14; from about amino acid 641 (extracellular end) to about amino acid 659 (cytoplasmic end) of SEQ ID NO: 14; from about amino acid 679 (cytoplasmic end) to about amino acid 702 (extracellular end) of SEQ ID NO: 14; from about amino acid 726 (extracellular end) to about amino acid 750 (cytoplasmic end) of SEQ ID NO: 14; from about amino acid 762 (cytoplasmic end) to about amino acid 782 (extracellular end) of SEQ ID NO: 14; and from about amino acid 799 (extracellular end) to about amino acid 810 (cytoplasmic end) of SEQ ID NO: 14; three extracellular loops located at about amino acids 624-640, 703-678, and 751-761 of SEQ ID NO: 14; three cytoplasmic loops located at about amino acid 591-599, 660-678, and 703-725 of SEQ ID NO: 14; and a C-terminal cytoplasmic domain is found at about amino acid residues 811-851 of SEQ ID NO: 14.

[0172] The 50289 receptor protein additionally contains: one GPCR family 3 signature 2 domain located at about amino acids 516-540 of SEQ ID NO: 14; nine predicted glycosylation sites located at about amino acids 85-88, 130-133, 264-267, 285-288, 380-383, 411-414, 432-435, 474-478, and 736-739 of SEQ ID NO: 14; nine predicted protein kinase C phosphorylation sites (PS00005) from about amino acids 153-155, 175-177, 189-191, 289-291, 293-295, 477-479, 480-482, 527-529 and 550-552 of SEQ ID NO: 14; three predicted casein kinase II phosphorylation sites (PS00006) from about amino acid 102-105, 175-178, and 214-217 of SEQ ID NO: 14; fourteen predicted N-myristoylation sites (PS00008) from about amino acids 20-25, 69-74, 92-97, 234-239, 319-324, 476-481, 580-585, 602-607, 645-650, 730-735, 762-767, 803-808, 830-835, and 838-843 of SEQ ID NO: 14; and one predicted cAMP/cGMP dependent protein kinase phosphorylation site located at about amino acids 555-558 of SEQ ID NO: 14.

[0173] A plasmid containing the nucleotide sequence encoding human 50289 (clone Fbh50289FL) was deposited with American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Va. 20110-2209, on ______ and assigned Accession Number ______. This deposit will be maintained under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. This deposit was made merely as a convenience for those of skill in the art and is not an admission that a deposit is required under 35 U.S.C. §112.

[0174] Human 52872

[0175] The human 52872 sequence (FIGS. 18A-18B; SEQ ID NO: 16), which is approximately 1609 nucleotides long including untranslated regions, contains a predicted methionine-initiated coding sequence of about 1197 nucleotides, including the termination codon (nucleotides indicated as coding of SEQ ID NO: 16 in FIGS. 18A-18B; SEQ ID NO: 18). The coding sequence encodes a 398 amino acid protein (FIG. 19; SEQ ID NO: 17).

[0176] The 52872 protein contains a predicted seven transmembrane (7 TM) domain (PFAM Accession Number PF00001) located at about amino acids 59 to 323 of SEQ ID NO: 17 (FIG. 20). The seven transmembrane domain shows homology to members of the rhodopsin family. An extracellular domain extends from about amino acids 1-42 of SEQ ID NO: 17. Predicted transmembrane domains extend from about amino acid 43 (extracellular end) to about amino acid 67 (cytoplasmic end) of SEQ ID NO: 17; from about amino acid 76 (cytoplasmic end) to about amino acid 110 (extracellular end) of SEQ ID NO: 17; from about amino acid 117 (extracellular end) to about amino acid 136 (cytoplasmic end) of SEQ ID NO: 17; from about amino acid 158 (cytoplasmic end) to about amino acid 180 (extracellular end) of SEQ ID NO: 17; from about amino acid 204 (extracellular end) to about amino acid 228 (cytoplasmic end) of SEQ ID NO: 17; from about amino acid 264 (cytoplasmic end) to about amino acid 285 (extracellular end) of SEQ ID NO: 17; and from about amino acid 310 (extracellular end) to about amino acid 326 (cytoplasmic end) of SEQ ID NO: 17; three cytoplasmic loops at about amino acids 68-75, 137-157, and 229-263 of SEQ ID NO: 17; three extracellular loops at about amino acid 111-116, 181-203, and 286-309 of SEQ ID NO: 17; and a C-terminal cytoplasmic domain at about amino acid residues 327-398 of SEQ ID NO: 17.

[0177] The 52872 receptor protein additionally contains: three predicted N-glycosylation sites (PS00001) from about amino acids 10-13, 18-21, and 28-31 of SEQ ID NO: 17; two predicted protein Kinase C phosphorylation sites (PS00005) at about amino acids 36-38 and 155-157 of SEQ ID NO: 17; and five predicted N-myristylation sites (PS00008) from about 14-19, 21-26, 56-61, 247-252, and 255-260 of SEQ ID NO: 17.

[0178] A plasmid containing the nucleotide sequence encoding human 52872 (clone Fbh52872FL) was deposited with American Type Culture Collection (ATCC), 10801 University Boulevard, Manassas, Va. 20110-2209, on ______ and assigned Accession Number ______. This deposit will be maintained under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. This deposit was made merely as a convenience for those of skill in the art is not an admission that a deposit is required under 35 U.S.C. §112. 1

TABLE 1
Summary of Sequence Information for GPCR Polypeptides

Gene	cDNA	Polypeptide	ORF	FIGURE

1983	SEQ ID NO:1	SEQ ID NO:2	SEQ ID NO:3
52881	SEQ ID NO:4	SEQ ID NO:5	SEQ ID NO:6
2398	SEQ ID NO:7	SEQ ID NO:8	SEQ ID NO:9
45449	SEQ ID NO:10	SEQ ID NO:11	SEQ ID NO:12
50289	SEQ ID NO:13	SEQ ID NO:14	SEQ ID NO:15
52872	SEQ ID NO:16	SEQ ID NO:17	SEQ ID NO:18	FIGS. 18A-18B

[0179] The 1983, 52881, 2398, 45449, 50289, and 52872 proteins contains a significant number of structural characteristics in common with members of the G protein-coupled receptor family. The term “family” when referring to the protein and nucleic acid molecules of the invention means two or more proteins or nucleic acid molecules having a common structural domain or motif and having sufficient amino acid or nucleotide sequence homology as defined herein. Such family members can be naturally or non-naturally occurring and can be from either the same or different species. For example, a family can contain a first protein of human origin as well as other distinct proteins of human origin, or alternatively, can contain homologues of non-human origin, e.g., rat or mouse proteins. Members of a family can also have common functional characteristics.

[0180] The G-protein coupled receptor family of proteins is an extensive group of proteins, which transduce extracellular signals triggered by, e.g., hormones, neurotransmitters, odorants and light, by interaction with guanine nucleotide-binding (G) proteins. G-protein coupled receptors typically have seven hydrophobic membrane spanning regions. The N-terminus of a G-protein coupled receptor is typically located on the extracellular side of the membrane and is often glycosylated, while the C-terminus is cytoplasmic and generally phosphorylated. Three extracellular loops alternate with three intracellular loops to link the seven transmembrane regions. Some G-protein coupled receptors possess a signal peptide. Generally, the most conserved portions of G-protein coupled receptors are the transmembrane regions and the first two cytoplasmic loops. A conserved acidic-arginine-aromatic triplet is present in the N-terminal extremity of the second cytoplasmic loop and may be implicated in the interaction with G proteins. An alignment of the transmembrane domains of 44 representative GPCRs can be found at <http://mgdkk1.nidll.nih.gov:8000/extended.html>.

[0181] Based on structural similarities, members of the GPCR family have been classified into various subfamilies, including: Subfamily I, which comprises receptors typified by rhodopsin and the beta2-adrenergic receptor and currently contains over 200 unique members (reviewed by Dohlman et al. (1991) Annu. Rev. Biochem. 60:653-688); Subfamily II, which includes the parathyroid hormone/calcitonin/secretin receptor family (Juppner et al. (1991) Science 254:1024-1026; Lin et al. (1991) Science 254:1022-1024); Subfamily III, which includes the metabotropic glutamate receptor family in mammals, such as the GABA receptors (Nakanishi et al. (1992) Science 258: 597-603); Subfamily IV, which includes the cAMP receptor family that is known to mediate the chemotaxis and development of D. discoideum (Klein et al. (1988) Science 241:1467-1472); and Subfamily V, which includes the fungal mating pheromone receptors such as STE2 (reviewed by Kujan I et al. (1992) Annu. Rev. Biochem. 61:1097-1129). Within each family, distinct, highly conserved motifs have been identified. These motifs have been suggested to be critical for the structural integrity of the receptor, as well as for coupling to G proteins.

[0182] Based upon the results of the HMM analysis (HMMER Version 2.1.1), the 52881, 2398, 45449, and 52872 polypeptides appear to belong to the rhodopsin subfamily of GPCRs (Subfamily I). 1983 appears to belong to the secretin subfamily of GPCRs (Subfamily II).

[0183] A 52881, 2398, 45449 or 52872 polypeptide can include a “rhodopsin-related seven transmembrane receptor domain” or regions homologous with a “rhodopsin-related seven transmembrane receptor domain”.

[0184] As used herein, the term “rhodopsin-related seven transmembrane receptor domain” includes an amino acid sequence of about 40-300 amino acid residues in length and having a bit score for the alignment of the sequence to the rhodopsin-related seven transmembrane receptor domain (HMM) of at least 15 or greater. Preferably, the rhodopsin-related seven transmembrane receptor domain includes an amino acid sequence which is about 50-280 amino acids, more preferably about 70-270 amino acids in length, and has a bit score for the alignment of the sequence to the rhodopsin-related seven transmembrane receptor domain (HMM) of at least 20 or greater, preferably 30 or greater. A 52881 protein preferably contains an amino acid sequence of about 75 amino acid residues in length, having a bit score for the alignment of the sequence to the rhodopsin-related seven transmembrane receptor domain at least 30. A 2398 protein preferably contains an amino acid sequence of about 246 amino acid residues in length, having a bit score for the alignment of the sequence to the rhodopsin-related seven transmembrane receptor domain at least 260. A 45449 protein preferably contains an amino acid sequence of about 176 amino acid residues in length, having a bit score for the alignment of the sequence to the rhodopsin-related seven transmembrane receptor domain at least 50. A 52872 protein preferably contains an amino acid sequence of about 265 amino acid residues in length, having a bit score for the alignment of the sequence to the rhodopsin-related seven transmembrane receptor domain at least 220.

What is claimed is:

1. An isolated nucleic acid molecule selected from the group consisting of: a) a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 1, 3, 7, 9, 10, 12, 13, 15, 16, 18, 27, 29, 30, 32, 34, 36, 40, 42, 45, 47, 50, 52, 53, 55, 60, 62, 77, 79, 87, or 89; and b) a nucleic acid molecule which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO: 2, 8, 11, 14, 17, 28, 31, 35, 41, 46, 51, 54, 61, 78, or 88.

2. The nucleic acid molecule of claim 1, further comprising vector nucleic acid sequences.

3. The nucleic acid molecule of claim 1, further comprising nucleic acid sequences encoding a heterologous polypeptide.

4. A host cell which contains the nucleic acid molecule of claim 1.

5. An isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 2, 8, 11, 14, 17, 28, 31, 35, 41, 46, 51, 54, 61, 78, or 88.

6. The polypeptide of claim 5 further comprising heterologous amino acid sequences.

7. An antibody or antigen-binding fragment thereof that selectively binds to a polypeptide of claim 5.

8. A method for producing a polypeptide comprising the amino acid sequence of SEQ ID NO: 2, 8, 11, 14, 17, 28, 31, 35, 41, 46, 51, 54, 61, 78, or 88, the method comprising culturing the host cell of claim 4 under conditions in which the nucleic acid molecule is expressed.

9. A method for detecting the presence of a polypeptide of claim 5 in a sample, comprising: a) contacting the sample with a compound which selectively binds to a polypeptide of claim 8; and b) determining whether the compound binds to the polypeptide in the sample.

10. The method of claim 9, wherein the compound which binds to the polypeptide is an antibody.

11. A kit comprising a compound which selectively binds to a polypeptide of claim 5 and instructions for use.

12. A method for detecting the presence of a nucleic acid molecule of claim 1 in a sample, comprising the steps of: a) contacting the sample with a nucleic acid probe or primer which selectively hybridizes to the nucleic acid molecule; and b) determining whether the nucleic acid probe or primer binds to a nucleic acid molecule in the sample.

13. The method of claim 12, wherein the sample comprises mRNA molecules and is contacted with a nucleic acid probe.

14. A kit comprising a compound which selectively hybridizes to a nucleic acid molecule of claim 1 and instructions for use.

15. A method for identifying a compound which binds to a polypeptide of claim 5 comprising the steps of: a) contacting a polypeptide, or a cell expressing a polypeptide of claim 5 with a test compound; and b) determining whether the polypeptide binds to the test compound.

16. A method for modulating the activity of a polypeptide of claim 5, comprising contacting a polypeptide or a cell expressing a polypeptide of claim 5 with a compound which binds to the polypeptide in a sufficient concentration to modulate the activity of the polypeptide.

17. A method of inhibiting aberrant activity of a 20716, 65494, 44576, 1983, 52881, 2398, 45449, 50289, 52872, 22105, 22109, 22108, 47916, 33395, 31939, or 84241-expressing cell, comprising contacting a 20716, 65494, 44576, 1983, 52881, 2398, 45449, 50289, 52872, 22105, 22109, 22108, 47916, 33395, 31939, or 84241-expressing cell with a compound that modulates the activity or expression of a polypeptide of claim 5, in an amount which is effective to reduce or inhibit the aberrant activity of the cell.

18. The method of claim 17, wherein the compound is selected from the group consisting of a peptide, a phosphopeptide, a small organic molecule, and an antibody.

19. A method of treating or preventing a disorder characterized by aberrant activity of a 20716, 65494, 44576, 1983, 52881, 2398, 45449, 50289, 52872, 22105, 22109, 22108, 47916, 33395, 31939, or 84241-expressing cell, in a subject, comprising: administering to the subject an effective amount of a compound that modulates the activity or expression of a nucleic acid molecule of claim 1, such that the aberrant activity of the 20716, 65494, 44576, 1983, 52881, 2398, 45449, 50289, 52872, 22105, 22109, 22108, 47916, 33395, 31939, or 84241-expressing cell is reduced or inhibited.