JP2002300881A - New g protein-conjugated receptor protein and gene encoding the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new G protein-conjugated receptor protein and a gene encoding the protein. SOLUTION: A G protein-conjugated receptor protein containing an amino acid sequence (substantialy) identical to the amino acid sequence shown by sequence no.2, 4 or 6 (ref. the specification) and a polynucleotide containing the base sequence encoding the protein are provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel G protein receptor protein, a polynucleotide encoding the protein, a recombinant vector containing the polynucleotide, a transformant containing the recombinant vector, and the protein. And a method for producing the same.

[0002]

2. Description of the Related Art Many physiologically active substances such as cytokines, hormones and neurotransmitters exert their functions in living organisms through specific receptor proteins present on cell membranes. Many of these receptor proteins have a common structure with seven transmembrane domains, and through activation of GTP-binding proteins (also called G proteins)
It is called a G protein-coupled receptor protein because it performs intracellular signaling. The G protein-coupled receptor protein transmits a signal into a cell through binding to a ligand (for example, the physiologically active substance) naturally present in a living body, and activates or suppresses cell growth by the signal. Various in vivo reactions are induced. Therefore, elucidating the relationship between a substance that regulates complex functions in various cells and organs in a living body and its specific receptor protein (particularly, a G protein-coupled receptor protein) has been elucidated by examining the cells of various living bodies. It will elucidate the physiological regulation functions of organs and organs and provide a very important means for drug development closely related to those functions.

By the way, the aging phenomenon means the deterioration of an individual in the functional and appearance changes of the individual who usually progress with aging, and it is known that the frequency of onset of various adult diseases increases with the aging. ing. Therefore, drugs that can control aging in some way are therapeutic, prophylactic and / or functional,
It is expected to be a protective agent and preventive agent for external deterioration. Heretofore, almost no drug has been scientifically proven to be effective. Gene-level research on individual aging has only recently begun, and molecular genetic information on individual aging has been almost nil. However, hereditary premature aging includes Turner syndrome, Werner syndrome, Hutchinson-Gilford syndrome
(Progeria) and some others are known. Especially for Werner syndrome, the causative gene has been identified [S
cience, 272 , 258 (1996)]. From the above, it is a definitive fact that genes involved in aging exist.
If aging is controlled by a gene, aging can be regulated by controlling the activity of the gene, and it can be used for the treatment and prevention of various adult diseases that are closely related to aging. It is considered possible.

[0004] Recently, the mth gene encoding a seven-transmembrane receptor protein was found in Drosophila, and it has been reported that deficiency of this gene delays senescence and prolongs life span [Science 282, 943-946]. (1998)].
However, a gene corresponding to the gene is not known in humans and mice.

[0005]

A substance that inhibits the binding between a G protein-coupled receptor protein and an in vivo ligand (antagonist), a substance that binds to the receptor and causes signal transmission similar to that of an in vivo ligand ( Agonists) have been used as pharmaceuticals that regulate the biological functions associated with the receptor. Therefore, finding a new G protein-coupled receptor protein and cloning the gene of the protein is not only important for scientific understanding of biological functions, but also effective for having a novel mechanism of action. It is extremely important for the development of new drugs. However, not all G protein-coupled receptors present in living organisms have been identified, and currently unknown G protein-coupled receptors and so-called orphan receptors whose corresponding ligands have not been identified yet. There are many such compounds, and there is an eager need to search for new G protein-coupled receptors and elucidate their functions.

[0006] The G protein-coupled receptor is used to search for a novel in vivo ligand using its signal transduction action as an index.
It is useful for searching for an agonist (stimulant) or antagonist (antagonist) for the receptor. On the other hand, even if a physiological ligand has not been identified, an agonist or antagonist for the receptor is produced by analyzing the physiological action of the receptor from the analysis of the receptor destruction experiment (knockout animal). It is also possible. The agonist or antagonist thus produced can be expected to be used as an agent for preventing, diagnosing, or treating a disease caused by dysfunction of the G protein-coupled receptor. Furthermore, an increase or decrease in the function of the G protein-coupled receptor in vivo due to a gene mutation may cause some disease.
In this case, the present invention can be applied to gene therapy by introducing the receptor gene into a living body (or a specific organ) or introducing an antisense nucleic acid against the receptor gene. In such a case, the nucleotide sequence of the receptor gene is essential information for examining the presence or absence of a deletion or mutation on the gene, and the receptor gene is used for diseases associated with dysfunction of the receptor. It can also be applied to prophylactic, diagnostic or therapeutic agents.

[0007] The present invention provides a novel G protein-coupled receptor protein useful as described above.
That is, a novel G protein-coupled receptor protein or a salt thereof, a partial peptide of the protein or a salt thereof,
Polynucleotide (DNA, RNA) containing a polynucleotide (DNA, RNA or a derivative thereof) encoding the G protein-coupled receptor protein or a partial peptide thereof
And derivatives thereof), a recombinant vector containing the polynucleotide, a transformant carrying the recombinant vector, a method for producing the G protein-coupled receptor protein or a salt thereof, and the G protein-coupled receptor protein An antibody against the partial peptide or a salt thereof,
A compound that changes the expression level of the G protein-coupled receptor protein, a method for determining a ligand for the G protein-coupled receptor, a compound that changes the binding property between the ligand and the G protein-coupled receptor protein (an antagonist, Agonist) or a salt thereof, a screening kit, the screening kit, a compound (antagonist, agonist) that alters the binding between the ligand obtained using the screening method or the screening kit and the G protein-coupled receptor protein
Or a salt thereof, and a compound (antagonist, agonist) that changes the binding between the ligand and the G protein-coupled receptor protein, or a compound that changes the expression level of the G protein-coupled receptor protein, or a salt thereof. Medical supplies and the like.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that mouse embryonic cDNA
The present invention succeeded in obtaining a gene encoding a seven-transmembrane G protein-coupled receptor protein and homologous to the Drosophila mth gene from the library and the human keratin-producing epidermal cell cDNA library. It was completed. That is, the present invention provides the following (1) to
(26).

(1) A G protein-coupled receptor protein or a salt thereof comprising an amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6. (2) A peptide or a salt thereof comprising a partial amino acid sequence of the G protein-coupled receptor protein of (1).

(3) A polynucleotide comprising a base sequence encoding the G protein-coupled receptor protein of (1) or the peptide of (2). (4) The polynucleotide according to the above (3), wherein the polynucleotide is DNA. (5) The polynucleotide of the above (3), comprising the nucleotide sequence represented by SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5, or a part of the nucleotide sequence.

(6) A recombinant vector containing the polynucleotide of (3). (7) A transformant transformed with the recombinant vector of (6). (8) culturing the transformant of the above (7) in a medium, and collecting the G protein-coupled receptor protein of the above (1) from the obtained culture, wherein the G protein-coupled receptor protein of the above (1) is collected. A method for producing a type receptor protein or a salt thereof.

(9) An antibody against the G protein-coupled receptor protein (1) or a salt thereof, or the peptide (2) or a salt thereof. (10) The antibody according to (9) above, wherein the antibody has an activity of inhibiting signal transmission of the G protein-coupled receptor protein of (1). (11) A pharmaceutical composition comprising the antibody of (9) as an active ingredient.

(12) A ligand for the G protein-coupled receptor protein of the above (1). (13) A pharmaceutical composition comprising the ligand of the above (12) as an active ingredient. (14) a step of examining the specific binding ability of the candidate ligand substance to the G protein-coupled receptor protein or a salt thereof of the above (1) or the peptide or a salt thereof of the above (2). A method for determining a ligand for a body protein.

(15) The ligand comprising the G protein-coupled receptor protein of the above (1) or a salt thereof, or the peptide of the above (2) or a salt thereof.
(1) A method for screening a substance that changes the binding property to a G protein-coupled receptor protein or a salt thereof.

(16) The above-mentioned (1), which comprises the above-mentioned (1) G protein-coupled receptor protein or a salt thereof and / or the above-mentioned (2) peptide or a salt thereof as a constituent element. A screening kit for a substance that changes the binding between a G protein-coupled receptor protein and a ligand of the receptor protein.

(17) The G protein-coupled receptor protein of (1) and a ligand of the receptor protein obtained by using the screening method of (15) or the screening kit of (16). A substance that changes the connectivity between (18) A pharmaceutical composition containing the substance of the above (17). (19) A polynucleotide that hybridizes with the polynucleotide of (3) above under stringent conditions.

(20) A nucleotide sequence complementary to the polynucleotide of (3) or a polynucleotide containing a part of the nucleotide sequence. (21) the mRNA of the G protein-coupled receptor protein of the above (1), which comprises a step of measuring the intensity of hybridization between the mRNA in the subject and the polynucleotide of the above (20). Quantitation method.

(22) The G protein-coupled receptor protein of (1), which comprises a step of measuring the strength of binding between the protein in the subject and the antibody of (9). Quantitation method. (23) The function of the G protein-coupled receptor of the above (1), wherein the method of quantifying the receptor protein mRNA of the above (21) or the method of quantifying the receptor protein of the above (22) is used. How to test for disease.

(24) The expression level of the G protein-coupled receptor protein of the above (1) in the test cells or test animals to which the candidate substance has been administered or exposed can be determined using the above-mentioned method (21). A method for screening a substance that alters the expression of G protein-coupled receptor of Jouki (1), which comprises a step of measuring at the protein level or at the protein level using the quantification method of (22).

(25) A substance that alters the expression of the G protein-coupled receptor of (1) obtained by using the screening method of (24). (26) A pharmaceutical composition comprising the substance of (25) as an active ingredient. Hereinafter, the present invention will be described in detail.

[0021]

BEST MODE FOR CARRYING OUT THE INVENTION The G protein-coupled receptor protein (also referred to as receptor protein) of the present invention has the same or substantially the same amino acid sequence as SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6. A receptor protein containing an amino acid sequence. The receptor protein can be obtained as follows.

1. Cloning of the Gene Encoding the Receptor Protein of the Present Invention (1) Preparation of cDNA Library As a source of mRNA for preparing a cDNA library, cells expressing the mRNA of the receptor protein of the present invention may be used. The cells are not particularly limited, and include, for example, all cells of humans and other mammals (eg, mouse, rat, guinea pig, rabbit, pig, sheep, cow, monkey, etc.) (eg, spleen cells, nerve cells, glial cells, bone marrow) Cells, Langerhans cells, epithelial cells, fibroblasts, fibrocytes, muscle cells, adipocytes, immune cells, etc.), or any tissue in which those cells are present (eg, brain, spinal cord, pituitary, stomach,
Pancreas, kidney, liver, gonad, thyroid, gall bladder, testis, testis, ovary, placenta, uterus, bone, joint, skeletal muscle, etc.). In particular, when preparing a cDNA library for cloning a human-derived receptor gene, a human aborted or spontaneously aborted human fetus-derived brain, a cDNA library for cloning a mouse-derived receptor gene When preparing E. coli, it is preferable to use a mouse embryo or the like as a source.

The preparation of mRNA can be performed by a method usually used in the art. For example, after treating the cells or tissues with a guanidine reagent, a phenol reagent, etc. to obtain total RNA, an Oligo (dT) cellulose column or
Poly (A) ⁺ RNA (mRNA) can be obtained by an affinity column method using Oligotex-dT30 or the like. If necessary, the mRNA may be further fractionated by sucrose density gradient centrifugation or the like.

Next, using the obtained mRNA as a template, a single-stranded cDNA is synthesized using an oligo dT primer and a reverse transcriptase, and then the DNA is synthesized from the single-stranded cDNA using DNA synthase I, DNA ligase, RnaseH and the like. To synthesize double-stranded cDNA. A cDNA library is prepared by blunting the synthesized double-stranded cDNA with T4 DNA synthase, ligation of an adapter (eg, EcoRI adapter), phosphorylation, etc., integration into a vector such as λgt11, and packaging in vivo. can do. Alternatively, a cDNA library can be prepared using a plasmid.

(2) Cloning of the Receptor Gene of the Present Invention From the cDNA library prepared as described above, selection of a clone containing the DNA encoding the receptor protein of the present invention is performed as follows. Can be. First,
A gene coding for a protein having homology to the amino acid sequence of the mth protein [Science 282: 943-946 (1998)] of a Drosophila-derived G protein receptor can be converted to a known gene database (for example, Infogene database of Sanger Center, Search from NCBI's EST database). Based on the base sequence of the homologous gene obtained by the search, primers or probes are designed and synthesized, and a clone containing the DNA encoding the target receptor gene is obtained from the cDNA library according to a conventional method. In the present invention, a target clone can also be obtained from a commercially available cDNA library.

Next, the nucleotide sequence of the obtained clone is determined. The nucleotide sequence can be determined by a known method such as the Maxam-Gilbert chemical modification method or the dideoxynucleotide chain termination method using M13 phage. Usually, an automatic nucleotide sequencer (for example, PERKIN-ELM) is used.
The sequence is determined using an ER 373A DNA sequencer. The obtained base sequence is analyzed by DNA analysis software such as DNASIS (Hitachi Software Engineering Co., Ltd.), and the protein coding portion encoded in the obtained DNA chain is found.

In the present invention, novel G protein receptor proteins cloned from humans and mice and genes encoding the proteins are exemplified as follows. That is, SEQ ID NO: 2 is the amino acid sequence of human-derived G protein receptor protein APG1α1, and SEQ ID NO: 1 is the base sequence of the gene encoding the protein. SEQ ID NO: 4 is the amino acid sequence of human-derived G protein receptor protein APG1β1, and SEQ ID NO: 3 is the nucleotide sequence of the gene encoding the protein. SEQ ID NO: 6 is a mouse-derived G
This is the amino acid sequence of the protein receptor protein APG1γ2, and SEQ ID NO: 5 is the nucleotide sequence of the gene encoding the protein.

Once the nucleotide sequence of the gene of the present invention has been determined, the polynucleotide of the present invention can be obtained by chemical synthesis or by PCR using the cDNA or genomic DNA of the gene as a template. For example, a DNA (SEQ ID NO: 1) encoding the full-length amino acid sequence (SEQ ID NO: 2) of the human APG1α1 protein of the present invention is obtained by using human fetal cDNA as a template and using 5′-atgatgtttcgctcagatcg-
3 '(SEQ ID NO: 10) and 5'-gcatgggccagttttgacaa-3'
By using a primer having the nucleotide sequence of (SEQ ID NO: 11), the gene (SEQ ID NO: 3) encoding the full-length amino acid sequence (SEQ ID NO: 4) of the human APG1β1 protein of the present invention can be obtained by using human fetal cDNA as a template. 5'-at
gatgtttcgctcagatcg-3 ′ (SEQ ID NO: 12) and 5′-attaaa
By using a primer having the nucleotide sequence of actttgtgctgtgg-3 ′ (SEQ ID NO: 13), the mouse APG of the present invention
DNA (SEQ ID NO: 5) encoding the full-length amino acid sequence of 1γ2 protein (SEQ ID NO: 6) was obtained using 5′-atgatgtttgacactctcgg-3 ′ (SEQ ID NO: 14) and 5′-ggagaaattatccgagtggc-3 ′ using mouse embryo-derived cDNA as a template. (SEQ ID NO: 1
By using a primer having the nucleotide sequence of 5), it can be easily prepared by PCR. However,
In the present invention, the primer is not limited to these.

2. Receptor protein of the present invention and partial peptide thereof The receptor protein of the present invention comprises SEQ ID NO: 2 and SEQ ID NO: 4
Or a protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 6. Here, the term "protein containing substantially the same amino acid sequence" refers to the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: about 50% or more, preferably about 70% or more.
Or more, more preferably about 80% or more, even more preferably about
It has an amino acid sequence having 90% or more, most preferably about 95% or more homology, and has substantially the same activity as a protein containing the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6. Refers to protein. “Substantially the same activity” means that the biological activity originally possessed by the receptor protein, such as a ligand binding activity and a signal transduction action, is of the same nature. More specifically, biological activities such as a ligand binding activity and a signal transduction effect are equivalent (for example, about 0.01 to 100 times, preferably about 0.5 to 20 times).
(More preferably about 0.5 to 2 times), the quantitative factor such as molecular weight may be different from the original protein.
In addition, the measurement of the activity such as the ligand binding activity and the signal information transduction action can be performed according to a known method. For example, the activity can be measured according to a ligand determination method described later.

The protein having an amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6 includes the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6. 1 or 2 or more (preferably, about 1 to 30, more preferably 1 to 30)
The amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6 in which about 10 amino acids have been deleted, more preferably 1 to 5 amino acids, and 1 or more (preferably 1 to 30 amino acids) (Preferably about 1 to 10, more preferably 1 to 5) amino acids, and 1 or 2 in the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6. Proteins containing an amino acid sequence in which at least one (preferably about 1 to 30, more preferably about 1 to 10, and still more preferably 1 to 5) amino acids are substituted with other amino acids are mentioned. The deletion, addition and substitution of the amino acids can be performed by modifying a gene encoding a receptor protein by a method known in the art. For example, substitution of a specific amino acid residue can be performed using a commercially available kit [for example, Mutan ^™ -G (TAKARA), Mutan ^™ -K
(TAKARA)] and the like, by a known method such as the Guppedduplex method or the Kunkel method, or a method analogous thereto.
It can be achieved by substitution of a base.

The C-terminus of the receptor protein of the present invention is usually a carboxyl group (—COOH), and the carboxyl group can be amide (—CONH ₂ ) or ester (—COO ₂ )
R) or the like may be chemically modified. Here, as R in the ester, a C _1-6 alkyl group (eg, methyl,
Ethyl, n-propyl, isopropyl, n-butyl), _C3-
8 cycloalkyl groups (eg, cyclopentyl, cyclohexyl), C _6-12 aryl groups (eg, phenyl, α
-Naphthyl), a phenyl-C _1-2 alkyl group (eg, benzyl, phenethyl), an α-naphthyl-C _1-2 alkyl group (eg, α-naphthylmethyl) and the like. In addition, pivaloyloxymethyl ester, which is widely used as an oral ester, can also be used. When the receptor protein of the present invention has a carboxyl group in the polypeptide chain other than the C-terminus, the protein of the present invention includes amidated or esterified carboxyl group. Examples of the ester in this case include the above esters. Likewise, N-terminal of the receptor protein of the present invention is generally an amino group (-NH ₂₎
However, the amino group may be chemically modified with a C _1-6 acyl group such as a formyl group and an acetyl group. In addition, the glutamyl group formed by cleavage of the N-terminal side in vivo is pyroglutamine-oxidized, or a substituent on the side chain of an amino acid in the molecule (for example, -OH, -SH, amino group, imidazole group, indole group) , A guanidino group, etc.) are chemically modified with an appropriate functional group (eg, formyl group, acetyl, etc.) and those having a sugar chain bonded thereto are also included in the protein of the present invention.

A peptide containing a partial amino acid sequence in any of the above receptor proteins (also referred to as a partial peptide)
Are also included in the scope of the present invention. That is, as long as the partial peptide of the present invention includes a partial amino acid sequence of the amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6, It may be. In particular, among the partial peptides of the present invention, a portion that is exposed outside the cell membrane when the receptor protein is naturally present and has ligand binding activity is particularly useful in determining the ligand of the receptor protein. Examples of such a partial peptide include a portion analyzed as an extracellular region (hydrophilic site) in a hydrophobic plot analysis of the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4, or SEQ ID NO: 6. The number of amino acids constituting the partial peptide of the present invention is at least 10 or more, preferably 30 or more, more preferably 80 or more. Usually, C-terminal, the carboxyl group of the partial peptide of the present invention (-COOH), but N-terminal is an amino group (-NH _2), these are as in the case of the receptor protein, it is chemically modified Good.

The receptor protein or its partial peptide of the present invention can be provided in the form of a salt, if necessary, preferably in the form of a physiologically acceptable acid addition salt. Examples of such salts include salts of inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid), organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid,
Citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and the like.

The receptor protein of the present invention or a salt thereof is
Encoding the receptor protein of the present invention by extraction and separation from cultured cells or tissues of humans and mammals expressing the receptor protein of the present invention, or as described below.
It can also be produced by culturing a transformant containing DNA. When manufacturing from human or mammalian tissues or cells, the human or mammalian tissues or cells are homogenized, extracted with an acid or the like, and the obtained extract is subjected to hydrophobic chromatography, reverse phase chromatography, ion exchange chromatography. It can be isolated and purified by combining various chromatography such as chromatography.

The partial peptide of the present invention or a salt thereof can be produced by a known peptide synthesis method or by cleaving the receptor protein with an appropriate peptidase (eg, trypsin, chymotrypsin, arginyl endopeptidase). it can. As the peptide synthesis method, for example, any of a solid phase synthesis method and a liquid phase synthesis method may be used. That is, a partial peptide or amino acid capable of constituting the receptor protein of the present invention is condensed with the remaining portion, and when the product has a protecting group, the protecting group is eliminated to produce the desired peptide. . After the synthesis reaction, the partial peptide of the present invention can be isolated and purified by a combination of ordinary purification methods, for example, solvent extraction, distillation, column chromatography, high performance liquid chromatography, recrystallization and the like. When the receptor protein or its partial peptide obtained by the above method is a free form, it can be converted to an appropriate salt by a known method, and conversely, when obtained by a salt, it can be converted by a known method. It can be converted to a free form.

3. Polynucleotide encoding the receptor protein of the present invention or a partial peptide thereof The polynucleotide encoding the receptor protein of the present invention or the partial peptide thereof is a nucleotide sequence (DNA or R
Any substance containing NA) may be used. Examples of the polynucleotide include DNA and mRNA such as mRNA encoding the receptor protein of the present invention, and may be double-stranded or single-stranded. In the case of double-stranded, it may be double-stranded DNA, double-stranded RNA or a hybrid of DNA and RNA. In the case of a single strand, it may be a sense strand (ie, a coding strand) or an antisense strand (ie, a non-coding strand). Using a polynucleotide encoding the receptor protein of the present invention, for example, the known experimental medicine special edition "New PCR and its application" 15 (7), by the method described in 1997 or a method analogous thereto, the receptor of the present invention Protein mRNA can be quantified. The DNA encoding the receptor protein of the present invention may be genomic DNA, genomic DNA
Library, cDNA derived from the above-mentioned one cell or tissue,
Alternatively, it may be one prepared from a cDNA library derived from the above-mentioned one cell or tissue, or a synthetic DNA. The vector used for the library may be any of bacteriophage, plasmid, cosmid, phagemid and the like. In addition, the RT-PCR method (Rev.
It can also be amplified by erseTranscriptase Polymerase Chain Reaction). Specifically, the polynucleotide encoding the receptor protein of the present invention includes:
SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5
A polynucleotide containing a nucleotide sequence represented by the following, and hybridizes with any of these polynucleotides under stringent conditions, and has substantially the same activity as the receptor protein of the present invention (for example,
Any polynucleotide may be used as long as it is a polynucleotide encoding a receptor protein having ligand binding activity and signal signal transduction action).

The DNA that can hybridize under stringent conditions to a polynucleotide containing the nucleotide sequence represented by SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO: 5 includes SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO: 5. DNAs containing a base sequence having a homology of about 70% or more, preferably about 80% or more, more preferably about 90% or more, and most preferably about 95% or more with the represented base sequence are exemplified. Here, "stringent conditions" refers to conditions in which the sodium concentration is about 20 to 40 mM, preferably about 20 to 25 mM, and the temperature is about 50 to 70 ° C, preferably about 60 to 65 ° C.

4. Preparation of Recombinant Vector and Transformant (1) Preparation of Recombinant Vector The recombinant vector of the present invention can be obtained by ligating a DNA encoding the receptor protein of the present invention to an appropriate vector. The vector for inserting the gene of the present invention is not particularly limited as long as it can be replicated in a host, and examples thereof include plasmid DNA and phage DNA. As plasmid DNA, plasmids derived from E. coli (for example, pBR322, pBR325, pUC118, pUC119, pUC18,
pUC19, pCBD-C, etc.), a plasmid derived from Bacillus subtilis (for example, pU
B110, pTP5, pC194, etc.), yeast-derived plasmids (eg,
YEp13, YEp24, YCp50, YIp30, etc.), and phage DNA includes λ phage. further,
Animal viruses such as retrovirus and vaccinia virus, and insect virus vectors such as baculovirus and togavirus can also be used.

The receptor gene of the present invention can be ligated to the vector by digesting the DNA encoding the receptor protein cloned in the above 1 as it is, or by digesting it with a restriction enzyme or adding a linker if desired, and adding a linker. It can be performed by inserting into a restriction enzyme site or a multiple cloning site. The DNA to be ligated may have ATG as a translation initiation codon at the 5 'end and TAA, TGA or TAG as a translation stop codon at the 3' end. These translation initiation codon and translation termination codon can also be added using an appropriate synthetic DNA adapter. It is necessary that the DNA to be ligated be incorporated into a vector so that the receptor protein of the present invention encoded in the DNA is expressed in a host cell. Therefore, in addition to the receptor protein coding sequence, a promoter, a selection marker, a terminator, an enhancer, a splicing signal, a polyA addition signal, a ribosome binding sequence (SD sequence), etc., should be ligated to the recombinant vector of the present invention. Can be.

Here, the promoter used in the present invention
Appropriate for the host used for gene expression
It is not particularly limited as long as it is a promoter. For example, animals
When using cells as hosts, SRα promoter, CM
V promoter, SV40 promoter, LTR promoter,
HSV-TK promoter and the like. If the host is E. coli
If necessary, trp promoter, lac promoter, recA
Promoter, λP _LPromoter, lpp promoter, etc.
However, when the host is Bacillus subtilis, SPO1 promoter,
SPO2 promoter, penP promoter, etc., the host is yeast
If, PHO5 promoter, PGK promoter
-, GAP promoter, ADH promoter, etc.
You. If the host is an insect cell, the polyhedrin promoter
And a P10 promoter. Select
Markers include ampicillin resistance gene, neomycin
Syn-resistance gene, dihydrofolate reductase gene, etc.
Can be

(2) Preparation of Transformant The transformant of the present invention can be obtained by introducing the recombinant vector of the present invention into a host so that the target gene can be expressed. Here, the host of the present invention
There is no particular limitation as long as it can express DNA. For example, E. coli (Escherichia coli) belonging to the genus Escherichia, such as, Bacillus subtilis (Bacillus subtili
s ), Pseudomonas putida ( Pseudom)
bacterium belonging to the genus Pseudomonas such as P. onas putida, the genus Rhizobium such as Rhizobium meliloti , and Saccharomyce.
s cerevisiae ), Schizosaccharomyces pombe ( Schizo
yeast such as saccharomyces pombe ), monkey cell COS-7, Ver
o, animal cells such as Chinese hamster ovary cells (CHO cells), mouse L cells, human GH3, human FL cells, or
And insect cells such as Sf9 and Sf21.

As a method for introducing a recombinant vector into Escherichia coli, a method using calcium ions [Cohen, SN et al.
al .: Proc. Natl. Acad. Sci., USA, 69: 2110 (197
2)] and electroporation. Methods for introducing a recombinant vector into yeast include electroporation [Becker, DM et al .: Methods. Enzymo
l., 194: 182 (1990)], spheroplast method [Hinnen, A.
et al .: Proc. Natl. Acad. Sci., USA, 75: 1929 (19
78)], lithium acetate method [Itoh, H .: J. Bacteriol., 153:
163 (1983)]. Methods for introducing a recombinant vector into animal cells include an electroporation method, a calcium phosphate method, and a lipofection method. As a method for introducing a recombinant vector into insect cells,
For example, calcium phosphate method, lipofection method, electroporation method and the like can be mentioned.

5. Production of the receptor protein of the present invention The receptor protein of the present invention can be produced by culturing the transformant obtained in the above item 4 and collecting from the culture. "Culture" refers to the culture supernatant,
Alternatively, it means any of cultured cells or cultured cells, or crushed cells or cells. The method for culturing the transformant of the present invention is performed according to a usual method used for culturing a host.

A culture medium for culturing a transformant obtained by using a microorganism such as Escherichia coli or yeast as a host contains a carbon source, a nitrogen source, inorganic salts, and the like which can be used by the microorganism. If the medium can be performed efficiently,
Either a natural medium or a synthetic medium may be used. Examples of the carbon source include carbohydrates such as glucose, fructose, sucrose, and starch; organic acids such as acetic acid and propionic acid; and alcohols such as ethanol and propanol. Nitrogen sources include ammonia, ammonium chloride,
In addition to ammonium salts of inorganic or organic acids such as ammonium sulfate, ammonium acetate and ammonium phosphate, and other nitrogen-containing compounds, peptone, meat extract, corn steep liquor and the like are used. As the inorganic salts, potassium (I) phosphate, potassium (II) phosphate, magnesium phosphate, magnesium sulfate, sodium chloride, ferrous sulfate, manganese sulfate, copper sulfate, calcium carbonate and the like are used.

The culturing is performed under conditions suitable for the host cell.
For example, as a medium for culturing E. coli, LB medium,
M9 medium and the like are preferred. If desired, an agent such as isopropyl-1-thio-β-D-galactoside, 3β-indolylacrylic acid can be added to make the promoter work efficiently. In the case of E. coli, the culture is usually about 15
The reaction is carried out at about 43 ° C. for about 3 to 24 hours, and if necessary, ventilation and stirring can be applied. When the host is Bacillus subtilis, the cultivation is usually performed at about 30 to 40 ° C. for about 6 to 24 hours, and if necessary, aeration and stirring may be added. Examples of a medium for culturing yeast include an SD medium and a YPD medium. The pH of the medium is preferably adjusted to about 5-8. Culture is usually about 20 ° C ~
Perform at 35 ° C for about 24-72 hours, adding aeration and agitation as needed. When culturing a transformant in which the host is an insect cell or an insect, the medium includes Grace's insect medium containing bovine serum and the like. Preferably, the pH of the medium is adjusted to about 6.2-6.4. The cultivation is usually performed at about 27 ° C. for about 3 to 5 days, and aeration and / or agitation are added as necessary. When culturing a transformant whose host is an animal cell, for example, a MEM medium containing about 5 to 20% fetal bovine serum, a DMEM medium, an RPMI 1640 medium, or the like is used as a medium. Preferably, the pH is between about 6 and 8. The cultivation is usually performed at about 30 ° C. to 40 ° C. for about 15 to 60 hours, and if necessary, aeration or stirring is added. As described above, the receptor protein of the present invention can be produced on the cell membrane or the like of the transformant. The receptor protein of the present invention can be separated and purified from the culture by, for example, the following method.

When the receptor protein of the present invention is extracted from cultured cells or cells, the cells or cells are collected by a known method after culturing, suspended in an appropriate buffer, and subjected to ultrasound, lysozyme and After the cells or cells are destroyed by freeze-thawing or the like, a method of obtaining a crude extract of the receptor protein by centrifugation or filtration is used as appropriate. The buffer may contain a protein denaturant such as urea or guanidine hydrochloride, or a surfactant such as Triton X-100. When the receptor protein is secreted into the culture solution, after culturing, the supernatant is separated from the cells or cells by a method known per se, and the supernatant is collected. Purification of the receptor protein contained in the culture supernatant or extract thus obtained can be performed by appropriately combining known separation and purification methods. As these known separation and purification methods, methods utilizing solubility such as salting out and solvent precipitation, dialysis, ultrafiltration, gel filtration, and
SDS-PAGE and other methods that mainly use differences in molecular weight, methods that use differences in charge such as ion exchange chromatography, methods that use specific affinity such as affinity chromatography, reverse-phase high-performance liquid chromatography, etc. A method using a difference in hydrophobicity, a method using a difference in isoelectric point such as isoelectric focusing, and the like are used.

6 Antisense Polynucleotide of the Present Invention An antisense polynucleotide capable of inhibiting the replication or expression of the gene encoding the receptor protein of the present invention is obtained by adding the antisense polynucleotide which has been cloned in the above item 1 to the nucleotide sequence information of the DNA encoding the receptor protein. Based on the design and synthesis. Specifically, the antisense polynucleotide of the present invention includes a G protein receptor protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6, or Polynucleotides that are complementary to a base sequence encoding a partial peptide of the protein or that can hybridize under stringent conditions are exemplified. Such an antisense polynucleotide is a polynucleotide having a nucleotide sequence complementary to at least a part of mRNA of the receptor protein gene of the present invention, and by hybridizing to the mRNA, the receptor protein gene Expression can be regulated or controlled. The antisense polynucleotide is useful for treating or diagnosing a disease associated with the receptor gene of the present invention, in addition to regulating or controlling the expression of the receptor protein of the present invention.

[0048] The antisense polynucleotide comprises 2-
Polydeoxyribonucleotides containing deoxy-D-ribose, polyribonucleotides containing D-ribose, other types of polynucleotides that are N-glycosides of purine or pyrimidine bases, or others having a non-nucleotide backbone Polymers (eg, commercially available peptide nucleic acids and synthetic sequence-specific nucleic acid polymers)
Or other polymers containing special bonds (but
The polymer contains a nucleotide having a configuration that allows base pairing and base attachment as found in DNA and RNA). They are double-stranded DNA,
Single-stranded DNA, double-stranded RNA, single-stranded RNA, or a hybrid of DNA and RNA, and further unmodified polynucleotide (or unmodified oligonucleotide), further added with known modifications, For example, those labeled in the art, capped, methylated, substituted for one or more natural nucleotides with analogs, modified with intranucleotide nucleotides, e.g. Those having a charged bond (eg, methylphosphonate, phosphotriester, phosphoramidate, carbamate, etc.), a charged bond or a sulfur-containing bond (eg,
Those having phosphorothioate, phosphorodithioate, etc., such as proteins (nucleases, nuclease inhibitors, toxins, antibodies, signal peptides, poly-L-lysine, etc.) and sugars (eg, monosaccharides). What you have, an interactive compound (eg, acridine, psoralen, etc.)
, Those containing chelating compounds (eg, metals, radioactive metals, boron, oxidizable metals, etc.), those containing alkylating agents, those with modified bonds (eg, α anomers) Type nucleic acid).

The antisense polynucleotide of the present invention comprises
It can be provided in a special form such as liposome or microsphere, or can be provided in a form to which a specific compound or a modifying group is bound. Specifically, as the substance to be bound to the antisense polynucleotide, when the antisense polynucleotide is DNA, a polycation such as polylysine, which acts to neutralize the charge of the phosphate backbone, or an antisense polynucleotide Crude aqueous substances such as phospholipids and cholesterol that enhance the interaction between nucleoti and cell membranes and increase the uptake of antisense polynucleotide into cells, polyethylene glycol and tetraethylene glycol that prevent degradation of antisense polynucleotide by nuclease But not limited thereto.

The activity of the antisense polynucleotide of the present invention for inhibiting the expression of the receptor protein gene is determined by the transformant of the present invention, the in vivo or in vitro gene expression system of the present invention, or the receptor of the present invention. It can be examined using in vivo and in vitro translation systems for proteins.

7. Method for Determining Ligand for Receptor Protein of the Present Invention In the method for determining a ligand of the present invention, the receptor protein of the present invention or a partial peptide thereof is contacted with a candidate substance (test substance). It is characterized by measuring the binding amount of the candidate substance to the partial peptide, the cell stimulating activity, and the like. More specifically,
The present invention provides a test compound, when the receptor protein or a salt thereof of the present invention or a partial peptide of the present invention or a salt thereof is contacted, the receptor protein or a salt thereof of a labeled candidate substance, or The method for determining a ligand for a receptor protein or a salt thereof of the present invention, which comprises measuring the amount of binding to the partial peptide or a salt thereof, a labeled candidate substance,
The present invention is characterized in that the amount of a labeled candidate substance bound to the cell or the membrane fraction when the cell is contacted with the cell containing the receptor protein of the present invention or the membrane fraction of the cell is measured. A method for determining a ligand for a receptor protein or a salt thereof, and contacting a labeled candidate substance with a receptor protein expressed on a cell membrane by culturing a transformant containing a DNA encoding the receptor protein of the present invention. In this case, the method for determining a ligand for the receptor protein of the present invention, which comprises measuring the amount of binding of a labeled candidate substance to the receptor protein or a salt thereof, and the method for determining a candidate substance for the receptor protein of the present invention Cell contact activity through a receptor protein when contacted with a cell containing
Intracellular Ca ²⁺ release, intracellular cAMP production, intracellular cGMP production, inositol phosphate production, cell membrane potential fluctuation, phosphorylation of intracellular proteins, activity to promote or suppress pH reduction, etc.) A method for determining a ligand to the receptor protein or a salt thereof of the present invention, and a candidate substance, on a cell membrane thereof by culturing a transformant containing a DNA encoding the receptor protein of the present invention. Cell contact stimulating activity through the receptor protein (eg, intracellular Ca ²⁺ release, intracellular cAMP production, intracellular cGMP production, inositol phosphate production, cell membrane potential fluctuation, cell contact when contacted with the expressed receptor protein) The activity of promoting or inhibiting the phosphorylation of internal proteins, the reduction of pH, etc.) Or to provide a method of determining a ligand to salts thereof. The receptor protein used in the ligand determination method of the present invention may be any one containing the above-described receptor protein of the present invention or the partial peptide of the present invention. Receptor proteins that have been made are particularly preferred.

8. Antibodies against the receptor protein of the present invention The antibody of the present invention is a G protein-coupled receptor protein comprising the same or substantially the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6. Or a salt thereof, or a peptide containing a partial amino acid sequence of the receptor protein, or an antibody against a salt thereof. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody as long as it can recognize the receptor protein of the present invention or a partial peptide thereof.
The antibody of the present invention can be produced by using the receptor protein of the present invention or a partial peptide thereof as an antigen according to a method for producing an antibody or antiserum known in the art.

(1) Preparation of Monoclonal Antibody (i) Preparation of Monoclonal Antibody-Producing Cell The receptor protein and the like of the present invention can be administered to a mammal at a site capable of producing the antibody by administration to itself or a carrier.
Administered with diluent. Complete Freund's adjuvant or incomplete Freund's adjuvant may be administered in order to enhance the antibody-producing ability upon administration. Administration is usually 2-
It is performed once every six weeks, for a total of 2 to 10 times. Examples of mammals used include monkeys, rabbits, dogs,
Guinea pigs, mice, rats, sheep and goats can be mentioned, and mice and rats are preferably used. When preparing monoclonal antibody-producing cells, a warm-blooded animal immunized with an antigen, for example, an individual having an antibody titer is selected from a mouse, and the spleen or lymph node is collected 2 to 5 days after the final immunization. By fusing the contained antibody-producing cells with myeloma cells, a monoclonal antibody-producing hybridoma can be prepared. The antibody titer in the antiserum can be measured, for example, by reacting a labeled receptor protein or the like described below with the antiserum, and then measuring the activity of a labeling agent bound to the antibody. The fusion operation can be performed according to a known method, for example, the method of Kohler and Milstein [Nature, 256, 495 (1975)]. Examples of the fusion promoter include polyethylene glycol (PEG) and Sendai virus, but PEG is preferably used. Examples of myeloma cells include, for example, NS-1, P3U1, SP2 / 0, and the like.
3U1 is preferably used. The preferred ratio between the number of antibody-producing cells (spleen cells) and the number of myeloma cells used is 1:
PEG (preferably PEG1000-PE
G6000) is added at a concentration of about 10-80%, and about 20-40
Incubation at about 30 ° C., preferably about 30 ° C. to 37 ° C. for about 1 to 10 minutes allows efficient cell fusion. Various methods can be used to screen for monoclonal antibody-producing hybridomas. For example, a hybridoma culture supernatant is added to a solid phase (eg, a microplate) on which an antigen such as a receptor protein is directly or adsorbed together with a carrier, and then A method for detecting a monoclonal antibody bound to a solid phase by adding an anti-immunoglobulin antibody (an anti-mouse immunoglobulin antibody is used when the cell used for cell fusion is a mouse) or protein A labeled with a radioactive substance, an enzyme, or the like A method of adding a hybridoma culture supernatant to a solid phase to which an anti-immunoglobulin antibody or protein A is adsorbed, adding a receptor protein or the like labeled with a radioactive substance or an enzyme, and detecting a monoclonal antibody bound to the solid phase. Is raised. The selection of the monoclonal antibody can be carried out according to a method known per se or a method analogous thereto. Usually, it can be carried out in a medium for animal cells to which HAT (hypoxanthine, aminopterin, thymidine) is added. As a selection and breeding medium, any medium can be used as long as a hybridoma can grow. For example, 1 to 20%, preferably 10
RPMI 1640 medium containing up to 20% fetal bovine serum, GIT medium containing 1 to 10% fetal bovine serum (Wako Pure Chemical Industries, Ltd.) or serum-free medium for hybridoma culture (SFM-101, Nissui Pharmaceutical) Co., Ltd.) can be used. The culturing temperature is usually 20 ° C to 40 ° C, preferably about 37 ° C. The culturing time is usually 5 days to 3 weeks, preferably 1 week to 2 weeks. The culture can be usually performed under 5% carbon dioxide. The antibody titer of the hybridoma culture supernatant can be measured in the same manner as the measurement of the antibody titer in the antiserum described above.

(Ii) Purification of Monoclonal Antibody Separation and purification of the monoclonal antibody can be performed by the same method as that used for ordinary polyclonal antibody separation and purification (eg, salting out, alcohol precipitation, isoelectric precipitation, Electrophoresis, adsorption / desorption with an ion exchanger, ultracentrifugation, gel filtration, antigen-bound solid phase or only antibody is collected using an active adsorbent such as protein A or protein G, and the bond is dissociated to obtain the antibody. Specific purification method).

(2) Preparation of polyclonal antibody The polyclonal antibody of the present invention can be produced according to a method known per se or a method analogous thereto. For example, a complex of an immunizing antigen (for example, a receptor protein) and a carrier protein is formed, and a mammal is immunized in the same manner as in the above-described method for producing a monoclonal antibody. The antibody can be produced by collecting the antibody-containing substance and separating and purifying the antibody. Regarding a complex of an immunizing antigen and a carrier protein used to immunize a mammal, the type of the carrier protein and the mixing ratio of the carrier and the hapten should be such that the antibody can be efficiently produced against the hapten immunized by crosslinking the carrier. Whatever may be cross-linked at any ratio, for example, bovine serum albumin, bovine thyroglobulin, keyhole limpet,
Hemocyanin, etc. in a weight ratio of about 0.1 to 2
A method of coupling at a ratio of 0, preferably about 1 to 5 is used. Various coupling agents can be used for coupling the hapten and the carrier. For example, glutaraldehyde, carbodiimide, a maleimide active ester, an active ester reagent containing a thiol group or a dithioviridyl group, or the like is used. Condensation product is itself or a carrier at a site capable of producing an antibody to a mammal,
Administered with diluent. Complete Freund's adjuvant or incomplete Freund's adjuvant may be administered in order to enhance the antibody-producing ability upon administration. The administration can usually be performed once every about 2 to 6 weeks, for a total of about 3 to 10 times. The polyclonal antibody can be collected from blood, ascites, or the like, preferably from blood, of the mammal immunized by the above method. The measurement of the polyclonal antibody titer in the antiserum can be performed in the same manner as the measurement of the antibody titer in the serum described above. The separation and purification of the polyclonal antibody can be performed according to the same immunoglobulin separation and purification method as the above-described separation and purification of the monoclonal antibody.

9. Other Medical and Pharmaceutical Applications of the Receptor Protein of the Present Invention and Its Partial Peptide The receptor protein of the present invention, its partial peptide or a salt thereof, and the polynucleotide encoding the same are ligands for the receptor protein of the present invention ( Agonist), preventive and / or therapeutic agent for diseases associated with dysfunction of the receptor protein of the present invention, gene diagnostic agent, quantification of ligand for receptor protein of the present invention, and receptor protein of the present invention and ligand Screening for compounds (agonists, antagonists, etc.) that alter the binding of the compound, prevention of various diseases containing compounds (agonists, antagonists) that alter the binding between the receptor protein and the ligand of the present invention, and / or
Alternatively, quantification of a therapeutic agent, the receptor protein of the present invention or its partial peptide, neutralization by an antibody against the receptor protein of the present invention or its partial peptide, preparation of a non-human animal having a gene encoding the receptor protein of the present invention And so on. In particular, by using a receptor binding assay system using the recombinant receptor protein expression system of the present invention, a substance that changes the binding of a ligand to a human or mammalian specific receptor protein (for example, (Agonists, antagonists) can be screened, and the agonist or antagonist can be used as an agent for preventing or treating various diseases.

Specifically, the receptor protein of the present invention, its partial peptide, or a salt thereof is a reagent for searching (screening) or determining a ligand (agonist) or antagonist for the receptor protein of the present invention. Useful as These reagents can be used as components of a kit for screening a substance that changes the binding property of a ligand to the receptor protein of the present invention. As described above, the present invention provides a ligand (agonist) for the receptor protein of the present invention, which comprises contacting the receptor protein of the present invention or its partial peptide, or a salt thereof, with a test substance.
Alternatively, a method for determining an antagonist is provided. The test substance includes a human or mammalian (eg, mouse, rat, pig, cow, sheep, monkey, etc.) tissue extract, cell culture supernatant, artificially synthesized compound, and the like.

To carry out the method of the present invention for determining a ligand for a receptor protein or a salt thereof, an appropriate receptor protein fraction and a labeled test substance are used. As the receptor protein fraction, a natural receptor protein fraction or a recombinant receptor protein fraction having an activity equivalent thereto is preferable. For example, to determine a ligand for the receptor protein of the present invention or a salt thereof, first, cells or a membrane fraction of the cell containing the receptor protein of the present invention are suspended in a buffer suitable for the determination method. To prepare a receptor preparation. The buffer may be any buffer, such as a phosphate buffer or a Tris-HCl buffer, as long as it does not inhibit the binding between the ligand and the receptor protein. Also,
For the purpose of reducing non-specific binding, CHAPS, Tween-80,
Surfactants such as deoxycholate and proteins such as bovine serum albumin and gelatin can also be added to the buffer. A fixed amount of a radiolabeled test substance is allowed to coexist in the solution containing the receptor protein. A reaction tube containing a large excess of unlabeled test compound is also prepared to determine the amount of non-specific binding. The reaction is carried out at about 4 to 50 ° C, preferably about 4 ° C to 37 ° C, for about 10 minutes to 24 hours, desirably about 30 minutes to
Perform for 3 hours. After the reaction, the mixture is filtered, washed with an appropriate amount of the same buffer, and the radioactivity remaining on the filter paper is measured with a liquid scintillation counter or the like. A test substance whose count obtained by subtracting the non-specific binding amount from the total binding amount exceeds 0 cpm can be selected as a ligand (agonist) for the receptor protein of the present invention or a salt thereof.

When the ligand for the receptor protein of the present invention is identified, the receptor protein of the present invention or a polynucleotide encoding the receptor protein can be replaced with the receptor protein of the present invention in accordance with the action of the ligand. Can be used as a medicament such as a preventive and / or therapeutic agent for a disease associated with dysfunction of.

The receptor protein of the present invention has homology to the Dth fly-derived mth protein which is a G protein-coupled receptor protein. Since the Drosophila artificially deficient in the mth protein has a prolonged life, the receptor protein of the present invention is useful for the prevention and / or treatment of aging-related diseases.
When the receptor protein of the present invention is used as the prophylactic / therapeutic agent, it can be formulated by a method well-known in the art.

[0061]

EXAMPLES The present invention will now be described specifically with reference to Examples, but the scope of the present invention is not limited to these Examples. [Example 1] cDNA cloning The Drosophila senescence-related gene mth gene encodes a G protein-coupled seven transmembrane receptor belonging to the secretin-like receptor family. For the purpose of obtaining novel mth-like proteins in humans and mice, cDNA cloning was performed by the following procedure. First, based on the amino acid sequence of the mth protein, the Infogene (I) of the Sanger Center
A homology search was performed by blast against the (nfogene) database. As a result, UHS002871, UHS00
Two sequences, 2873, were hit. These two sequences have a G-protein-coupled receptor-like sequence, and although some of the sequences are different, they are homologous in many parts, and it is expected that the prediction of the coding region is different from the same gene. Was done. Whether the alignment between mth protein and UHS002871, the alignment between mth protein and UHS002873 is statistically significant is tested by PRSS attached to FASTA,
The alignment was confirmed to be significant. next,
Using a sequence common to UHS002871 and UHS002873, NCBI
(National Center for Biotechnology Information) E
ST (expressed sequence tag) database (d
When blast was performed on (bEST), several clones were found. Duplicate EST clones were detected by NCBI's UniGene server, of which the clone length was the longest (4.1 kb).
Obtained from rtium. The nucleotide sequence of this mouse EST clone was determined by DNA sequencing, and it was revealed that the mouse EST clone was a partial sequence of a mouse G protein-coupled receptor having significant homology to UHS002871 and UHS002873. The sequence of the upstream region was obtained by PCR using a mouse embryonic 17-day cDNA library (Clontech). First, 5'-cacaagagcaatgtacatgtgg-3 '
(SEQ ID NO: 16) was used to obtain a portion of the upstream sequence. Furthermore, 5'-ctgtgtctcaatgttcacatg-3 '
Using (SEQ ID NO: 17), the upstream sequence was obtained. Using a part of the mouse cDNA fragment as a probe,
Screening was performed using a cDNA library (Stratagene) to obtain two types of cDNA fragments having different splicing. The sequence of the further upstream region was obtained by PCR using a human keratin-producing epidermal cell cDNA library (Clontech). First, 5'-tattgct as primer
Using tggaagaccaatgc-3 ′ (SEQ ID NO: 18), a part of the upstream sequence was obtained. In addition, 5'-gacacatgc as a primer
The upstream sequence was obtained using atctcattcgcac-3 ′ (SEQ ID NO: 19).

Human and mouse cDs obtained by the above method
NA had a novel nucleotide sequence (human-derived: SEQ ID NO: 7 and SEQ ID NO: 8, mouse-derived: SEQ ID NO: 9). Based on those cDNAs, the translation of the base sequence thereof allows the novel protein APG1 [hAPG1α1 (SEQ ID NO: 2), h
APG1β1 (SEQ ID NO: 4) and mAPG1γ2 (SEQ ID NO: 6)] were obtained.

[0063]

Industrial Applicability According to the present invention, a novel G protein receptor protein, a polynucleotide encoding the protein, a recombinant vector containing the polynucleotide, a transformant containing the recombinant vector, and production of the protein Methods and the like are provided. The above proteins, etc.
It is useful for developing new pharmaceuticals.

[0064]

[Sequence List] SEQUENCE LISTING <110> Pharmadesign, Inc. <120> Genes coding for nobel proteins APG1 <130> P01-0235 <160> 19 <210> 1 <211> 3663 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1) .. (3663) <400> 1 atg atg ttt cgc tca gat cga atg tgg agc tgc cat tgg aaa tgg aag 48 Met Met Phe Arg Ser Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys 1 5 10 15 ccc agt cct ctc ctg ttc tta ttt gct tta tat atc atg tgt gtt cct 96 Pro Ser Pro Leu Leu Phe Leu Phe Ala Leu Tyr Ile Met Cys Val Pro 20 25 30 cac tca gtg tgg gga tgt gcc aac tgc cga gtg gtt ttg tcc aac cct 144 His Ser Val Trp Gly Cys Ala Asn Cys Arg Val Val Leu Ser Asn Pro 35 40 45 tct ggg acc ttt act tct cca tgc tac cct aac gac tac cca aac agc 192 Ser Gly Thr Phe Thr Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Ser 50 55 60 cag gct tgc atg tgg acg ctc cga gcc ccc acc ggt tat atc att cag 240 Gln Ala Cys Met Trp Thr Leu Arg Ala Pro Thr Gly Tyr Ile Ile Gln 65 70 75 80 ata aca ttt aac gac ttt gac att gaa gaa gct ccc aat tgc att tat 288 Ile Thr Phe Asn Asp Phe Asp Ile Glu Glu Ala Pro Asn Cys Ile Tyr 85 90 95 gac tca tta tcc ctt gat aat gga gag agc cag act aaa ttt tgt gga 336 Asp Ser Leu Ser Leu Asp Asn Gly Glu Ser Gln Thr Lys Phe Cys Gly 100 105 110 gca act gcc aaa ggc cta tca ttt aac tca agt gcg aat gag atg cat 384 Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Ala Asn Glu Met His 115 120 125 gtg tcc ttt tca agt gac ttt agc atc cag aag aaa ggt ttc aat gcc 432 Val Ser Phe Ser Ser Asp Phe Ser Ile Gln Lys Lys Gly Phe Asn Ala 130 135 140 agc tac atc aga gtt gcc gtg tcc tta agg aat caa aag gtc att tta 480 Ser Tyr Ile Arg Val Ala Val Ser Leu Arg Asn Gln Lys Val Ile Leu 145 150 155 160 ccc cag aca tca gat gct tac cag gta tct gtt gca aaa agc atc tct 528 Pro Gln Thr Ser Asp Ala Tyr Gln Val Ser Val Ala Lys Ser Ile Ser 165 170 175 att cca gag ctc agt gct ttc aca ctc tgc ttt gaa gca acc aaa gtt 576 Ile Pro Glu Leu Ser Ala Phe Thr Leu Cys Phe Glu Ala Thr Lys Val 180 185 190 ggc cat gaa gac agt gat tgg aca gct ttc tcc tac tca aat gca tcc 624 Gly His Glu Asp Ser Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser 195 200 205 ttc aca caa ttg ctc agt ttt gga aag gcc aag agt ggc tac ttt cta 672 Phe Thr Gln Leu Leu Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu210 215 220 tcc att tct gat tca aaa tgt ttg ttg aat aat gca tta cct gtc aaa 720 Ser Ile Ser Asp Ser Lys Cys Leu Leu Asn Asn Ala Leu Pro Val Lys 225 230 235 240 gaa aaa gaa gac att ttt gca gaa agc ttt gaa cag ctc tgc ctt gtt 768 Glu Lys Glu Asp Ile Phe Ala Glu Ser Phe Glu Gln Leu Cys Leu Val 245 250 255 tgg aat aat tct ttg ggc tct att ggt gta aat ttc aaa aga aac tat 816 Trp Asn Asn Ser Le G Ile Gly Val Asn Phe Lys Arg Asn Tyr 260 265 270 gaa aca gtt cca tgt gat tct acc att agt aaa gtt att cct ggg aat 864 Glu Thr Val Pro Cys Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn 275 280 285 ggg aaa ttg ttg ttg ggc tcc aat caa aat gaa att gtc tct cta aaa 912 Gly Lys Leu Leu Leu Gly Ser Asn Gln Asn Glu Ile Val Ser Leu Lys 290 295 300 ggg gac att tat aac ttt cga ctt tgg aat tcc acc atg aat 960 Gly Asp Ile Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asn Ala Lys 305 310 315 320 atc ctc tcc aac ctc agc tgt aat gtg aaa ggg aat gta gtc gac tgg 1008 Ile Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Val Val Asp Trp 325 330 335 caa aat gac ttc tgg aat atc cca aac cta gct ctg aaa gct gaa agc 1056 Gln Asn Asp Phe Trp Asn Ile Pro Asn Leu Ala Leu Lys Ala Glu Ser 340 345 350 aac cta agc tgt ggt tcc ctg atc ccg ctc cca gca gca gaa ctg 1104 Asn Leu Ser Cys Gly Ser Tyr Leu Ile Pro Leu Pro Ala Ala Glu Leu 355 360 365 gcc agc tgt gca gac ctg ggg acc ctc tgt caa gct act gta aac tct 1152 Ala Ser Cys A Asp Leu Gly Thr Leu Cys Gln Ala Thr Val Asn Ser 370 375 380 cct agt act aca cca ccc act gtc acc act aac atg cct gtt act aac 1200 Pro Ser Thr Thr Pro Pro Thr Val Thr Thr Asn Met Pro Val Thr Asn 385 390 395 400 aga atc gat aaa caa agg aat gat gga att atc tat aga ata tcc gta 1248 Arg Ile Asp Lys Gln Arg Asn Asp Gly Ile Ile Tyr Arg Ile Ser Val 405 410 415 gtg att cag aac atc ctt cgt cac cct gag gta aaa gta cag agc aag 1296 Val Ile Gln Asn Ile Leu Arg His Pro Glu Val Lys Val Gln Ser Lys 420 425 430 gtg gca gaa tgg ctc aat tca acc ttc caa aat tgg aac tac acg gtt 1344 Val Ala Glu Trp Leu Asn Ser Thr Phe Gln Asn Trp Asn Tyr Thr Val 435 440 445 tat gt gtc gtt aat atc agt ttt cac ctg agt gct gga gag gac aag att 1392 Tyr Val Val Asn Ile Ser Phe His Leu Ser Ala Gly Glu Asp Lys Ile 450 455 460 aaa gtc aag aga agc ctt gag gat gag cca agg ttg gtg ctt tgg gcc 1440 Lys Val Lys Arg Ser Leu Glu Asp Glu Pro Arg Leu Val Leu Trp Ala 465 470 475 480 ctt cta gtt tac aat gct acc aac aat act aat tta gaa gga aaa atc 1488 Leu Leu Val Tyr Asn Ala Thr Asn Asn Thr Asn Leu Glu Gly Lys Ile 485 490 495 att cag cag aag ctc cta aaa aat aat gag tcc ttg gat gaa ggc ttg 1536 Ile Gln Gln Lys Leu Leu Lys Asn Aslu Glu Asp Glu Gly Leu 500 505 510 agg cta cat aca gtg aat gtg aga caa ctg ggt cat tgt ctt gcc atg 1584 Arg Leu His Thr Val Asn Val Arg Gln Leu Gly His Cys Leu Ala Met 515 520 525 gag gaa ccc aaa ggc tac tac tgg cca tct atc caa cct tct gaa tac 1632 Glu Glu Pro Lys Gly Tyr Tyr Trp Pro Ser Ile Gln Pro Ser Glu Tyr 530 535 540 gtt ctt cct tgt cca gac aag cct ggc ttt tct gct tct cgg ata tgt 1680 Val Leu Pro Cys Pro Asp Lys Pro Gly Phe Ser Ala Ser Arg Ile Cys 545 550 555 560 ttt tac aat gct acc aac cca ttg gta acc tac tgg gga cct gtt gat 1728 Phe Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp Gly Pro Val Asp 565 570 575 atc tcc aac tgt tta aaa gaa gca aat gaa gtt gct aac cag att tta 1776 Ile Ser Asn Cys Leu Lys Glu Ala Asn Glu Val Ala Asn Gln Ile Leu 580 585 590 aat tta act gct gat ggg cag aactta acc tca gcc aat att acc aac 1824 Asn Leu Thr Ala Asp Gly Gln Asn Leu Thr Ser Ala Asn Ile Thr Asn 595 600 605 att gtg gaa cag gtc aaa aga att gtg aat aaa gaa gaa aac att gat 1872 Ile Val Glu Gln Val Lys Ar Ile Val Asn Lys Glu Glu Asn Ile Asp 610 615 620 ata aca ctt ggc tca act cta atg aat ata ttt tct aat atc tta agc 1920 Ile Thr Leu Gly Ser Thr Leu Met Asn Ile Phe Ser Asn Ile Leu Ser 625 630 630 635 640 agt tca gac agt gac ttg ctt gag tca tct tct gaa gct tta aaa aca 1968 Ser Ser Asp Ser Asp Leu Leu Glu Ser Ser Ser Glu Ala Leu Lys Thr 645 650 655 att gat gaa ttg gcc ttc aag ata gac cta aat agc aca tc a cat gtg 2016 Ile Asp Glu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr Ser His Val 660 665 670 aat att aca act cgg aac ttg gct ctc agc gta tca tcc ctg tta cca 2064 Asn Ile Thr Thr Arg Asn Leu Ala Leu Ser Val Ser Ser Leu Leu Pro 675 680 685 ggg aca aat gca att tca aat ttt agc att ggt ctt cca agc aat aat 2112 Gly Thr Asn Ala Ile Ser Asn Phe Ser Ile Gly Leu Pro Ser Asn Asn 690 695 700 gaa tcg tat ttc cag atg gat ttt gag agt gga caa gtg gat cca ctg 2160 Glu Ser Tyr Phe Gln Met Asp Phe Glu Ser Gly Gln Val Asp Pro Leu 705 710 715 720 gca tct gta att ttg cct cca aac tta ctt gag aat tta agt cca gaa 2208 Ser Val Ile Leu Pro Pro Asn Leu Leu Glu Asn Leu Ser Pro Glu 725 730 735 gat tct gta tta gtt aga aga gca cag ttt act ttc ttc aac aaa act 2256 Asp Ser Val Leu Val Arg Arg Ala Gln Phe Thr Phe Phe Asn Lys Thr 740 745 750 gga ctt ttc cag gat gta gga ccc caa aga aaa act tta gtg agt tat 2304 Gly Leu Phe Gln Asp Val Gly Pro Gln Arg Lys Thr Leu Val Ser Tyr 755 760 765 gtg atg gcg tgc agt att gga aac att act atc cag aat ctg aag gat 2352 Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gln Asn Leu Lys Asp 770 775 780 cct gtt caa ata aaa atc aaa cat aca aga act cag gaa gtg cat cat 2400 Pro Val Gln Ile Lys Ile Lys His Thr Arg Thr Gln Glu Val His His 785 790 795 800 ccc atc tgt gcc ttc tgg gat ctg aac aaa aac aaa agt ttt gga gga 2448 Pro Ile Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly 805 810 810 815 tgg aac acg tca gga tgt gtt gca cac aga gat tca gat gca agt gag 2496 Trp Asn Thr Ser Gly Cys Val Ala His Arg Asp Ser Asp Ala Ser Glu 820 825 830 aca gtc tgc ctg tgt aac cac ttc aca cac tttgga gtt atg gac 2544 Thr Val Cys Leu Cys Asn His Phe Thr His Phe Gly Val Leu Met Asp 835 840 845 ctt cca aga agt gcc tca cag tta gat gca aga aac act aaa gtc ctc 2592 Leu Pro Arg Ser Ala Ser Gln Leu Asp Ala Arg Asn Thr Lys Val Leu 850 855 860 act ttc atc agc tat att ggg tgt gga ata tct gct att ttt tca gca 2640 Thr Phe Ile Ser Tyr Ile Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala 865 870 875 880 880 gca act ctc ctg aca tat gtt gct ttt gag aaa ttg cga agg gat tat 2688 Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg Arg Asp Tyr 885 890 895 ccc tcc aaa atc ttg atg aac ctg agc aca gcc ctg ctg atc ttg Pro Ser Lys Ile Leu Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn 900 905 910 ctc ctc ttc ctc cta gat ggc tgg atc acc tcc ttc aat gtg gat gga 2784 Leu Leu Phe Leu Leu Asp Gly Trp Ile Thr Ser Phe Val Asp Gly 915 920 925 ctt tgc att gct gtt gca gtc ctg ttg cat ttc ttc ctt ctg gca acc 2832 Leu Cys Ile Ala Val Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr 930 935 940 ttt acc tgg atg ggg cta gaa cac atg tac att gct cta gtt 2880 Phe Thr Trp Met Gly Leu Glu Ala Ile His Met Tyr Ile Ala Leu Val 945 950 955 960 aaa gta ttt aac act tac att cgc cga tac att cta aaa ttc tgc atc 2928 Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile 965 970 975 att ggc tgg ggt ttg cct gcc tta gtg gtg tca gtt gtt cta gcg agc 2976 Ile Gly Trp Gly Leu Pro Ala Leu Val Val Ser Val Val Leu Ala Ser 980 9 85 990 aga aac aac aat gaa gtc tat gga aaa gaa agt tat ggg aaa gaa aaa 3024 Arg Asn Asn Asn Glu Val Tyr Gly Lys Glu Ser Tyr Gly Lys Glu Lys 995 1000 1005 ggt gat gaa ttc tgt tgg att cagt gatca ttt tat gtg acc 3072 Gly Asp Glu Phe Cys Trp Ile Gln Asp Pro Val Ile Phe Tyr Val Thr 1010 1015 1020 tgt gct ggg tat ttt gga gtc atg ttt ttt ctg aac att gcc atg ttc 3120 Cys Ala Gly Tyr Phe Gly Val Met Pet Phe Leu Asn Ile Ala Met Phe 1025 1030 1035 1040 att gtg gta atg gtg cag atc tgt ggg agg aat ggc aag aga agc aac 3168 Ile Val Val Met Val Gln Ile Cys Gly Arg Asn Gly Lys Arg Ser Asn 1045 1050 10g cgg acc aga gaa gaa gtg tta agg aac ctg cgc agt gtg gtt agc 3216 Arg Thr Leu Arg Glu Glu Val Leu Arg Asn Leu Arg Ser Val Val Ser 1060 1065 1070 ttg acc ttt ctg ttg ggc atg aca tgg ggt ttt gcattc Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp 1075 1080 1085 gga ccc tta aat atc ccc ttc atg tac ctc ttc tcc atc ttc aat tca 3312 Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser 1090 1095 1100 tta caa ggc tta ttt ata ttc atc ttc cac tgt gct atg aag gag aat 3360 Leu Gln Gly Leu Phe Ile Phe Ile Phe His Cys Ala Met Lys Glu Asn 1105 1110 1115 1120 g aaa cag tgg cgg cgg cat ctc tgc tgt ggt aga ttt cgg tta 3408 Val Gln Lys Gln Trp Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu 1125 1130 1135 gca gat aac tca gat tgg agt aag aca gct acc aat atc atc aag aaa 3456 Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys 1140 1145 1150 agt tct gat aat cta gga aaa tct ttg tct tca agc tcc att ggt tcc 3504 Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser Ile Gly Ser 1155 1160 1165 aac tca acc tat ctt aca tcc aaa tct aaa tcc agc tct acc acc tat 3552 Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr 1170 1175 1180 ttc aaa agg aat agc cac aca gat aat gtc tcc tat gag cat tcc ttc 3600 Phe Lys Arg Asn Ser His Thr Asp Asn Val Ser Tyr Glu His Ser Phe 1185 1190 1195 1200 aac aaa agt gga tca ctc aga cag tgc ttc cat gga caa gt c ctt gtc 3648 Asn Lys Ser Gly Ser Leu Arg Gln Cys Phe His Gly Gln Val Leu Val 1205 1210 1215 aaa act ggc cca tgc 3663 Lys Thr Gly Pro Cys 1220 <210> 2 <211> 1221 <212> PRT <213> Homo sapiens <400> 2 Met Met Phe Arg Ser Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys 1 5 10 15 Pro Ser Pro Leu Leu Phe Leu Phe Ala Leu Tyr Ile Met Cys Val Pro 20 25 30 His Ser Val Trp Gly Cys Ala Asn Cys Arg Val Val Leu Ser Asn Pro 35 40 45 Ser Gly Thr Phe Thr Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Ser 50 55 60 Gln Ala Cys Met Trp Thr Leu Arg Ala Pro Thr Gly Tyr Ile Ile Gln 65 70 75 80 Ile Thr Phe Asn Asp Phe Asp Ile Glu Glu Ala Pro Asn Cys Ile Tyr 85 90 95 Asp Ser Leu Ser Leu Asp Asn Gly Glu Ser Gln Thr Lys Phe Cys Gly 100 105 110 Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Ala Asn Glu Met His 115 120 125 Val Ser Phe Ser Ser Asp Phe Ser Ile Gln Lys Lys Gly Phe Asn Ala 130 135 140 Ser Tyr Ile Arg Val Ala Val Ser Leu Arg Asn Gln Lys Val Ile Leu 145 150 155 160 Pro Gln Thr Ser Asp Ala Tyr Gln Val Ser Val Ala Lys Ser Ile Ser 165 170 175 Ile Pro Glu Leu Ser Ala Phe Thr Leu Cys Phe Glu Ala Thr Lys Val 180 185 190 Gly His Glu Asp Ser Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser 195 200 205 Phe Thr Gln Le u Leu Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu 210 215 220 Ser Ile Ser Asp Ser Lys Cys Leu Leu Asn Asn Ala Leu Pro Val Lys 225 230 235 240 Glu Lys Glu Asp Ile Phe Ala Glu Ser Phe Glu Gln Leu Cys Leu Val 245 250 255 Trp Asn Asn Ser Leu Gly Ser Ile Gly Val Asn Phe Lys Arg Asn Tyr 260 265 270 Glu Thr Val Pro Cys Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn 275 280 285 Gly Lys Leu Leu Leu Gly Ser Asn Gln Asn Glu Ile Val Ser Leu Lys 290 295 300 Gly Asp Ile Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asn Ala Lys 305 310 315 320 Ile Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Asn Val Val Asp Trp 325 330 335 Gln Asn Asp Phe Trp Asn Ile Pro Asn Leu Ala Leu Lys Ala Glu Ser 340 345 350 Asn Leu Ser Cys Gly Ser Tyr Leu Ile Pro Leu Pro Ala Ala Glu Leu 355 360 365 Ala Ser Cys Ala Asp Leu Gly Thr Leu Cys Gln Ala Thr Val Asn Ser 370 375 380 Pro Ser Thr Thr Pro Pro Thr Val Thr Thr Asn Met Pro Val Thr Asn 385 390 395 400 Arg Ile Asp Lys Gln Arg Asn Asp Gly Ile Ile Tyr Arg Ile Ser Val 405 410 415 Val Ile Gln A sn Ile Leu Arg His Pro Glu Val Lys Val Gln Ser Lys 420 425 430 Val Ala Glu Trp Leu Asn Ser Thr Phe Gln Asn Trp Asn Tyr Thr Val 435 440 445 Tyr Val Val Asn Ile Ser Phe His Leu Ser Ala Gly Glu Asp Lys Ile 450 455 460 Lys Val Lys Arg Ser Leu Glu Asp Glu Pro Arg Leu Val Leu Trp Ala 465 470 475 480 Leu Leu Val Tyr Asn Ala Thr Asn Asn Thr Asn Leu Glu Gly Lys Ile 485 490 495 495 Ile Gln Gln Lys Leu Leu Lys Asn Asn Glu Ser Leu Asp Glu Gly Leu 500 505 510 Arg Leu His Thr Val Asn Val Arg Gln Leu Gly His Cys Leu Ala Met 515 520 525 Glu Glu Pro Lys Gly Tyr Tyr Trp Pro Ser Ile Gln Pro Ser Glu Tyr 530 535 540 Val Leu Pro Cys Pro Asp Lys Pro Gly Phe Ser Ala Ser Arg Ile Cys 545 550 555 560 Phe Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp Gly Pro Val Asp 565 570 575 Ile Ser Asn Cys Leu Lys Glu Ala Asn Glu Val Ala Asn Gln Ile Leu 580 585 590 Asn Leu Thr Ala Asp Gly Gln Asn Leu Thr Ser Ala Asn Ile Thr Asn 595 600 605 Ile Val Glu Gln Val Lys Arg Ile Val Asn Lys Glu Glu Asn Ile Asp 610 615 620 620 Ile Thr Leu Gly S er Thr Leu Met Asn Ile Phe Ser Asn Ile Leu Ser 625 630 635 640 Ser Ser Asp Ser Asp Leu Leu Glu Ser Ser Ser Glu Ala Leu Lys Thr 645 650 655 Ile Asp Glu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr Ser His Val 660 665 670 Asn Ile Thr Thr Arg Asn Leu Ala Leu Ser Val Ser Ser Leu Leu Pro 675 680 685 Gly Thr Asn Ala Ile Ser Asn Phe Ser Ile Gly Leu Pro Ser Asn Asn 690 695 700 Glu Ser Tyr Phe Gln Met Asp Phe Glu Ser Gly Gln Val Asp Pro Leu 705 710 715 715 720 Ala Ser Val Ile Leu Pro Pro Asn Leu Leu Glu Asn Leu Ser Pro Glu 725 730 735 Asp Ser Val Leu Val Arg Arg Ala Gln Phe Thr Phe Phe Asn Lys Thr 740 745 750 Gly Leu Phe Gln Asp Val Gly Pro Gln Arg Lys Thr Leu Val Ser Tyr 755 760 765 Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gln Asn Leu Lys Asp 770 775 780 Pro Val Gln Ile Lys Ile Lys His Thr Arg Thr Gln Glu Val His His 785 790 795 800 Pro Ile Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly 805 810 815 Trp Asn Thr Ser Gly Cys Val Ala His Arg Asp Ser Asp Ala Ser Glu 820 825 830 Thr Val Cys LeuCys Asn His Phe Thr His Phe Gly Val Leu Met Asp 835 840 845 Leu Pro Arg Ser Ala Ser Gln Leu Asp Ala Arg Asn Thr Lys Val Leu 850 855 860 Thr Phe Ile Ser Tyr Ile Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala 865 870 875 880 Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg Arg Asp Tyr 885 890 895 Pro Ser Lys Ile Leu Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn 900 905 910 910 Leu Leu Phe Leu Leu Asp Gly Trp Ile Thr Ser Phe Asn Val Asp Gly 915 920 925 925 Leu Cys Ile Ala Val Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr 930 935 940 Phe Thr Trp Met Gly Leu Glu Ala Ile His Met Tyr Ile Ala Leu Val 945 950 955 960 Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile 965 970 975 Ile Gly Trp Gly Leu Pro Ala Leu Val Val Ser Val Val Leu Ala Ser 980 985 990 Arg Asn Asn Asn Glu Val Tyr Gly Lys Glu Ser Tyr Gly Lys Glu Lys 995 1000 1005 Gly Asp Glu Phe Cys Trp Ile Gln Asp Pro Val Ile Phe Tyr Val Thr 1010 1015 1020 Cys Ala Gly Tyr Phe Gly Val Met Phe Phe Leu Asn Ile Ala Met Phe 1025 1030 1035 1040 Ile Val Val Met Val Gln Ile Cys Gly Arg Asn Gly Lys Arg Ser Asn 1045 1050 1055 Arg Thr Leu Arg Glu Glu Val Leu Arg Asn Leu Arg Ser Val Val Ser 1060 1065 1070 Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp 1075 1080 1085 Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser 1090 1095 1100 Leu Gln Gly Leu Phe Ile Phe Ile Phe His Cys Ala Met Lys Glu Asn 1105 1110 1115 1120 Val Gln Lys Gln Trp Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu 1125 1130 1135 Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys 1140 1145 1150 Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser Ile Gly Ser 1155 1160 1165 Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr 1170 1175 1180 Phe Lys Arg Asn Ser His Thr Asp Asn Val Ser Tyr Glu His Ser Phe 1185 1190 1195 1200 Asn Lys Ser Gly Ser Leu Arg Gln Cys Phe His Gly Gln Val Leu Val 1205 1210 1215 Lys Thr Gly Pro Cys 1220 <210> 3 <211> 3750 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (1) .. (3750) <400> 3 atg atg ttt cgc tca gat cga atg tgg agc tgc cat tgg aaa tgg aag 48 Met Met Phe Arg Ser Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys 1 5 10 15 ccc agt cct ctc ctg ttc tta ttt gct tta tat atc atg tgt gtt cct 96 Pro Ser Pro Leu Leu Phe Leu Phe Ala Leu Tyr Ile Met Cys Val Pro 20 25 30 cac tca gtg tgg gga tgt gcc aac tgc cga gtg gtt ttg tcc aac cct 144 His Ser Val Trp Gly Cys Ala Asn Cys Arg Val Val Leu Ser Asn Pro 35 40 45 tct ggg acc ttt act tct cca tgc tac cct aac gac tac cca aac agc 192 Ser Gly Thr Phe Thr Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Ser 50 55 60 cag gct tgc atg tgg acg ctc cga gcc ccc acc ggt tat atc att cag 240 Gln Ala Cys Met Trp Thr Leu Arg Ala Pro Thr Gly Tyr Ile Ile Gln 65 70 75 80 ata aca ttt aac gac ttt gac att gaa gaa gct ccc aat tgc att tat 288 Ile Thr Phe Asn Asp Phe Asp Ile Glu Glu Ala Pro Asn Cys Ile Tyr 85 90 95 gac tca tta tcc ctt gat aat gga gag agc cag act aaa ttt tgt gga 336 Asp Ser Leu Ser Leu Asp Asn Gly Glu Ser Gln Thr Lys Phe Cys Gly 100 105 110 gca act gcc aaa ggc cta tca ttt aac tca agt gcg aat gag atg cat 384 Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Ala Asn Glu Met His 115 120 125 gtg tcc ttt tca agt gac ttt agc atc cag aag aaa ggt ttc aat gcc 432 Val Ser Phe Ser Ser Asp Phe Ser Ile Gln Lys Lys Gly Phe Asn Ala 130 135 140 agc tac atc aga gtt gcc gtg tcc tta agg aat caa aag gtc att tta 480 Ser Tyr Ile Arg Val Ala Val Ser Leu Arg Asn Gln Lys Val Ile Leu 145 150 155 160 ccc cag aca tca gat gct tac cag gta tct gtt gca aaa agc atc tct 528 Pro Gln Thr Ser Asp Ala Tyr Gln Val Ser Val Ala Lys Ser Ile Ser 165 170 175 att cca gag ctc agt gct ttc aca ctc tgc ttt gaa gca acc aaa gtt 576 Ile Pro Glu Leu Ser Ala Phe Thr Leu Cys Phe Glu Ala Thr Lys Val 180 185 190 ggc cat gaa gac agt gat tgg aca gct ttc tcc tac tca aat gca tcc 624 Gly His Glu Asp Ser Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser 195 200 205 ttc aca caa ttg ctc agt ttt gga aag gcc aag agt ggc tac ttt cta 672 Phe Thr Gln Leu Leu Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu 210 215 220 tcc att tct gat tca aaa tgt ttg ttg aat aat gca tta cct gtc aaa 720 Ser Ile Ser Asp Ser Lys Cys Leu Leu Asn Asn Ala Leu Pro Val Lys 225 230 235 240 gaa aaa gaa gac att ttt gca gaa agc ttt gaa cag ctc tgc ctt gtt 768 Glu Lys Glu Asp Ile Phe Ala Glu Ser Phe Glu Gln Leu Cys Leu Val 245 250 255 tgg aat aat tct ttg ggc tct att ggt gta aat ttc aaa aga aac tat 816 Trp Asn Asn Ser Le G Ile Gly Val Asn Phe Lys Arg Asn Tyr 260 265 270 gaa aca gtt cca tgt gat tct acc att agt aaa gtt att cct ggg aat 864 Glu Thr Val Pro Cys Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn 275 280 285 ggg aaa ttg ttg ttg ggc tcc aat caa aat gaa att gtc tct cta aaa 912 Gly Lys Leu Leu Leu Gly Ser Asn Gln Asn Glu Ile Val Ser Leu Lys 290 295 300 ggg gac att tat aac ttt cga ctt tgg aat tcc acc atg aat 960 Gly Asp Ile Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asn Ala Lys 305 310 315 320 atc ctc tcc aac ctc agc tgt aat gtg aaa ggg aat gta gtc gac tgg 1008 Ile Leu Ser Asn Leu Ser Cys Asn Val Lys Gly n Val Val Asp Trp 325 330 335 caa aat gac ttc tgg aat atc cca aac cta gct ctg aaa gct gaa agc 1056 Gln Asn Asp Phe Trp Asn Ile Pro Asn Leu Ala Leu Lys Ala Glu Ser 340 345 345 350 aac cta agc tgt ggt tac ctg atc ccg ctc cca gca gca gaa ctg 1104 Asn Leu Ser Cys Gly Ser Tyr Leu Ile Pro Leu Pro Ala Ala Glu Leu 355 360 365 gcc agc tgt gca gac ctg ggg acc ctc tgt caa gct act gta aac tct Cyla Ala Asp Leu Gly Thr Leu Cys Gln Ala Thr Val Asn Ser 370 375 380 cct agt act aca cca ccc act gtc acc act aac atg cct gtt act aac 1200 Pro Ser Thr Thr Pro Pro Thr Val Thr Thr Asn Met Pro Val Thr Asn 385 390 395 400 aga atc gat aaa caa agg aat gat gga att atc tat aga ata tcc gta 1248 Arg Ile Asp Lys Gln Arg Asn Asp Gly Ile Ile Tyr Arg Ile Ser Val 405 410 415 gtg att cag aac atc ctt cgt cac cct gagta aaa gta cag agc aag 1296 Val Ile Gln Asn Ile Leu Arg His Pro Glu Val Lys Val Gln Ser Lys 420 425 430 gtg gca gaa tgg ctc aat tca acc ttc caa aat tgg aac tac acg gtt 1344 Val Ala Glu Trp Leu Asn Se r Thr Phe Gln Asn Trp Asn Tyr Thr Val 435 440 445 445 tat gtc gtt aat atc agt ttt cac ctg agt gct gga gag gac aag att 1392 Tyr Val Val Asn Ile Ser Phe His Leu Ser Ala Gly Glu Asp Lys Ile 450 455 460 aaa gtc aag aga agc ctt gag gat gag cca agg ttg gtg ctt tgg gcc 1440 Lys Val Lys Arg Ser Leu Glu Asp Glu Pro Arg Leu Val Leu Trp Ala 465 470 475 475 480 ctt cta gtt tac aat gct acc aac aat act aat tta ga g aaa atc 1488 Leu Leu Val Tyr Asn Ala Thr Asn Asn Thr Asn Leu Glu Gly Lys Ile 485 490 495 att cag cag aag ctc cta aaa aat aat gag tcc ttg gat gaa ggc ttg 1536 Ile Gln Gln Lys Leu Leu Lys Asn Asn Leu Asp Glu Gly Leu 500 505 510 agg cta cat aca gtg aat gtg aga caa ctg ggt cat tgt ctt gcc atg 1584 Arg Leu His Thr Val Asn Val Arg Gln Leu Gly His Cys Leu Ala Met 515 520 525 gag gaa ccc aaa ggc tac tac tgg cca tct atc caa cct tct gaa tac 1632 Glu Glu Pro Lys Gly Tyr Tyr Tyr Trp Pro Ser Ile Gln Pro Ser Glu Tyr 530 535 540 gtt ctt cct tgt cca gac aag cct ggc ttt tct gct tct cgg ata tgt 1680 Val Leu Pro Cys Pro Asp Lys Pro Gly Phe Ser Ala Ser Arg Ile Cys 545 550 555 560 ttt tac aat gct acc aac cca ttg gta acc tac tgg gga cct gtt gat 1728 Phe Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp Gly Pro Val Asp 565 570 575 atc tcc aac tgt tta aaa gaa gca aat gaa gtt gct aac cag att tta 1776 Ile Ser Asn Cys Leu Lys Glu Ala Asn Glu Val Ala Asn Gln Ile Leu 580 585 590 aat tta act gct gat ggg cag aactta acc tca gcc aat att acc aac 1824 Asn Leu Thr Ala Asp Gly Gln Asn Leu Thr Ser Ala Asn Ile Thr Asn 595 600 605 att gtg gaa cag gtc aaa aga att gtg aat aaa gaa gaa aac att gat 1872 Ile Val Glu Gln Val Lys Ar Ile Val Asn Lys Glu Glu Asn Ile Asp 610 615 620 ata aca ctt ggc tca act cta atg aat ata ttt tct aat atc tta agc 1920 Ile Thr Leu Gly Ser Thr Leu Met Asn Ile Phe Ser Asn Ile Leu Ser 625 630 630 635 640 agt tca gac agt gac ttg ctt gag tca tct tct gaa gct tta aaa aca 1968 Ser Ser Asp Ser Asp Leu Leu Glu Ser Ser Ser Glu Ala Leu Lys Thr 645 650 655 att gat gaa ttg gcc ttc aag ata gac cta aat agc aca t ca cat gtg 2016 Ile Asp Glu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr Ser His Val 660 665 670 aat att aca act cgg aac ttg gct ctc agc gta tca tcc ctg tta cca 2064 Asn Ile Thr Thr Arg Asn Leu Ala Leu Ser Val Ser Ser Leu Leu Pro 675 680 685 ggg aca aat gca att tca aat ttt agc att ggt ctt cca agc aat aat 2112 Gly Thr Asn Ala Ile Ser Asn Phe Ser Ile Gly Leu Pro Ser Asn Asn 690 695 700 gaa tcg tat ttc cag atg gat ttt gag agt gga caa gtg gat cca ctg 2160 Glu Ser Tyr Phe Gln Met Asp Phe Glu Ser Gly Gln Val Asp Pro Leu 705 710 715 720 gca tct gta att ttg cct cca aac tta ctt gag aat tta agt cca gaa 2208 Ser Val Ile Leu Pro Pro Asn Leu Leu Glu Asn Leu Ser Pro Glu 725 730 735 gat tct gta tta gtt aga aga gca cag ttt act ttc ttc aac aaa act 2256 Asp Ser Val Leu Val Arg Arg Ala Gln Phe Thr Phe Phe Asn Lys Thr 740 745 750 gga ctt ttc cag gat gta gga ccc caa aga aaa act tta gtg agt tat 2304 Gly Leu Phe Gln Asp Val Gly Pro Gln Arg Lys Thr Leu Val Ser Tyr 755 760 765 gtg atg gcg tgc agt att gga aac at t act atc cag aat ctg aag gat 2352 Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gln Asn Leu Lys Asp 770 775 780 cct gtt caa ata aaa atc aaa cat aca aga act cag gaa gtg cat cat 2400 Pro Val Gln Ile Lys Ile Lys His Thr Arg Thr Gln Glu Val His His 785 790 795 800 ccc atc tgt gcc ttc tgg gat ctg aac aaa aac aaa agt ttt gga gga 2448 Pro Ile Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly 805 810 815 tgg aac acg tca gga tgt gtt gca cac aga gat tca gat gca agt gag 2496 Trp Asn Thr Ser Gly Cys Val Ala His Arg Asp Ser Asp Ala Ser Glu 820 825 830 aca gtc tgc ctg tgt aac cac ttc aca cac ttt gga ctg atg gac 2544 Thr Val Cys Leu Cys Asn His Phe Thr His Phe Gly Val Leu Met Asp 835 840 845 ctt cca aga agt gcc tca cag tta gat gca aga aac act aaa gtc ctc 2592 Leu Pro Arg Ser Ala Ser Gln Leu Asp Ala Arg Asn Thr Lys Val Leu 850 855 860 act ttc atc agc tat att ggg tgt gga ata tct gct att ttt tca gca 2640 Thr Phe Ile Ser Tyr Ile Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala 865 870 875 875 880 gca act ctc ctg aca tat gtt gct ttt gag aaa ttg cga agg gat tat 2688 Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg Arg Asp Tyr 885 890 895 ccc tcc aaa atc ttg atg aac ctg agc aca gcc ctg ctg atc ttg Pro Ser Lys Ile Leu Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn 900 905 910 ctc ctc ttc ctc cta gat ggc tgg atc acc tcc ttc aat gtg gat gga 2784 Leu Leu Phe Leu Leu Asp Gly Trp Ile Thr Ser Phe Val Asp Gly 915 920 925 ctt tgc att gct gtt gca gtc ctg ttg cat ttc ttc ctt ctg gca acc 2832 Leu Cys Ile Ala Val Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr 930 935 940 ttt acc tgg atg ggg cta gag cac atg tac att gct cta gtt 2880 Phe Thr Trp Met Gly Leu Glu Ala Ile His Met Tyr Ile Ala Leu Val 945 950 955 960 aaa gta ttt aac act tac att cgc cga tac att cta aaa ttc tgc atc 2928 Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile 965 970 975 att ggc tgg ggt ttg cct gcc tta gtg gtg tca gtt gtt cta gcg agc 2976 Ile Gly Trp Gly Leu Pro Ala Leu Val Val Ser Val Val Leu Ala Ser 980 985 990 aga aac aac aat gaa gtc tat gga aaa gaa agt tat ggg aaa gaa aaa 3024 Arg Asn Asn Asn Glu Val Tyr Gly Lys Glu Ser Tyr Gly Lys Glu Lys 995 1000 1005 ggt gat gaa ttc tgt tgg att cagta cat ttt tat gtg acc 3072 Gly Asp Glu Phe Cys Trp Ile Gln Asp Pro Val Ile Phe Tyr Val Thr 1010 1015 1020 tgt gct ggg tat ttt gga gtc atg ttt ttt ctg aac att gcc atg ttc 3120 Cys Ala Gly Tyr Phe Gly Val Met Pet Phe Leu Asn Ile Ala Met Phe 1025 1030 1035 1040 att gtg gta atg gtg cag atc tgt ggg agg aat ggc aag aga agc aac 3168 Ile Val Val Met Val Gln Ile Cys Gly Arg Asn Gly Lys Arg Ser Asn 1045 1050 10g cgg acc aga gaa gaa gtg tta agg aac ctg cgc agt gtg gtt agc 3216 Arg Thr Leu Arg Glu Glu Val Leu Arg Asn Leu Arg Ser Val Val Ser 1060 1065 1070 ttg acc ttt ctg ttg ggc atg aca tgg ggt ttt gcattc Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp 1075 1080 1085 gga ccc tta aat atc ccc ttc atg tac ctc ttc tcc atc ttc aat tca 3312 Gly Pro Leu Asn Ile Pro Phe Me t Tyr Leu Phe Ser Ile Phe Asn Ser 1090 1095 1100 tta caa ggc tta ttt ata ttc atc ttc cac tgt gct atg aag gag aat 3360 Leu Gln Gly Leu Phe Ile Phe Ile Phe His Cys Ala Met Lys Glu Asn 1105 1110 1115 1120 g cag aaa cag tgg cgg cgg cat ctc tgc tgt ggt aga ttt cgg tta 3408 Val Gln Lys Gln Trp Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu 1125 1130 1135 gca gat aac tca gat tgg agt aag aca gct acc aat atc atcag aaa 3456 Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys 1140 1145 1150 agt tct gat aat cta gga aaa tct ttg tct tca agc tcc att ggt tcc 3504 Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser Ile Gly Ser 1155 1160 1165 aac tca acc tat ctt aca tcc aaa tct aaa tcc agc tct acc acc tat 3552 Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Ser Thr Thr Tyr 1170 1175 1180 ttc aaa agg aat agc cac aca gac agt gct tcc atg gac aag tcc ttg 3600 Phe Lys Arg Asn Ser His Thr Asp Ser Ala Ser Met Asp Lys Ser Leu 1185 1190 1195 1200 tca aaa ctg gcc cat gct gat gga gat caa aca tca atc atc cct gtc 3648 Ser Lys Leu Ala His Ala Asp Gly Asp Gln Thr Ser Ile Ile Pro Val 1205 1210 1215 cat cag gtc att gat aag gtc aag ggt tat tgc aat gct cat tca gac 3696 His Gln Val Ile Asp Lys Val Lys Gly Tyr Cys Asn Ala His Ser Asp 1220 1225 1230 aac ttc tat aaa aat att atc atg tca gac acc ttc agc cac agc aca 3744 Asn Phe Tyr Lys Asn Ile Ile Met Ser Asp Thr Phe Ser His Ser Thr 1235 1240 1245 aag ttt 3750 Lys Phe 1250 <210> 4 <211> 1250 <212> PRT <213> Homo sapiens <400> 4 Met Met Phe Arg Ser Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys 1 5 10 15 Pro Ser Pro Leu Leu Phe Leu Phe Ala Leu Tyr Ile Met Cys Val Pro 20 25 30 His Ser Val Trp Gly Cys Ala Asn Cys Arg Val Val Leu Ser Asn Pro 35 40 45 Ser Gly Thr Phe Thr Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Ser 50 55 60 Gln Ala Cys Met Trp Thr Leu Arg Ala Pro Thr Gly Tyr Ile Ile Gln 65 70 75 80 Ile Thr Phe Asn Asp Phe Asp Ile Glu Glu Ala Pro Asn Cys Ile Tyr 85 90 95 Asp Ser Leu Ser Leu Asp Asn Gly Glu Ser Gln Thr Lys Phe Cys Gly 100 105 110 Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Ala Asn Glu Met His 115 120 125 Val Ser Phe Ser Ser Asp Phe Ser Ile Gln Lys Lys Gly Phe Asn Ala 130 135 140 Ser Tyr Ile Arg Val Ala Val Ser Leu Arg Asn Gln Lys Val Ile Leu 145 150 155 160 Pro Gln Thr Ser Asp Ala Tyr Gln Val Ser Val Ala Lys Ser Ile Ser 165 170 175 Ile Pro Glu Leu Ser Ala Phe Thr Leu Cys Phe Glu Ala Thr Lys Val 180 185 190 Gly His Glu Asp Ser Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser 195 200 205 Phe Thr Gln Le u Leu Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu 210 215 220 Ser Ile Ser Asp Ser Lys Cys Leu Leu Asn Asn Ala Leu Pro Val Lys 225 230 235 240 Glu Lys Glu Asp Ile Phe Ala Glu Ser Phe Glu Gln Leu Cys Leu Val 245 250 255 Trp Asn Asn Ser Leu Gly Ser Ile Gly Val Asn Phe Lys Arg Asn Tyr 260 265 270 Glu Thr Val Pro Cys Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn 275 280 285 Gly Lys Leu Leu Leu Gly Ser Asn Gln Asn Glu Ile Val Ser Leu Lys 290 295 300 Gly Asp Ile Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asn Ala Lys 305 310 315 320 Ile Leu Ser Asn Leu Ser Cys Asn Val Lys Gly Asn Val Val Asp Trp 325 330 335 Gln Asn Asp Phe Trp Asn Ile Pro Asn Leu Ala Leu Lys Ala Glu Ser 340 345 350 Asn Leu Ser Cys Gly Ser Tyr Leu Ile Pro Leu Pro Ala Ala Glu Leu 355 360 365 Ala Ser Cys Ala Asp Leu Gly Thr Leu Cys Gln Ala Thr Val Asn Ser 370 375 380 Pro Ser Thr Thr Pro Pro Thr Val Thr Thr Asn Met Pro Val Thr Asn 385 390 395 400 Arg Ile Asp Lys Gln Arg Asn Asp Gly Ile Ile Tyr Arg Ile Ser Val 405 410 415 Val Ile Gln A sn Ile Leu Arg His Pro Glu Val Lys Val Gln Ser Lys 420 425 430 Val Ala Glu Trp Leu Asn Ser Thr Phe Gln Asn Trp Asn Tyr Thr Val 435 440 445 Tyr Val Val Asn Ile Ser Phe His Leu Ser Ala Gly Glu Asp Lys Ile 450 455 460 Lys Val Lys Arg Ser Leu Glu Asp Glu Pro Arg Leu Val Leu Trp Ala 465 470 475 480 Leu Leu Val Tyr Asn Ala Thr Asn Asn Thr Asn Leu Glu Gly Lys Ile 485 490 495 495 Ile Gln Gln Lys Leu Leu Lys Asn Asn Glu Ser Leu Asp Glu Gly Leu 500 505 510 Arg Leu His Thr Val Asn Val Arg Gln Leu Gly His Cys Leu Ala Met 515 520 525 Glu Glu Pro Lys Gly Tyr Tyr Trp Pro Ser Ile Gln Pro Ser Glu Tyr 530 535 540 Val Leu Pro Cys Pro Asp Lys Pro Gly Phe Ser Ala Ser Arg Ile Cys 545 550 555 560 Phe Tyr Asn Ala Thr Asn Pro Leu Val Thr Tyr Trp Gly Pro Val Asp 565 570 575 Ile Ser Asn Cys Leu Lys Glu Ala Asn Glu Val Ala Asn Gln Ile Leu 580 585 590 Asn Leu Thr Ala Asp Gly Gln Asn Leu Thr Ser Ala Asn Ile Thr Asn 595 600 605 Ile Val Glu Gln Val Lys Arg Ile Val Asn Lys Glu Glu Asn Ile Asp 610 615 620 620 Ile Thr Leu Gly S er Thr Leu Met Asn Ile Phe Ser Asn Ile Leu Ser 625 630 635 640 Ser Ser Asp Ser Asp Leu Leu Glu Ser Ser Ser Glu Ala Leu Lys Thr 645 650 655 Ile Asp Glu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr Ser His Val 660 665 670 Asn Ile Thr Thr Arg Asn Leu Ala Leu Ser Val Ser Ser Leu Leu Pro 675 680 685 Gly Thr Asn Ala Ile Ser Asn Phe Ser Ile Gly Leu Pro Ser Asn Asn 690 695 700 Glu Ser Tyr Phe Gln Met Asp Phe Glu Ser Gly Gln Val Asp Pro Leu 705 710 715 715 720 Ala Ser Val Ile Leu Pro Pro Asn Leu Leu Glu Asn Leu Ser Pro Glu 725 730 735 Asp Ser Val Leu Val Arg Arg Ala Gln Phe Thr Phe Phe Asn Lys Thr 740 745 750 Gly Leu Phe Gln Asp Val Gly Pro Gln Arg Lys Thr Leu Val Ser Tyr 755 760 765 Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gln Asn Leu Lys Asp 770 775 780 Pro Val Gln Ile Lys Ile Lys His Thr Arg Thr Gln Glu Val His His 785 790 795 800 Pro Ile Cys Ala Phe Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly 805 810 815 Trp Asn Thr Ser Gly Cys Val Ala His Arg Asp Ser Asp Ala Ser Glu 820 825 830 Thr Val Cys LeuCys Asn His Phe Thr His Phe Gly Val Leu Met Asp 835 840 845 Leu Pro Arg Ser Ala Ser Gln Leu Asp Ala Arg Asn Thr Lys Val Leu 850 855 860 Thr Phe Ile Ser Tyr Ile Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala 865 870 875 880 Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg Arg Asp Tyr 885 890 895 Pro Ser Lys Ile Leu Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn 900 905 910 910 Leu Leu Phe Leu Leu Asp Gly Trp Ile Thr Ser Phe Asn Val Asp Gly 915 920 925 925 Leu Cys Ile Ala Val Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr 930 935 940 Phe Thr Trp Met Gly Leu Glu Ala Ile His Met Tyr Ile Ala Leu Val 945 950 955 960 Lys Val Phe Asn Thr Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile 965 970 975 Ile Gly Trp Gly Leu Pro Ala Leu Val Val Ser Val Val Leu Ala Ser 980 985 990 Arg Asn Asn Asn Glu Val Tyr Gly Lys Glu Ser Tyr Gly Lys Glu Lys 995 1000 1005 Gly Asp Glu Phe Cys Trp Ile Gln Asp Pro Val Ile Phe Tyr Val Thr 1010 1015 1020 Cys Ala Gly Tyr Phe Gly Val Met Phe Phe Leu Asn Ile Ala Met Phe 1025 1030 1035 1040 Ile Va l Val Met Val Gln Ile Cys Gly Arg Asn Gly Lys Arg Ser Asn 1045 1050 1055 Arg Thr Leu Arg Glu Glu Val Leu Arg Asn Leu Arg Ser Val Val Ser 1060 1065 1070 Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp 1075 1080 1085 Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser 1090 1095 1100 Leu Gln Gly Leu Phe Ile Phe Ile Phe His Cys Ala Met Lys Glu Asn 1105 1110 1115 1120 Val Gln Lys Gln Trp Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu 1125 1130 1135 Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys 1140 1145 1150 Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser Ile Gly Ser 1155 1160 1165 Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr 1170 1175 1180 Phe Lys Arg Asn Ser His Thr Asp Ser Ala Ser Met Asp Lys Ser Leu 1185 1190 1195 1200 Ser Lys Leu Ala His Ala Asp Gly Asp Gln Thr Ser Ile Ile Pro Val 1205 1210 1215 His Gln Val Ile Asp Lys Val Lys Gly Tyr Cys Asn Ala His Ser Asp 1220 1225 1230 Asn Phe Tyr Lys Asn Ile Ile Met Ser Asp Thr Phe Ser His Ser Thr 1235 1240 1245 Lys Phe 1250 <210> 5 <211> 3495 <212> DNA <213> Mus musculus <220> <221> CDS <222> (1) .. (3495) <400> 5 atg atg ttt gac act ctc ggg aag agg tgc tgc cct tgg aga ctg aag 48 Met Met Phe Asp Thr Leu Gly Lys Arg Cys Cys Pro Trp Arg Leu Lys 1 5 10 15 cca agc gcc ctg ctg ttc gtt gtt tta tgt gtt acc tgt gtt cct 96 Pro Ser Ala Leu Leu Phe Leu Phe Val Leu Cys Val Thr Cys Val Pro 20 25 30 ctc tca gtg tgc gga tgt ggc agc tgc aga ctt gtc ctg tcc aat cct 144 Leu Ser Val Cys Gly Cys Gly Ser Cys Arg Leu Val Leu Ser Asn Pro 35 40 45 tcc ggt acc ttt acg tct ccg tgt tac cct aat gac tac cct aat acc 192 Ser Gly Thr Phe Thr Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Thr 50 55 60 cag tct tgt tcg tgg acc ctc cga gcc cct gcc ggc tac atc att cag 240 Gln Ser Cys Ser Trp Thr Leu Arg Ala Pro Ala Gly Tyr Ile Ile Gln 65 70 75 80 ata acg ttc aat gac ttc gac att gaa gaa gct ccc aac t atc tat 288 Ile Thr Phe Asn Asp Phe Asp Ile Glu Glu Ala Pro Asn Cys Ile Tyr 85 90 95 gac tca ttg tcc ctc gat aat gga gag agc cag aca aaa ttc tgt gga 336 Asp Ser Leu Ser Leu Asp Asn Gly Glu Ser Gln Thr Lys Phe Cys Gly 100 105 110 gcg act gcc aag ggc ctg tca ttt aac tcc agc gtg aat gag atg cat 384 Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Val Asn Glu Met His 115 120 125 gtg tcc ttt tca agt gac ttt agt atc cag aag aaa ggt ttc aac gcc 432 Val Ser Phe Ser Ser Asp Phe Ser Ile Gln Lys Lys Gly Phe Asn Ala 130 135 140 agc tac atc aga gtt gct gtg tcc ttg agg aat caa aag gtc att ttg 480 Ser Tyr Ile Arg Val Ala Val Ser Leu Arg Asn Gln Lys Val Ile Leu 145 150 155 160 ccc cag aca tta gat gct tac cag gta tca gtt gca aaa agc atc tcc 528 Pro Gln Thr Leu Asp Ala Tyr Gln Val Ser Val Ala Lys Ser Ile Ser 165 170 175 att cct gaa ctc aaa gct ttc acg ctc tgt ttt gaa gcc tcc aaa gtt 576 Ile Pro Glu Leu Lys Ala Phe Thr Leu Cys Phe Glu Ala Ser Lys Val 180 185 190 ggc aat gaa ggt ggt gac tgg aca gct ttc tcc tac tca gac gag tcc 624 Gc Glu Gly Gly Asp Trp Thr Ala Phe Ser Tyr Ser Asp Glu Ser 195 200 205 ctt aca cag ctg ctc agt ctt gaa aag gcc agt aat ggc tac ttc ctg 672 Leu Thr Gln Leu Leu Ser Leu Glu Lys Ala Ser Asn Gly Tyr Phe Leu210 215 220 tcc atc tct ggc tca aga tgc ttg ttg aac aat gcg tta cct gtg aag 720 Ser Ile Ser Gly Ser Arg Cys Leu Leu Asn Asn Ala Leu Pro Val Lys 225 230 235 240 gac aaa gag gac atc ttc aca gaa aactt gag cag ctc tgt ctt gtg 768 Asp Lys Glu Asp Ile Phe Thr Glu Asn Leu Glu Gln Leu Cys Leu Val 245 250 255 tgg aat aat tct tgg ggc tcc att ggt ata aat ttc aaa aag aac tat 816 Trp Asn Asn Ser Trp G Ser Ile Gly Ile Asn Phe Lys Lys Asn Tyr 260 265 270 gaa aca gtt cca tgt gat tcc acc atc agt gct gtc gta ccc ggg gat 864 Glu Thr Val Val Pro Cys Asp Ser Thr Ile Ser Ala Val Val Pro Gly Asp 275 280 285 ggg aca ttg ctg ttg ggc tcc gac aga gat gag gtc gcc tct cta agg 912 Gly Thr Leu Leu Leu Gly Ser Asp Arg Asp Glu Val Ala Ser Leu Arg 290 295 300 ggc agc atc tat aac ttt cga ctt tgg aat ttt acc atgat 960 Gly Ser Ile Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asp Leu Lys 305 310 315 320 gcc ctc tcc aac ctc agc tgt agt gtg tct ggg aat gtc ata gac tgg 1008 Ala Leu Ser Asn Leu Ser Cys Ser Val Ser Gly Asn Val Ile Asp Trp 325 330 335 cac aat gac ttt tgg agc atc tca acc caa gct ctg aaa gcc gag ggc 1056 His Asn Asp Phe Trp Ser Ile Ser Thr Gln Ala Leu Lys Ala Glu Gly 340 345 350 aac ctg agc tgt ggt tcc tac ctg atc cag ctt cct gca gca gag ctg 1104 Asn Leu Ser Cys Gly Ser Tyr Leu Ile Gln Leu Pro Ala Ala Glu Leu 355 360 365 aca aac tgt tca gaa ctg ggg act ctc tgt caa gac gga ata atg tat 1152 Thr Asn Cys Ser Glu Leu Gly Thr Leu Cys Gln Asp Gly Ile Met Tyr 370 375 380 cga ata tct gtt gtg att cac aat gac ttt aat cac cct gaa gta aaa 1200 Arg Ile Ser Val Val Ile His Asn Asp Phe Asn His Pro Glu Val Lys 385 390 395 400 gtg cag acc aaa gta gca gaa tgg ctc aat tca acc ttt cag aat tgg 1248 Val Gln Thr Lys Val Ala Glu Trp Leu Asn Ser Thr Phe Gln Asn Trp 405 410 415 aac tac act gtt tat gtg gtt aat ata agt ttt cat caa aaa gta gga 1296 Asn Tyr Thr Val Tyr Val Val Asn Ile Ser Phe His Gln Lys Val Gly 420 425 430 gag gac agg atg aaa gtc aag aga gac atc atg gac gat gac aaa agg 1344 Glu Asp Arg Met Lys Val Lys Arg Asp Ile Met Asp Asp Asp Lys Arg 435 440 445 ttg gtg ctc tgg gcc ctt cta gtc tac aat gct acc aat aac gtc agc 1392 Leu Val Leu Trp Ala Leu Leu Val Tyr Asn Ala Thr Asn Asn Val Ser 450 a455 460460g gaa gag aag att aaa caa aag ctt atg aca aat aat gca tca 1440 Leu Asn Glu Glu Lys Ile Lys Gln Lys Leu Met Thr Asn Asn Ala Ser 465 470 475 475 480 cta gag gat gga ctg agg ctg tgt gaa gtc gac gg ggt 1488 Leu Glu Asp Gly Leu Arg Leu Cys Glu Val Asp Val Asn Gln Leu Gly 485 490 495 atg tgt agc gcc ttg gag gat cca gac ggc ttt agt tgg cca gcc acc 1536 Met Cys Ser Ala Leu Glu Asp Pro Asp Gly Phe Trp Pro Ala Thr 500 505 510 tta ccc tct gtc tac aaa caa cca tgt cca aac aag cct ggc ttt ttt 1584 Leu Pro Ser Val Tyr Lys Gln Pro Cys Pro Asn Lys Pro Gly Phe Phe 515 520 525 atg act cga gcg tgc ctt tct aat gga aca tca acc ttc tgg ggc cct 1632 Met Thr Arg Ala Cys Leu Ser Asn Gly Thr Ser Thr Phe Trp Gly Pro 530 535 540 gtt gac act tcc aac tgt tca aga caa tca aat gaa gtg gcc aat gag 1680 Val Asp Thr Ser Asn Cys Ser Arg Gln Ser Asn Glu Val Ala Asn Glu 545 550 555 560 att tta aac caa act ggt gat ggg cag aac ctc acc tcg gct aat atc 1728 Ile Leu Asn Gln Thr Gly Asp Gly Gln Asn Leu Thr Ser Ala Asn Ile 565 570 575 aac agc att gta gaa aag gtc aaa cgg atc gtg aac aaa gaa gaa aac 1776 Asn Ser Ile Val Glu Lys Val Lys Arg Ile Val Asn Lys Glu Glu Asn 580 585 590 att gac atc acc ctc ggc tcc aat ata ttt tct aat atc 1824 Ile Asp Ile Thr Leu Gly Ser Thr Leu Met Asn Ile Phe Ser Asn Ile 595 600 605 tta agc agt tca gat agc gat ttg ctt gag tct tct act gaa gct tta 1872 Leu Ser Ser Ser Asp Ser Asp Leu Leu Glu Ser Ser Thr Glu Ala Leu 610 615 620 aaa aca att gac gag cta gcc ttc aaa ata gac ctg aat agc acc cca 1920 Lys Thr Ile Asp Glu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr Pro 625 630 630 635 640 cat gtg aac att gag aca cag aat ttg gcc ctt gga gtc tca tcc cta 1968 His Val Asn Ile Glu Thr Gln Asn Leu Ala Leu Gly Val Ser Ser Leu 645 650 655 att cca gga aca aat gca cct tca aat ttt agc att ggc c tt cca agc 2016 Ile Pro Gly Thr Asn Ala Pro Ser Asn Phe Ser Ile Gly Leu Pro Ser 660 665 670 aat aat gaa tcg tac ttc cag atg gac ttc ggg aac gga cag aca gat 2064 Asn Asn Glu Ser Tyr Phe Gln Met Asp Phe Gly Asn Gly Gln Thr Asp 675 680 685 cca ctg gca tct gtg att ttg cct cca aat ttg ctt gag aat tta agc 2112 Pro Leu Ala Ser Val Ile Leu Pro Pro Asn Leu Leu Glu Asn Leu Ser 690 695 700 ccc gaa gat tct ttg gtc agg aga gca cag ttc act ttc ttc aac 2160 Pro Glu Asp Ser Val Leu Val Arg Arg Ala Gln Phe Thr Phe Phe Asn 705 710 715 720 aaa acc gga ctt ttc cag gat gtt gga tct caa aga aaa gtc ctc gtg 2 Thr Gly Leu Phe Gln Asp Val Gly Ser Gln Arg Lys Val Leu Val 725 730 735 agt tat gtg atg gcg tgc agc att gga aac att act atc cag aat ctg 2256 Ser Tyr Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gln Asn Leu 740 745 750 aaa gat ccg gtt caa atc aaa atc aaa cac acc aga aca cag gaa gtg 2304 Lys Asp Pro Val Gln Ile Lys Ile Lys His Thr Arg Thr Gln Glu Val 755 760 765 cat cat cct atc tgt gcc ttc tgg ga t atg aac aaa aac aaa agt ttc 2352 His His Pro Ile Cys Ala Phe Trp Asp Met Asn Lys Asn Lys Ser Phe 770 775 780 ggg ggg tgg aac acc tca gga tgt gtt gcc cac tct gat ttg gac gct 2400 Gly Gly Tly Asrp Thr Ser Gly Cys Val Ala His Ser Asp Leu Asp Ala 785 790 795 800 ggt gag acc att tgt ctg tgc agc cac ttc act cac ttt gga gtt ctg 2448 Gly Glu Thr Ile Cys Leu Cys Ser His Phe Thr His Phe Gly Val Leu 805 810 815 atg gat ctt cca agg agt gcc tca caa ata gat gga aga aac aca aaa 2496 Met Asp Leu Pro Arg Ser Ala Ser Gln Ile Asp Gly Arg Asn Thr Lys 820 825 830 gtc ctc acg ttc att acc tat att ggg tgc gga ata gcc att ttc 2544 Val Leu Thr Phe Ile Thr Tyr Ile Gly Cys Gly Ile Ser Ala Ile Phe 835 840 845 tca gct gca act ctc ctg aca tat gtt gct ttt gag aag ctg cgc agg 2592 Ser Ala Ala Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg Arg 850 855 860 gat tat ccc tcc aaa atc ctg atg aat ctg agc tcg gcc ttg ctc ttc 2640 Asp Tyr Pro Ser Lys Ile Leu Met Asn Leu Ser Ser Ala Leu Leu Phe 865 870 875 880c gct atc ttc ctc ctg gat ggc tgg gtc act tcc ttt ggc gtg 2688 Leu Asn Leu Ile Phe Leu Leu Asp Gly Trp Val Thr Ser Phe Gly Val 885 890 895 gct gga ctc tgc acg gct gtg gct gcc ctg ttgc ctg ttgc ctg ttgc Ala Gly Leu Cys Thr Ala Val Ala Ala Leu Leu His Phe Phe Leu Leu 900 905 910 gct acc ttc acc tgg atg ggg ctg gaa gcc atc cac atg tac att gct 2784 Ala Thr Phe Thr Trp Met Gly Leu Glu Ala Ile His Met Tyr Ile Ala 915 920 925 ctt gtg aaa gtg ttt aac act tac atc cac cgc tat att cta aaa ttc 2832 Leu Val Lys Val Phe Asn Thr Tyr Ile His Arg Tyr Ile Leu Lys Phe 930 935 940 tgc atc ata ggc tgg ggtg gct ctg ttg gtg gtg tca att att cta 2880 Cys Ile Ile Gly Trp Gly Leu Pro Ala Leu Val Val Ser Ile Ile Leu 945 950 955 960 gtg agc aga aga caa aat gaa gta tat gga aaa gaa agt tat ggg aaa 29g Val Ser Arg Asn Glu Val Tyr Gly Lys Glu Ser Tyr Gly Lys 965 970 975 gat cag gat gat gaa ttc tgc tgg att cag gat cct gtg gtg ttt tat 2976 Asp Gln Asp Asp Glu Phe Cys Trp Ile Gln Asp Pro Val Val Phe Tyr 980 985 990 gtg agc tgt gcc ggg tac ttc gga gtc atg ttc ttc ctg aat gtc gcc 3024 Val Ser Cys Ala Gly Tyr Phe Gly Val Met Phe Phe Leu Asn Val Ala 995 1000 1005 atg ttc att gtg gtc atg gtg ca aat gga aag aga 3072 Met Phe Ile Val Val Met Val Gln Ile Cys Gly Arg Asn Gly Lys Arg 1010 1015 1020 agc aac cgg acc ctg aga gaa gag gtt tta aga aac ctg cgc agt gtg 3120 Ser Asn Arg Thr Leu Arg Glu Leu Arg Asn Leu Arg Ser Val 1025 1030 1035 1040 gtc agc ctg acc ttc ctg ctt ggc atg acg tgg ggg ttt gct ttc ttt 3168 Val Ser Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe Phe 1045 1050 1055 gcc t ccc tta aat att cct ttc atg tac ctc ttc tcc atc ttc 3216 Ala Trp Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser Ile Phe 1060 1065 1070 aat tca tta caa ggt tta ttt ata ttc atc ttc cac tgt gcgg264 Asn Ser Leu Gln Gly Leu Phe Ile Phe Ile Phe His Cys Ala Met Lys 1075 1080 1085 gag aat gtt cag aaa cag tgg agg cgt cac ctc tgc tgt ggc agg ttt 3312 Glu Asn Val Gln Lys Gln Trp Arg Arg His Leu Cys Cys Gly Arg Phe 1090 1095 1100 cgg cta gca gac aac tca gat tgg agt aag aca gct acc aat atc atc 3360 Arg Leu Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile Ile 1105 1110 1115 1120 aag aag agc tcc gat aac ctg ggg aaa tct ttg tct tca agc tcc att 3408 Lys Lys Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ile 1125 1130 1135 ggc tcc aat tca aca tat ctc aca tcc aaa tca aag tcc agc tcc acc 3456 Gly Ser Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Thr 1140 1145 1150 acc tat ttc aaa aga aac agc cac tcg gat aat ttc tcc 3495 Thr Tyr Phe Lys Arg Asn Ser His Ser Asp Asn Phe Ser 1155 1160 1165 <210> 6 <211> 1165 <212> PRT <213> Mus musculus <400> 6 Met Met Phe Asp Thr Leu Gly Lys Arg Cys Cys Pro Trp Arg Leu Lys 1 5 10 15 Pro Ser Ala Leu Leu Phe Leu Phe Val Leu Cys Val Thr Cys Val Pro 20 25 30 Leu Ser Val Cys Gly Cys Gly Ser Cys Arg Leu Val Leu Ser Asn Pro 35 40 45 Ser Gly Thr Phe Thr Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Thr 50 55 60 Gln Ser Cys Ser Trp Thr Leu Arg Ala Pro Ala Gly Tyr Ile Ile Gln 65 70 75 80 Ile Thr Phe Asn Asp Phe Asp Ile Glu Glu Ala Pro Asn Cys Ile Tyr 85 90 95 Asp Ser Leu Ser Leu Asp Asn Gly Glu Ser Gln Thr Lys Phe Cys Gly 100 105 110 Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Val Asn Glu Met His 115 120 125 Val Ser Phe Ser Ser Asp Phe Ser Ile Gln Lys Lys Gly Phe Asn Ala 130 135 140 Ser Tyr Ile Arg Val Ala Val Ser Leu Arg Asn Gln Lys Val Ile Leu 145 150 155 160 Pro Gln Thr Leu Asp Ala Tyr Gln Val Ser Val Ala Lys Ser Ile Ser 165 170 175 Ile Pro Glu Leu Lys Ala Phe Thr Leu Cys Phe Glu Ala Ser Lys Val 180 185 190 Gly Asn Glu Gly Gly Asp Trp Thr Ala Phe Ser Tyr Ser Asp Glu Ser 195 200 205 Leu Thr Gln Le u Leu Ser Leu Glu Lys Ala Ser Asn Gly Tyr Phe Leu 210 215 220 Ser Ile Ser Gly Ser Arg Cys Leu Leu Asn Asn Ala Leu Pro Val Lys 225 230 235 240 Asp Lys Glu Asp Ile Phe Thr Glu Asn Leu Glu Gln Leu Cys Leu Val 245 250 255 Trp Asn Asn Ser Trp Gly Ser Ile Gly Ile Asn Phe Lys Lys Asn Tyr 260 265 270 Glu Thr Val Pro Cys Asp Ser Thr Ile Ser Ala Val Val Pro Gly Asp 275 280 285 Gly Thr Leu Leu Leu Gly Ser Asp Arg Asp Glu Val Ala Ser Leu Arg 290 295 300 Gly Ser Ile Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met Asp Leu Lys 305 310 315 320 Ala Leu Ser Asn Leu Ser Cys Ser Val Ser Gly Asn Val Ile Asp Trp 325 330 335 His Asn Asp Phe Trp Ser Ile Ser Thr Gln Ala Leu Lys Ala Glu Gly 340 345 350 Asn Leu Ser Cys Gly Ser Tyr Leu Ile Gln Leu Pro Ala Ala Glu Leu 355 360 365 Thr Thr Asn Cys Ser Glu Leu Gly Thr Leu Cys Gln Asp Gly Ile Met Tyr 370 375 380 Arg Ile Ser Val Val Ile His Asn Asp Phe Asn His Pro Glu Val Lys 385 390 395 400 400 Val Gln Thr Lys Val Ala Glu Trp Leu Asn Ser Thr Phe Gln Asn Trp 405 410 415 Asn Tyr Thr V al Tyr Val Val Asn Ile Ser Phe His Gln Lys Val Gly 420 425 430 Glu Asp Arg Met Lys Val Lys Arg Asp Ile Met Asp Asp Asp Lys Arg 435 440 445 Leu Val Leu Trp Ala Leu Leu Val Tyr Asn Ala Thr Asn Asn Val Ser 450 455 460 Leu Asn Glu Glu Lys Ile Lys Gln Lys Leu Met Thr Asn Asn Ala Ser 465 470 475 480 Leu Glu Asp Gly Leu Arg Leu Cys Glu Val Asp Val Asn Gln Leu Gly 485 490 495 Met Cys Ser Ala Leu Glu Asp Pro Asp Gly Phe Ser Trp Pro Ala Thr 500 505 510 510 Leu Pro Ser Val Tyr Lys Gln Pro Cys Pro Asn Lys Pro Gly Phe Phe 515 520 525 Met Thr Arg Ala Cys Leu Ser Asn Gly Thr Ser Thr Phe Trp Gly Pro 530 535 540 Val Asp Thr Ser Asn Cys Ser Arg Gln Ser Asn Glu Val Ala Asn Glu 545 550 555 560 Ile Leu Asn Gln Thr Gly Asp Gly Gln Asn Leu Thr Ser Ala Asn Ile 565 570 575 Asn Ser Ile Val Glu Lys Val Lys Arg Ile Val Asn Lys Glu Glu Asn 580 585 590 Ile Asp Ile Thr Leu Gly Ser Thr Leu Met Asn Ile Phe Ser Asn Ile 595 600 605 Leu Ser Ser Ser Asp Ser Asp Leu Leu Glu Ser Ser Thr Glu Ala Leu 610 615 620 Lys Thr Ile Asp G lu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr Pro 625 630 635 640 His Val Asn Ile Glu Thr Gln Asn Leu Ala Leu Gly Val Ser Ser Leu 645 650 655 Ile Pro Gly Thr Asn Ala Pro Ser Asn Phe Ser Ile Gly Leu Pro Ser 660 665 670 Asn Asn Glu Ser Tyr Phe Gln Met Asp Phe Gly Asn Gly Gln Thr Asp 675 680 685 Pro Leu Ala Ser Val Ile Leu Pro Pro Asn Leu Leu Glu Asn Leu Ser 690 695 700 Pro Glu Asp Ser Val Leu Val Arg Arg Ala Gln Phe Thr Phe Phe Asn 705 710 715 720 720 Lys Thr Gly Leu Phe Gln Asp Val Gly Ser Gln Arg Lys Val Leu Val 725 730 735 Ser Tyr Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gln Asn Leu 740 745 750 Lys Asp Pro Val Gln Ile Lys Ile Lys His Thr Arg Thr Gln Glu Val 755 760 765 His His Pro Ile Cys Ala Phe Trp Asp Met Asn Lys Asn Lys Ser Phe 770 775 780 Gly Gly Trp Asn Thr Ser Gly Cys Val Ala His Ser Asp Leu Asp Ala 785 790 795 800 Gly Glu Thr Ile Cys Leu Cys Ser His Phe Thr His Phe Gly Val Leu 805 810 815 Met Asp Leu Pro Arg Ser Ala Ser Gln Ile Asp Gly Arg Asn Thr Lys 820 825 830 Val Leu Thr PheIle Thr Tyr Ile Gly Cys Gly Ile Ser Ala Ile Phe 835 840 845 Ser Ala Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg Arg 850 855 860 Asp Tyr Pro Ser Lys Ile Leu Met Asn Leu Ser Ser Ala Leu Leu Phe 865 870 875 880 Leu Asn Leu Ile Phe Leu Leu Asp Gly Trp Val Thr Ser Phe Gly Val 885 890 895 Ala Gly Leu Cys Thr Ala Val Ala Ala Leu Leu His Phe Phe Leu Leu 900 905 910 Ala Thr Phe Thr Trp Met Gly Leu Glu Ala Ile His Met Tyr Ile Ala 915 920 925 925 Leu Val Lys Val Phe Asn Thr Tyr Ile His Arg Tyr Ile Leu Lys Phe 930 935 940 Cys Ile Ile Gly Trp Gly Leu Pro Ala Leu Val Val Ser Ile Ile Leu 945 950 955 960 Val Ser Arg Arg Gln Asn Glu Val Tyr Gly Lys Glu Ser Tyr Gly Lys 965 970 975 Asp Gln Asp Asp Glu Phe Cys Trp Ile Gln Asp Pro Val Val Phe Tyr 980 985 990 Val Ser Cys Ala Gly Tyr Phe Gly Val Met Phe Phe Leu Asn Val Ala 995 1000 1005 Met Phe Ile Val Val Met Val Gln Ile Cys Gly Arg Asn Gly Lys Arg 1010 1015 1020 Ser Asn Arg Thr Leu Arg Glu Glu Val Leu Arg Asn Leu Arg Ser Val 1025 1030 1035 1040 Val Ser Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe Phe 1045 1050 1055 Ala Trp Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser Ile Phe 1060 1065 1070 Asn Ser Leu Gln Gly Leu Phe Ile Phe Ile Phe His Cys Ala Met Lys 1075 1080 1085 Glu Asn Val Gln Lys Gln Trp Arg Arg His Leu Cys Cys Gly Arg Phe 1090 1095 1100 Arg Leu Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile Ile 1105 1110 1115 1120 Lys Lys Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser Ile 1125 1130 1135 Gly Ser Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser Thr 1140 1145 1150 Thr Tyr Phe Lys Arg Asn Ser His Ser Asp Asn Phe Ser 1155 1160 1165 <210> 7 <211> 6947 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (402) .. (4064) <400> 7 ccaagtacct agggtggtgg ccgagtcccg cctcccgcca gcgggggcga ggacctgcga 60 cgcgcacccc tgcctggccc ggtctcctca gcaccagccc cacgcacacc ctacttcctc 120 agcttctcgc cctcaccctg ccaacttccc tgcgaggagg gacctgccgc cagcctgctt 180 cctcgtccgc aggccctgcg ctgaacgctg ccgcgcccag ggttcacctt gcgccgtcgg 240 gaaagcccat gaactctcca gaaacggcgt aaaggagggt cccgccgcgg cgcagggctg 300 gggcgcctgg gttccccctg ggtggagcag cggcagcaga gcgggaaagt ggtggaggat 360 gatcttgcgg ccaaagggga cctcggcgca gtaatgtcaa c atg atg ttt cgc tca 416 Met Met Phe Arg Ser 1 5 gat cga atg tgg agc tgc cat tgg aaa tgg aag ccc agt cct ctc ctg 464 Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys Pro Ser Pro Leu Leu 10 15 20 ttc tta ttt gct tta tat atc atg tgt gtt cct cac tca gtg tgg gga 512 Phe Leu Phe Ala Leu Tyr Ile Met Cys Val Pro His Ser Val Trp Gly 25 30 35 tgt gcc aac tgc cga gtg gtt ttg tcc aac cct tct ggg acc ttt act 560 Cys Ala Asn Cys Arg Val Val Leu Ser Asn Pro Ser Gly Thr Phe Thr 40 45 50 tct cca tgc tac cct aac gac tac cca aac agc cag gct tgc atg tgg 608 Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Ser Gln Ala Cys Met Trp 55 60 65 acg ctc cga gcc ccc acc ggt tat atc att cag ata aca ttt aac gac 656 Thr Leu Arg Ala Pro Thr Gly Tyr Ile Ile Gln Ile Thr Phe Asn Asp 70 75 80 85 ttt gac att gaa gaa gct ccc aat tgc att tat gac tca tta tcc ctt 704 Phe Asp Ile Glu Glu Ala Pro Asn Cys Ile Tyr Asp Ser Leu Ser Leu 90 95 100 gat aat gga gag agc cag act aaa ttt tgt gga gca act gcc aaa ggc 752 Asp Asn Gly Glu Ser Gln Thr Lys Phe Cys Gly Ala Thr Ala Lys Gly 105 110 115 cta tca ttt aac tca agt gcg aat gag atg cat gtg tcc ttt tca agt 800 Leu Ser Phe Asn Ser Ser Ala Asn Glu Met His Val Ser Phe Ser Ser 120 125 130 gac ttt agc atc cag aag aaa ggt ttc aat gcc agc tac atc aga gtt 848 Asp Phe Ser Ile Gln Lys Lys Gly Phe Asn Ala Ser Tyr Ile Arg Val 135 140 145 gcc gtg tcc tta agg aat caa aag gtc att tta ccc cag aca tca gat 896 Ala Val Ser Leu Arg Asn Gln Lys Val Ile Leu Pro Gln Thr Ser Asp 150 155 160 165 gct tac cag gta tct gtt gca aaa agc atc tct att cca gag ctc agt 944 Ala Tyr Gln Val Ser Val Ala Lys Ser Ile Ser Ile Pro Glu Leu Ser 170 175 180 gct ttc aca ctc tgc ttt gaa gca acc aaa gtt ggc cat gaa gac agt 992 Ala Phe Thr Leu Cys Phe Glu Ala Thr Lys Val Gly His Glu Asp Ser 185 190 195 gat tgg aca gct ttc tcc tac tca aat gca tcc ttc aca caa ttg ctc 1040 Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser Phe Thrhr Gln Leu Leu 200 205 210 agt ttt gga aag gcc aag agt ggc tac ttt cta tcc att tct gat tca 1088 Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu Ser Ile Ser Asp Ser 215 220 225 aaa tgt ttg ttg aat aat gca tta cct gtc aaa gaa aaa gaa gac att 1136 Cys Leu Leu Asn Asn Ala Leu Pro Val Lys Glu Lys Glu Asp Ile 230 235 240 245 ttt gca gaa agc ttt gaa cag ctc tgc ctt gtt tgg aat aat tct ttg 1184 Phe Ala Glu Ser Phe Glu Gln Leu Cys Leu Val Trp Asn Ser Leu 250 255 260 ggc tct att ggt gta aat ttc aaa aga aac tat gaa aca gtt cca tgt 1232 Gly Ser Ile Gly Val Asn Phe Lys Arg Asn Tyr Glu Thr Val Pro Cys 265 270 275 gat tct acc att agt aaa gtt att cct ggg aat ggg aaa ttg ttg ttg 1280 Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn Gly Lys Leu Leu Leu 280 285 290 ggc tcc aat caa aat gaa att gtc tct cta aaa ggg gac att tat aac 1328 Glyn Sern Gln Glu Ile Val Ser Leu Lys Gly Asp Ile Tyr Asn 295 300 305 ttt cga ctt tgg aat ttt acc atg aat gcc aaa atc ctc tcc aac ctc 1376 Phe Arg Leu Trp Asn Phe Thr Met Asn Ala Lys Ile Leu Ser Asn Leu 310 315 320 325 agc tgt aat gtg aaa ggg aat gta gtc gac tgg caa aat gac ttc tgg 1424 Ser Cys Asn Val Lys Gly Asn Val Val Asp Trp Gln Asn Asp Phe Trp 330 335 340 aat atc cca aac cta gct ctg aaa gct agag agc tgt ggt 1472 Asn Ile Pro Asn Leu Ala Leu Lys Ala Glu Ser Asn Leu Ser Cys Gly 345 350 355 tcc tac ctg atc ccg ctc cca gca gca gaa ctg gcc agc tgt gca gac 1520 Ser Tyr Leu Ile Pro Leulu Ala Ala Leu Ala Ser Cys Ala Asp 360 365 370 ctg ggg acc ctc tgt caa gct act gta aac tct cct agt act aca cca 1568 Leu Gly Thr Leu Cys Gln Ala Thr Val Asn Ser Pro Ser Thr Thr Pro 375 380 385 ccc act gtc acc act aac atg cct gtt act aac aga atc gat aaa caa 1616 Pro Thr Val Thr Thr Asn Met Pro Val Thr Asn Arg Ile Asp Lys Gln 390 395 400 405 agg aat gat gga att atc tat aga ata tcc gta gtg att cag aac atc 1664 Arg Asn Asp Gly Ile Ile Tyr Arg Ile Ser Val Val Ile Gln Asn Ile 410 415 420 ctt cgt cac cct gag gta aaa gta cag agc aag gtg gca gaa tgg ctc 1712 Leu Arg His Pro Glu Val Lys Val Gln Ser Lys Val Ala Glu Trp Leu 425 430 435 aat tca acc ttc caa aat tgg aac tac acg gtt tat gtc gtt aat atc 1760 Asn Ser Thr Phe Gln Asn Trp Asn Tyr Thr Val Tyr Val Val Asn Ile 440 445 450 agt ttt cac ctg agt gct gga gag gac aag att aaa gtc aag aga agc 1808 Ser Phe His Leu Ser Ala Gly Glu Asp Lys Ile Lys Val Lys Arg Ser 455 460 465 ctt gag gat gag cca agg ttg gtg ctt tgg gcc ctt cta gtt tac aat 1856 Leu Glu Asp Glu Arg Leu Val Leu Trp Ala Leu Leu Val Tyr Asn 470 475 480 485 gct acc aac aat act aat tta gaa gga aaa atc att cag cag aag ctc 1904 Ala Thr Asn Asn Thr Asn Leu Glu Gly Lys Ile Ile Gln Gln Lys Leu 4 90 495 500 cta aaa aat aat gag tcc ttg gat gaa ggc ttg agg cta cat aca gtg 1952 Leu Lys Asn Asn Glu Ser Leu Asp Glu Gly Leu Arg Leu His Thr Val 505 510 515 aat gtg aga caa ctg ggt at tgt ctt gcc gag gaa ccc aaa ggc 2000 Asn Val Arg Gln Leu Gly His Cys Leu Ala Met Glu Glu Pro Lys Gly 520 525 530 tac tac tgg cca tct atc caa cct tct gaa tac gtt ctt cct tgt cca 2048 Tyr Tyr Trp Pro Ser Ile Gln Pro Ser Glu Tyr Val Leu Pro Cys Pro 535 540 545 gac aag cct ggc ttt tct gct tct cgg ata tgt ttt tac aat gct acc 2096 Asp Lys Pro Gly Phe Ser Ala Ser Arg Ile Cys Phe Tyr Asn Ala Thr 550 555 560 560 565 aac cca ttg gta acc tac tgg gga cct gtt gat atc tcc aac tgt tta 2144 Asn Pro Leu Val Thr Tyr Trp Gly Pro Val Asp Ile Ser Asn Cys Leu 570 575 580 aaa gaa gca aat gaa gtt gct aac cag att tta aat tta act gct gat 2192 Lys Glu Ala Asn Glu Val Ala Asn Gln Ile Leu Asn Leu Thr Ala Asp 585 590 595 ggg cag aac tta acc tca gcc aat att acc aac att gtg gaa cag gtc 2240 Gly Gln Asn Leu Thr Ser Ala Asn Ile Thr Asn Il e Val Glu Gln Val 600 605 610 aaa aga att gtg aat aaa gaa gaa aac att gat ata aca ctt ggc tca 2288 Lys Arg Ile Val Asn Lys Glu Glu Asn Ile Asp Ile Thror Leu Gly Ser 615 620 625 625 act cta atg aat ata ttt tct aat atc tta agc agt tca gac agt gac 2336 Thr Leu Met Asn Ile Phe Ser Asn Ile Leu Ser Ser Ser Asp Ser Asp 630 635 640 645 ttg ctt gag tca tct tct gaa gct tta aaa aca att gat gaa ttg gcc 2384u Glu Ser Ser Ser Glu Ala Leu Lys Thr Ile Asp Glu Leu Ala 650 655 660 ttc aag ata gac cta aat agc aca tca cat gtg aat att aca act cgg 2432 Phe Lys Ile Asp Leu Asn Ser Thr Ser His Val Asn Ile Thr Thr Arg 665 670 675 aac ttg gct ctc agc gta tca tcc ctg tta cca ggg aca aat gca att 2480 Asn Leu Ala Leu Ser Val Ser Ser Leu Leu Pro Gly Thr Asn Ala Ile 680 685 690 tca aat ttt agc att ggt ctt acagat gaa tcg tat ttc cag 2528 Ser Asn Phe Ser Ile Gly Leu Pro Ser Asn Asn Glu Ser Tyr Phe Gln 695 700 705 atg gat ttt gag agt gga caa gtg gat cca ctg gca tct gta att ttg 2576 Met Asp Phe Glu Ser Gly Gl n Val Asp Pro Leu Ala Ser Val Ile Leu 710 715 720 725 cct cca aac tta ctt gag aat tta agt cca gaa gat tct gta tta gtt 2624 Pro Pro Asn Leu Leu Glu Asn Leu Ser Pro Glu Asp Ser Val Leu Val 730 735 740 aga aga gca cag ttt act ttc ttc aac aaa act gga ctt ttc cag gat 2672 Arg Arg Ala Gln Phe Thr Phe Phe Asn Lys Thr Gly Leu Phe Gln Asp 745 750 755 gta gga ccc caa aga aaa act tta gtg ggt atg gtg atg tgc agt 2720 Val Gly Pro Gln Arg Lys Thr Leu Val Ser Tyr Val Met Ala Cys Ser 760 765 770 att gga aac att act atc cag aat ctg aag gat cct gtt caa ata aaa 2768 Ile Gly Asn Ile Thr Ile Gln Asn Leu Lys Asp Pro Val Gln Ile Lys 775 780 785 atc aaa cat aca aga act cag gaa gtg cat cat ccc atc tgt gcc ttc 2816 Ile Lys His Thr Arg Thr Gln Glu Val His His Pro Ile Cys Ala Phe 790 795 800 805 tgg gat ctg aac aaa aac aaa agt ttt gga gga tgg aac acg tca gga 2864 Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly Trp Asn Thr Ser Gly 810 815 820 tgt gtt gca cac aga gat tca gat gca agt gag aca gtc tgc ctg tgt 2912 Cy Val Ala His Arg Asp Ser Asp Ala Ser Glu Thr Val Cys Leu Cys 825 830 835 aac cac ttc aca cac ttt gga gtt ctg atg gac ctt cca aga agt gcc 2960 Asn His Phe Thr His Phe Gly Val Leu Met Asp Leu Pro Arg Ser Ala 840 845 850 tca cag tta gat gca aga aac act aaa gtc ctc act ttc atc agc tat 3008 Ser Gln Leu Asp Ala Arg Asn Thr Lys Val Leu Thr Phe Ile Ser Tyr 855 860 860 att ggg tgt gga ata tct gct att tttca gca gca act ctc ctg aca 3056 Ile Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala Ala Thr Leu Leu Thr 870 875 880 885 885 tat gtt gct ttt gag aaa ttg cga agg gat tat ccc tcc aaa atc ttg 3104 Tyr Val Ala Phe Glu Ly Leu Arg Arg Asp Tyr Pro Ser Lys Ile Leu 890 895 900 atg aac ctg agc aca gcc ctg ctg ttc ctg aat ctc ctc ttc ctc cta 3152 Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn Leu Leu Phe Leu Leu 905 ggc tgg atc acc tcc ttc aat gtg gat gga ctt tgc att gct gtt 3200 Asp Gly Trp Ile Thr Ser Phe Asn Val Asp Gly Leu Cys Ile Ala Val 920 925 930 gca gtc ctg ttg cat ttc ttc ctt ctg gca acctt acc gg atg ggg 3248 Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr Phe Thr Trp Met Gly 935 940 945 cta gaa gca att cac atg tac att gct cta gtt aaa gta ttt aac act 3296 Leu Glu Ala Ile His Met Tyr Ile Ala Leu Val Lys Val Phe Asn Thr 950 955 960 965 tac att cgc cga tac att cta aaa ttc tgc atc att ggc tgg ggt ttg 3344 Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile Ile Gly Trp Gly Leu 970 975 980 cct g gtg tca gtt gtt cta gcg agc aga aac aac aat gaa 3392 Pro Ala Leu Val Val Ser Val Val Leu Ala Ser Arg Asn Asn Asn Glu 985 990 995 gtc tat gga aaa gaa agt tat ggg aaa gaa aaa ggt gat gaa ttc gtc Tyr Gly Lys Glu Ser Tyr Gly Lys Glu Lys Gly Asp Glu Phe Cys 1000 1005 1010 tgg att caa gat cca gtc ata ttt tat gtg acc tgt gct ggg tat ttt 3488 Trp Ile Gln Asp Pro Val Ile Phe Tyr Val Thr Cys Ala Gly Tyr Phe 1015 1020 1025 gga gtc atg ttt ttt ctg aac att gcc atg ttc att gtg gta atg gtg 3536 Gly Val Met Phe Phe Leu Asn Ile Ala Met Phe Ile Val Val Met Val 1030 1035 1040 1045 cag atc tgt ggg agg aat ggc aag aga agc aac cgg acc ctg aga gaa 3584 Gln Ile Cys Gly Arg Asn Gly Lys Arg Ser Asn Arg Thr Leu Arg Glu 1050 1055 1060 gaa gtg tta agg aac ctg cgc agt gtg gtt agc ttg acct gttg acct Leu Arg Asn Leu Arg Ser Val Val Ser Leu Thr Phe Leu Leu 1065 1070 1075 ggc atg aca tgg ggt ttt gca ttc ttt gcc tgg gga ccc tta aat atc 3680 Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp Gly Pro Leu Asn Ile 1080 1085 1090 ccc ttc atg tac ctc ttc tcc atc ttc aat tca tta caa ggc tta ttt 3728 Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser Leu Gln Gly Leu Phe 1095 1100 1105 ata ttc atc ttc cac tgt gag atg gtt cag aaa cag tgg 3776 Ile Phe Ile Phe His Cys Ala Met Lys Glu Asn Val Gln Lys Gln Trp 1110 1115 1120 1125 cgg cgg cat ctc tgc tgt ggt aga ttt cgg tta gca gat aac tca gat 3824 Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu Ala Asp Asn Ser Asp 1130 1135 1140 tgg agt aag aca gct acc aat atc atc aag aaa agt tct gat aat cta 3872 Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys Ser Ser Asp A sn Leu 1145 1150 1155 gga aaa tct ttg tct tca agc tcc att ggt tcc aac tca acc tat ctt 3920 Gly Lys Ser Leu Ser Ser Ser Ser Ile Gly Ser Asn Ser Thr Tyr Leu 1160 1165 1170 aca tcc aaa tct aaa tcc agc tct acc acc tat ttc aaa agg aat agc 3968 Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr Phe Lys Arg Asn Ser 1175 1180 1185 cac aca gat aat gtc tcc tat gag cat tcc ttc aac aaa agt gga tca 4016 His Thr Asp Asn Val Ser Tyr Glu His Ser Phe Asn Lys Ser Gly Ser 1190 1195 1200 1205 ctc aga cag tgc ttc cat gga caa gtc ctt gtc aaa act ggc cca tgc 4064 Leu Arg Gln Cys Phe His Gly Gln Val Leu Val Lys Thr Gly Pro Cys 1210 1215 1220 tgatggagat caaacatcaa tcatccctgt cctcaggtca ttgataaggt caagggttat 4124 tgcaatgctc attcagacaa cttctataaa aatattatca tgtcagacac cttcagccac 4184 agcacaaagt tttaatgtct ttaagaaaaa gaaatcaatc tgcagaaatg tgaagatttg 4244 caagcagtgt aaactgcaac tagtgatgta aatgtgctat tacctaggta actgcatata 4304 tataaggaat gtattttgtt aagaaggctt ttgtgaaatt cagaattttt ctttttaata 4364 tatttcttcc atggaagagt tgtc atcact aaaacttcag tactgagagt aacatgactc 4424 agtagccaca gaagctatga tttgtaaaat atataattga atcagagtaa tcataatgca 4484 ggggagacat tcaaattaga gacaagggag aagcaatgct gaggaagacc ctagatagag 4544 ctcattttac tccacctaat cgttatatct ggatataccc attttctgca tcttctttct 4604 caacaataaa aaatgtaact attttgaatg cccacaaatc ccattccagt gttactttct 4664 gtgaatgcag taccatattc tcattttcaa tgacatttca accacaggca gaaaagactg 4724 tttactcctt gacccaaaga ttaaaaagga ttttttatta ttttaaatat tacaccttca 4784 gaaccataac atgcttaaga aaactttccc aaaatgttga cctagttaaa tgaggctata 4844 taaatttcta atattttact tattctattc aaggcatagg gccaaagcat taagtataat 4904 ttaatcccat acattcgagt taagtttagt gttgatgttc catcattctg gacctcccag 4964 gagttgttta agaatgaatc tcttacacct ctacttttgc ccctctactg tatattaagc 5024 ccataggctt gtgggaggaa ggagaatttc cattaggcaa gctgtatgca gtggaatttt 5084 ccttttagga gacacacaat taagactctc tggttctgtc cttgctttgg agactttaag 5144 acatttccta aagcacaaat aaaagcctcg tatttcccca ttgagagttt tgttccaagg 5204 aatatgaagt gagacatatg ggtgagtcat aataatcaaa ataatttatg aagagctggg 5264 tctgcaatag ctagtctaaa aactacttgt gtgtcagtcc tctggttata gtatataaga 5324 gcctgaggag gtctggcaag atagatggtg tattatttat ggatcaggct gctgcataca 5384 aaccttgcat actattatgc agcttaccta actctcagac tattctgagt aatgcttgct 5444 tgctaatgaa tgtataggag accacattgt aattgttctt agatgatgga gtccatgcag 5504 tttcttagaa atcggtctca gtgcatgctg tgctttttca catttgctct gggttatctg 5564 ggaagtatca ggttctggga ggcaacagca ttaagtgata agaaaaggag acattctggc 5624 aaagccaatc tgcttaaagg caaagtccag aacctggaac ctagaggcct ttctctctgc 5684 acgaaaaaca ggtagtttgc agtctgagat atgggagagc ttttaggcta cacagcaacc 5744 caagggacct ctcacctttt gctgagcttc aatcaggaag ctatttgcct ggctccagca 5804 gatgatgaga taatgaggta gtgggttttt tattactgtt ccattttgca acatcctgca 5864 acaccatcct gggagacaag agcattaccc agcttggctt tcacggggga gggttgtatt 5924 cagtaaaaaa gaatagtaaa tataaggtca ctgagattct aagtaagata gtaaatctaa 5984 ggtcactgag ccaaatcctt ttcaataggc atatattaac aggctgctta ttttggcgga 6044 ggttacatat ggatgaaaat gaatcttagt cactg aatat tcatatacat ttcccccaaa 6104 accttagaca ttcatagtag attttaatta gttagctttc taactagtca gatttctgcc 6164 caaagtgctt agtcaatagt aattaagata taggtaatta agatatagct tcaaaaatgg 6224 ctttgctttt gatttctact catattcgta tggctccaga aaaatatttt tttcatattt 6284 gacaatgtca gctccacttt agaaattttc aataaccaga tgagaaaaaa attaagaaat 6344 tgctcaaggg aaacatttgt aaatggattt gaaagattga gccaaattct gttgtcagtt 6404 ctaagcatgc agttctcacc tccatttagt cccccatcag aacagaggtc aggaatttag 6464 ctggggagcc taaatttagt tcagcttacc tttgagaata gcatcaattc agactctctt 6524 ttcattatgt tttcttttct ttttccctct ttttaaacta cattgtgtta gagtcatagt 6584 ctaggatcct gagagatttt ccattcttgt caccattcac ttgcattgta aagattttct 6644 ttgtctgttg ttggcataga ttcttttgta catatttatt tatttgtgtt tatatatgtc 6704 aattggtttc ctttcttagc ttgatattgc ctagctttgt tgttttaatt aactttctat 6764 tagagagact gtatatattt tttctaaata ctttgtgaaa tcatttttgg tagcaatatc 6824 tttgaatatg atgaataaaa gtgactgtga gtgcaaatag aattagcagt aagaagctac 6884 tctagctaat ttgccatttt acttaaatgg aaaatgtttt tcaaataaat acttatgttg 6944 ttc 6947 <210> 8 <211> 6902 <212> DNA <213> Homo sapiens <220> <221> CDS <222> (402) .. (4151) <400> 8 ccaagtacct agggtggtgg ccgagtcccg cctcccgcca gcgggggcga ggacctgcga 60 cgcgcacccc tgcctggccc ggtctcctca gcaccagccc cacgcacacc ctacttcctc 120 agcttctcgc cctcaccctg ccaacttccc tgcgaggagg gacctgccgc cagcctgctt 180 cctcgtccgc aggccctgcg ctgaacgctg ccgcgcccag ggttcacctt gcgccgtcgg 240 gaaagcccat gaactctcca gaaacggcgt aaaggagggt cccgccgcgg cgcagggctg 300 gggcgcctgg gttccccctg ggtggagcag cggcagcaga gcgggaaagt ggtggaggat 360 gatcttgcgg ccaaagggga cctcggcgca gtaatgtcaa c atg atg ttt cgc tca 416 Met Met Phe Arg Ser 1 5 gat cga atg tgg agc tgc cat tgg aaa tgg aag ccc agt cct ctc ctg 464 Asp Arg Met Trp Ser Cys His Trp Lys Trp Lys Pro Ser Pro Leu Leu 10 15 20 ttc tta ttt gct tta tat atc atg tgt gtt cct cac tca gtg tgg gga 512 Phe Leu Phe Ala Leu Tyr Ile Met Cys Val Pro His Ser Val Trp Gly 25 30 35 tgt gcc aac tgc cga gtg gtt ttg tcc aac cct tct ggg acc ttt act 560 Cys Ala Asn Cys Arg Val Val Leu Ser Asn Pro Ser Gly Thr Phe Thr 40 45 50 tct cca tgc tac cct aac gac tac cca aac agc cag gct tgc atg tgg 608 Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn Ser Gln Ala Cys Met Trp 55 60 65 acg ctc cga gcc ccc acc ggt tat atc att cag ata aca ttt aac gac 656 Thr Leu Arg Ala Pro Thr Gly Tyr Ile Ile Gln Ile Thr Phe Asn Asp 70 75 80 85 ttt gac att gaa gaa gct ccc aat tgc att tat gac tca tta tcc ctt 704 Phe Asp Ile Glu Glu Ala Pro Asn Cys Ile Tyr Asp Ser Leu Ser Leu 90 95 100 gat aat gga gag agc cag act aaa ttt tgt gga gca act gcc aaa ggc 752 Asp Asn Gly Glu Ser Gln Thr Lys Phe Cys Gly Ala Thr Ala Lys Gly 105 110 115 cta tca ttt aac tca agt gcg aat gag atg cat gtg tcc ttt tca agt 800 Leu Ser Phe Asn Ser Ser Ala Asn Glu Met His Val Ser Phe Ser Ser 120 125 130 gac ttt agc atc cag aag aaa ggt ttc aat gcc agc tac atc aga gtt 848 Asp Phe Ser Ile Gln Lys Lys Gly Phe Asn Ala Ser Tyr Ile Arg Val 135 140 145 gcc gtg tcc tta agg aat caa aag gtc att tta ccc cag aca tca gat 896 Ala Val Ser Leu Arg Asn Gln Lys Val Ile Leu Pro Gln Thr Ser Asp 150 155 160 165 gct tac cag gta tct gtt gca aaa agc atc tct att c ca gag ctc agt 944 Ala Tyr Gln Val Ser Val Ala Lys Ser Ile Ser Ile Pro Glu Leu Ser 170 175 180 gct ttc aca ctc tgc ttt gaa gca acc aaa gtt ggc cat gaa gac agt 992 Ala Phe Thr Leu Cys Phe Glu Ala Thr Lys Val Gly His Glu Asp Ser 185 190 195 gat tgg aca gct ttc tcc tac tca aat gca tcc ttc aca caa ttg ctc 1040 Asp Trp Thr Ala Phe Ser Tyr Ser Asn Ala Ser Phe Thrhr Gln Leu Leu 200 205 210 agt ttt gga aag gcc aag agt ggc tac ttt cta tcc att tct gat tca 1088 Ser Phe Gly Lys Ala Lys Ser Gly Tyr Phe Leu Ser Ile Ser Asp Ser 215 220 225 aaa tgt ttg ttg aat aat gca tta cct gtc aaa gaa aaa gaa gac att 1136 Cys Leu Leu Asn Asn Ala Leu Pro Val Lys Glu Lys Glu Asp Ile 230 235 240 245 ttt gca gaa agc ttt gaa cag ctc tgc ctt gtt tgg aat aat tct ttg 1184 Phe Ala Glu Ser Phe Glu Gln Leu Cys Leu Val Trp Asn Ser Leu 250 255 260 ggc tct att ggt gta aat ttc aaa aga aac tat gaa aca gtt cca tgt 1232 Gly Ser Ile Gly Val Asn Phe Lys Arg Asn Tyr Glu Thr Val Pro Cys 265 270 275 gat tct acc att agt aaa gtt att cct ggg aat ggg aaa ttg ttg ttg 1280 Asp Ser Thr Ile Ser Lys Val Ile Pro Gly Asn Gly Lys Leu Leu Leu 280 285 290 ggc tcc aat caa aat gaa att gtc tct cta aaa ggg gac att tat aac 1328 Glyn Sern Gln Glu Ile Val Ser Leu Lys Gly Asp Ile Tyr Asn 295 300 305 ttt cga ctt tgg aat ttt acc atg aat gcc aaa atc ctc tcc aac ctc 1376 Phe Arg Leu Trp Asn Phe Thr Met Asn Ala Lys Ile Leu Ser Asn Leu 310 315 320 325 agc tgt aat gtg aaa ggg aat gta gtc gac tgg caa aat gac ttc tgg 1424 Ser Cys Asn Val Lys Gly Asn Val Val Asp Trp Gln Asn Asp Phe Trp 330 335 340 aat atc cca aac cta gct ctg aaa gct agag agc tgt ggt 1472 Asn Ile Pro Asn Leu Ala Leu Lys Ala Glu Ser Asn Leu Ser Cys Gly 345 350 355 tcc tac ctg atc ccg ctc cca gca gca gaa ctg gcc agc tgt gca gac 1520 Ser Tyr Leu Ile Pro Leulu Ala Ala Leu Ala Ser Cys Ala Asp 360 365 370 ctg ggg acc ctc tgt caa gct act gta aac tct cct agt act aca cca 1568 Leu Gly Thr Leu Cys Gln Ala Thr Val Asn Ser Pro Ser Thr Thr Pro 375 380 385 ccc act gtc acc act aac atg cct gtt act aac aga atc gat aaa caa 1616 Pro Thr Val Thr Thr Asn Met Pro Val Thr Asn Arg Ile Asp Lys Gln 390 395 400 405 agg aat gat gga att atc tat aga ata tcc gta gtg att cag aac atc 1664 Arg Asn Asp Gly Ile Ile Tyr Arg Ile Ser Val Val Ile Gln Asn Ile 410 415 420 ctt cgt cac cct gag gta aaa gta cag agc aag gtg gca gaa tgg ctc 1712 Leu Arg His Pro Glu Val Lys Val Gln Ser Lys Val Ala Glu Trp Leu 425 430 435 aat tca acc ttc caa aat tgg aac tac acg gtt tat gtc gtt aat atc 1760 Asn Ser Thr Phe Gln Asn Trp Asn Tyr Thr Val Tyr Val Val Asn Ile 440 445 450 agt ttt cac ctg agt gct gga gag gac aag att aaa gtc aag aga agc 1808 Ser Phe His Leu Ser Ala Gly Glu Asp Lys Ile Lys Val Lys Arg Ser 455 460 465 ctt gag gat gag cca agg ttg gtg ctt tgg gcc ctt cta gtt tac aat 1856 Leu Glu Asp Glu Arg Leu Val Leu Trp Ala Leu Leu Val Tyr Asn 470 475 480 485 gct acc aac aat act aat tta gaa gga aaa atc att cag cag aag ctc 1904 Ala Thr Asn Asn Thr Asn Leu Glu Gly Lys Ile Ile Gln Gln Lys Leu 4 90 495 500 cta aaa aat aat gag tcc ttg gat gaa ggc ttg agg cta cat aca gtg 1952 Leu Lys Asn Asn Glu Ser Leu Asp Glu Gly Leu Arg Leu His Thr Val 505 510 515 aat gtg aga caa ctg ggt at tgt ctt gcc gag gaa ccc aaa ggc 2000 Asn Val Arg Gln Leu Gly His Cys Leu Ala Met Glu Glu Pro Lys Gly 520 525 530 tac tac tgg cca tct atc caa cct tct gaa tac gtt ctt cct tgt cca 2048 Tyr Tyr Trp Pro Ser Ile Gln Pro Ser Glu Tyr Val Leu Pro Cys Pro 535 540 545 gac aag cct ggc ttt tct gct tct cgg ata tgt ttt tac aat gct acc 2096 Asp Lys Pro Gly Phe Ser Ala Ser Arg Ile Cys Phe Tyr Asn Ala Thr 550 555 560 560 565 aac cca ttg gta acc tac tgg gga cct gtt gat atc tcc aac tgt tta 2144 Asn Pro Leu Val Thr Tyr Trp Gly Pro Val Asp Ile Ser Asn Cys Leu 570 575 580 aaa gaa gca aat gaa gtt gct aac cag att tta aat tta act gct gat 2192 Lys Glu Ala Asn Glu Val Ala Asn Gln Ile Leu Asn Leu Thr Ala Asp 585 590 595 ggg cag aac tta acc tca gcc aat att acc aac att gtg gaa cag gtc 2240 Gly Gln Asn Leu Thr Ser Ala Asn Ile Thr Asn Il e Val Glu Gln Val 600 605 610 aaa aga att gtg aat aaa gaa gaa aac att gat ata aca ctt ggc tca 2288 Lys Arg Ile Val Asn Lys Glu Glu Asn Ile Asp Ile Thror Leu Gly Ser 615 620 625 625 act cta atg aat ata ttt tct aat atc tta agc agt tca gac agt gac 2336 Thr Leu Met Asn Ile Phe Ser Asn Ile Leu Ser Ser Ser Asp Ser Asp 630 635 640 645 ttg ctt gag tca tct tct gaa gct tta aaa aca att gat gaa ttg gcc 2384u Glu Ser Ser Ser Glu Ala Leu Lys Thr Ile Asp Glu Leu Ala 650 655 660 ttc aag ata gac cta aat agc aca tca cat gtg aat att aca act cgg 2432 Phe Lys Ile Asp Leu Asn Ser Thr Ser His Val Asn Ile Thr Thr Arg 665 670 675 aac ttg gct ctc agc gta tca tcc ctg tta cca ggg aca aat gca att 2480 Asn Leu Ala Leu Ser Val Ser Ser Leu Leu Pro Gly Thr Asn Ala Ile 680 685 690 tca aat ttt agc att ggt ctt acagat gaa tcg tat ttc cag 2528 Ser Asn Phe Ser Ile Gly Leu Pro Ser Asn Asn Glu Ser Tyr Phe Gln 695 700 705 atg gat ttt gag agt gga caa gtg gat cca ctg gca tct gta att ttg 2576 Met Asp Phe Glu Ser Gly Gl n Val Asp Pro Leu Ala Ser Val Ile Leu 710 715 720 725 cct cca aac tta ctt gag aat tta agt cca gaa gat tct gta tta gtt 2624 Pro Pro Asn Leu Leu Glu Asn Leu Ser Pro Glu Asp Ser Val Leu Val 730 735 740 aga aga gca cag ttt act ttc ttc aac aaa act gga ctt ttc cag gat 2672 Arg Arg Ala Gln Phe Thr Phe Phe Asn Lys Thr Gly Leu Phe Gln Asp 745 750 755 gta gga ccc caa aga aaa act tta gtg ggt atg gtg atg tgc agt 2720 Val Gly Pro Gln Arg Lys Thr Leu Val Ser Tyr Val Met Ala Cys Ser 760 765 770 att gga aac att act atc cag aat ctg aag gat cct gtt caa ata aaa 2768 Ile Gly Asn Ile Thr Ile Gln Asn Leu Lys Asp Pro Val Gln Ile Lys 775 780 785 atc aaa cat aca aga act cag gaa gtg cat cat ccc atc tgt gcc ttc 2816 Ile Lys His Thr Arg Thr Gln Glu Val His His Pro Ile Cys Ala Phe 790 795 800 805 tgg gat ctg aac aaa aac aaa agt ttt gga gga tgg aac acg tca gga 2864 Trp Asp Leu Asn Lys Asn Lys Ser Phe Gly Gly Trp Asn Thr Ser Gly 810 815 820 tgt gtt gca cac aga gat tca gat gca agt gag aca gtc tgc ctg tgt 2912 Cy Val Ala His Arg Asp Ser Asp Ala Ser Glu Thr Val Cys Leu Cys 825 830 835 aac cac ttc aca cac ttt gga gtt ctg atg gac ctt cca aga agt gcc 2960 Asn His Phe Thr His Phe Gly Val Leu Met Asp Leu Pro Arg Ser Ala 840 845 850 tca cag tta gat gca aga aac act aaa gtc ctc act ttc atc agc tat 3008 Ser Gln Leu Asp Ala Arg Asn Thr Lys Val Leu Thr Phe Ile Ser Tyr 855 860 860 att ggg tgt gga ata tct gct att tttca gca gca act ctc ctg aca 3056 Ile Gly Cys Gly Ile Ser Ala Ile Phe Ser Ala Ala Thr Leu Leu Thr 870 875 880 885 885 tat gtt gct ttt gag aaa ttg cga agg gat tat ccc tcc aaa atc ttg 3104 Tyr Val Ala Phe Glu Ly Leu Arg Arg Asp Tyr Pro Ser Lys Ile Leu 890 895 900 atg aac ctg agc aca gcc ctg ctg ttc ctg aat ctc ctc ttc ctc cta 3152 Met Asn Leu Ser Thr Ala Leu Leu Phe Leu Asn Leu Leu Phe Leu Leu 905 ggc tgg atc acc tcc ttc aat gtg gat gga ctt tgc att gct gtt 3200 Asp Gly Trp Ile Thr Ser Phe Asn Val Asp Gly Leu Cys Ile Ala Val 920 925 930 gca gtc ctg ttg cat ttc ttc ctt ctg gca acctt acc gg atg ggg 3248 Ala Val Leu Leu His Phe Phe Leu Leu Ala Thr Phe Thr Trp Met Gly 935 940 945 cta gaa gca att cac atg tac att gct cta gtt aaa gta ttt aac act 3296 Leu Glu Ala Ile His Met Tyr Ile Ala Leu Val Lys Val Phe Asn Thr 950 955 960 965 tac att cgc cga tac att cta aaa ttc tgc atc att ggc tgg ggt ttg 3344 Tyr Ile Arg Arg Tyr Ile Leu Lys Phe Cys Ile Ile Gly Trp Gly Leu 970 975 980 cct g gtg tca gtt gtt cta gcg agc aga aac aac aat gaa 3392 Pro Ala Leu Val Val Ser Val Val Leu Ala Ser Arg Asn Asn Asn Glu 985 990 995 gtc tat gga aaa gaa agt tat ggg aaa gaa aaa ggt gat gaa ttc gtc Tyr Gly Lys Glu Ser Tyr Gly Lys Glu Lys Gly Asp Glu Phe Cys 1000 1005 1010 tgg att caa gat cca gtc ata ttt tat gtg acc tgt gct ggg tat ttt 3488 Trp Ile Gln Asp Pro Val Ile Phe Tyr Val Thr Cys Ala Gly Tyr Phe 1015 1020 1025 gga gtc atg ttt ttt ctg aac att gcc atg ttc att gtg gta atg gtg 3536 Gly Val Met Phe Phe Leu Asn Ile Ala Met Phe Ile Val Val Met Val 1030 1035 1040 1045 cag atc tgt ggg agg aat ggc aag aga agc aac cgg acc ctg aga gaa 3584 Gln Ile Cys Gly Arg Asn Gly Lys Arg Ser Asn Arg Thr Leu Arg Glu 1050 1055 1060 gaa gtg tta agg aac ctg cgc agt gtg gtt agc ttg acct ttg acct Leu Arg Asn Leu Arg Ser Val Val Ser Leu Thr Phe Leu Leu 1065 1070 1075 ggc atg aca tgg ggt ttt gca ttc ttt gcc tgg gga ccc tta aat atc 3680 Gly Met Thr Trp Gly Phe Ala Phe Phe Ala Trp Gly Pro Leu Asn Ile 1080 1085 1090 ccc ttc atg tac ctc ttc tcc atc ttc aat tca tta caa ggc tta ttt 3728 Pro Phe Met Tyr Leu Phe Ser Ile Phe Asn Ser Leu Gln Gly Leu Phe 1095 1100 1105 ata ttc atc ttc cac tgt gag atg gtt cag aaa cag tgg 3776 Ile Phe Ile Phe His Cys Ala Met Lys Glu Asn Val Gln Lys Gln Trp 1110 1115 1120 1125 cgg cgg cat ctc tgc tgt ggt aga ttt cgg tta gca gat aac tca gat 3824 Arg Arg His Leu Cys Cys Gly Arg Phe Arg Leu Ala Asp Asn Ser Asp 1130 1135 1140 tgg agt aag aca gct acc aat atc atc aag aaa agt tct gat aat cta 3872 Trp Ser Lys Thr Ala Thr Asn Ile Ile Lys Lys Ser Ser Asp A sn Leu 1145 1150 1155 gga aaa tct ttg tct tca agc tcc att ggt tcc aac tca acc tat ctt 3920 Gly Lys Ser Leu Ser Ser Ser Ser Ile Gly Ser Asn Ser Thr Tyr Leu 1160 1165 1170 aca tcc aaa tct aaa tcc agc tct acc acc tat ttc aaa agg aat agc 3968 Thr Ser Lys Ser Lys Ser Ser Ser Thr Thr Tyr Phe Lys Arg Asn Ser 1175 1180 1185 cac aca gac agt gct tcc atg gac aag tcc ttg tca aaa ctg gcc cat 4016 His Thr Asp Ser Ala Ser Met Asp Lys Ser Leu Ser Lys Leu Ala His 1190 1195 1200 1205 gct gat gga gat caa aca tca atc atc cct gtc cat cag gtc att gat 4064 Ala Asp Gly Asp Gln Thr Ser Ile Ile Pro Val His Gln Val Ile Asp 1210 1215 1220 aag gtc aag ggt tat tgc aat gct cat tca gac aac ttc tat aaa aat 4112 Lys Val Lys Gly Tyr Cys Asn Ala His Ser Asp Asn Phe Tyr Lys Asn 1225 1230 1235 att atc atg tca gac acc ttc agc cac agc acaag ttt 4161 Ile Ile Met Ser Asp Thr Phe Ser His Ser Thr Lys Phe 1240 1245 1250 aagaaaaaga aatcaatctg cagaaatgtg aagatttgca agcagtgtaa actgcaacta 4221 gtgatgtaaa tgtgctatta ccta ggtaac tgcatatata taaggaatgt attttgttaa 4281 gaaggctttt gtgaaattca gaatttttct ttttaatata tttcttccat ggaagagttg 4341 tcatcactaa aacttcagta ctgagagtaa catgactcag tagccacaga agctatgatt 4401 tgtaaaatat ataattgaat cagagtaatc ataatgcagg ggagacattc aaattagaga 4461 caagggagaa gcaatgctga ggaagaccct agatagagct cattttactc cacctaatcg 4521 ttatatctgg atatacccat tttctgcatc ttctttctca acaataaaaa atgtaactat 4581 tttgaatgcc cacaaatccc attccagtgt tactttctgt gaatgcagta ccatattctc 4641 attttcaatg acatttcaac cacaggcaga aaagactgtt tactccttga cccaaagatt 4701 aaaaaggatt ttttattatt ttaaatatta caccttcaga accataacat gcttaagaaa 4761 actttcccaa aatgttgacc tagttaaatg aggctatata aatttctaat attttactta 4821 ttctattcaa ggcatagggc caaagcatta agtataattt aatcccatac attcgagtta 4881 agtttagtgt tgatgttcca tcattctgga cctcccagga gttgtttaag aatgaatctc 4941 ttacacctct acttttgccc ctctactgta tattaagccc ataggcttgt gggaggaagg 5001 agaatttcca ttaggcaagc tgtatgcagt ggaattttcc ttttaggaga cacacaatta 5061 agactctctg gttctgtcct tgctttggag actttaagac atttcctaaa gcacaaataa 5121 aagcctcgta tttccccatt gagagttttg ttccaaggaa tatgaagtga gacatatggg 5181 tgagtcataa taatcaaaat aatttatgaa gagctgggtc tgcaatagct agtctaaaaa 5241 ctacttgtgt gtcagtcctc tggttatagt atataagagc ctgaggaggt ctggcaagat 5301 agatggtgta ttatttatgg atcaggctgc tgcatacaaa ccttgcatac tattatgcag 5361 cttacctaac tctcagacta ttctgagtaa tgcttgcttg ctaatgaatg tataggagac 5421 cacattgtaa ttgttcttag atgatggagt ccatgcagtt tcttagaaat cggtctcagt 5481 gcatgctgtg ctttttcaca tttgctctgg gttatctggg aagtatcagg ttctgggagg 5541 caacagcatt aagtgataag aaaaggagac attctggcaa agccaatctg cttaaaggca 5601 aagtccagaa cctggaacct agaggccttt ctctctgcac gaaaaacagg tagtttgcag 5661 tctgagatat gggagagctt ttaggctaca cagcaaccca agggacctct caccttttgc 5721 tgagcttcaa tcaggaagct atttgcctgg ctccagcaga tgatgagata atgaggtagt 5781 gggtttttta ttactgttcc attttgcaac atcctgcaac accatcctgg gagacaagag 5841 cattacccag cttggctttc acgggggagg gttgtattca gtaaaaaaga atagtaaata 5901 taaggtcact gagattctaa gtaagatagt aaatc taagg tcactgagcc aaatcctttt 5961 caataggcat atattaacag gctgcttatt ttggcggagg ttacatatgg atgaaaatga 6021 atcttagtca ctgaatattc atatacattt cccccaaaac cttagacatt catagtagat 6081 tttaattagt tagctttcta actagtcaga tttctgccca aagtgcttag tcaatagtaa 6141 ttaagatata ggtaattaag atatagcttc aaaaatggct ttgcttttga tttctactca 6201 tattcgtatg gctccagaaa aatatttttt tcatatttga caatgtcagc tccactttag 6261 aaattttcaa taaccagatg agaaaaaaat taagaaattg ctcaagggaa acatttgtaa 6321 atggatttga aagattgagc caaattctgt tgtcagttct aagcatgcag ttctcacctc 6381 catttagtcc cccatcagaa cagaggtcag gaatttagct ggggagccta aatttagttc 6441 agcttacctt tgagaatagc atcaattcag actctctttt cattatgttt tcttttcttt 6501 ttccctcttt ttaaactaca ttgtgttaga gtcatagtct aggatcctga gagattttcc 6561 attcttgtca ccattcactt gcattgtaaa gattttcttt gtctgttgtt ggcatagatt 6621 cttttgtaca tatttattta tttgtgttta tatatgtcaa ttggtttcct ttcttagctt 6681 gatattgcct agctttgttg ttttaattaa ctttctatta gagagactgt atatattttt 6741 tctaaatact ttgtgaaatc atttttggta gcaatatctt tgaatatgat gaataaaagt 6801 gactgtgagt gcaaatagaa ttagcagtaa gaagctactc tagctaattt gccattttac 6861 ttaaatggaa aatgtttttc aaataaatac ttatgttgtt c 6902 <210> 9 <211> 6533 <212> DNA <213> Mus musculus <220> <221> CDS <222> (123) .. (3617) <400> 9 cgtcctgcgg gtcgcggtcc cgaaagccgg gatcttcttc ggtggagctt gagggcaaca 60 acgcagagag cgctggagga tgagtgtgcg gcctctggga atctccacac ggtaatgcca 120 gc atg atg tg g tt gc tg g ct g c t g g act tg g 1 5 10 15 aag cca agc gcc ctg ctg ttc ctg ttt gtt tta tgt gtt acc tgt gtt 215 Lys Pro Ser Ala Leu Leu Phe Leu Phe Val Leu Cys Val Thr Cys Val 20 25 30 cct ctc tca gtg tgc gga tgt ggc agc tg aga ctt gtc ctg tcc aat 263 Pro Leu Ser Val Cys Gly Cys Gly Ser Cys Arg Leu Val Leu Ser Asn 35 40 45 cct tcc ggt acc ttt acg tct ccg tgt tac cct aat gac tac cct aat 311 Pro Ser Gly Thr Phe Thr Ser Pro Cys Tyr Pro Asn Asp Tyr Pro Asn 50 55 60 acc cag tct tgt tcg tgg acc ctc cga gcc cct gcc ggc tac atc att 359 Thr Gln Ser Cys Ser Trp Thr Leu Arg Ala Pro Ala Gly Tyr Ile Ile 65 70 75 cag ata acg ttc aat gac ttc gac att gaa gaa gct ccc aac tgt atc 407 Gln Ile Thr Phe Asn Asp Phe Asp Ile Glu Glu Ala Pro Asn Cys Ile 80 85 90 95 tat gac tca ttg tcc ctc gat aat gga gag agc cag aca aaa ttc tgt 455 Tyr Asp Ser Leu Ser Leu Asp Asn Gly Glu Ser Gln Thr Lys Phe Cys 100 105 110 gga gcg act gcc aag ggc ctg tca ttt aac tcc agc atg ag gat g 503 Gly Ala Thr Ala Lys Gly Leu Ser Phe Asn Ser Ser Val Asn Glu Met 115 120 125 cat gtg tcc ttt tca agt gac ttt agt atc cag aag aaa ggt ttc aac 551 His Val Ser Phe Ser Ser Asp Phe Ser Ile Gln Lys Lys Gly Phe Asn 130 135 140 gcc agc tac atc aga gtt gct gtg tcc ttg agg aat caa aag gtc att 599 Ala Ser Tyr Ile Arg Val Ala Val Ser Leu Arg Asn Gln Lys Val Ile 145 150 155 ttg ccc cag aca tta gat gct tac cag gta tca gtt gca aaa agc atc 647 Leu Pro Gln Thr Leu Asp Ala Tyr Gln Val Ser Val Ala Lys Ser Ile 160 165 170 175 tcc att cct gaa ctc aaa gct ttc acg ctc tgt ttt gaa gcc tcc aaa 695 Ser Ile Pro Glu Leu Lys Ala Phe Thr Leu Cys Phe Glu Ala Ser Lys 180 185 190 gtt ggc aat gaa ggt ggt gac tgg aca gct ttc tcc tac tca gac gag 743 Val Gly Asn Glu Gly Gly Asp Trp Thr Ala Phe Ser Tyr Ser Asp Glu 195 200205 tcc ctt aca cag ctg ctc agt ctt gaa aag gcc agt aat ggc tac ttc 791 Ser Leu Thr Gln Leu Leu Ser Leu Glu Lys Ala Ser Asn Gly Tyr Phe 210 215 220 ctg tcc atc tct ggc tca aga tgc ttg atc gtt g ttg tta cct gtg 839 Leu Ser Ile Ser Gly Ser Arg Cys Leu Leu Asn Asn Ala Leu Pro Val 225 230 235 aag gac aaa gag gac atc ttc aca gaa aac ttg gag cag ctc tgt ctt 887 Lys Asp Lys Glu Asp Ile Phe Thr Gn Leu Glu Gln Leu Cys Leu 240 245 250 255 gtg tgg aat aat tct tgg ggc tcc att ggt ata aat ttc aaa aag aac 935 Val Trp Asn Asn Ser Trp Gly Ser Ile Gly Ile Asn Phe Lys Lys Asn 260 265 265 270 tat gaa aca gtt cca tgt gat tcc acc atc agt gct gtc gta ccc ggg 983 Tyr Glu Thr Val Pro Cys Asp Ser Thr Ile Ser Ala Val Val Pro Gly 275 280 285 gat ggg aca ttg ctg ttg ggc tcc gac aga gat gag gtc gcc tct cta 1031 Asp Gly Thr Leu Leu Leu Gly Ser Asp Arg Asp Glu Val Ala Ser Leu 290 295 300 agg ggc agc atc tat aac ttt cga ctt tgg aat ttt acc atg gat ctg 1079 Arg Gly Ser Ile Tyr Asn Phe Arg Leu Trp Asn Phe Thr Met A sp Leu 305 310 315 aaa gcc ctc tcc aac ctc agc tgt agt gtg tct ggg aat gtc ata gac 1127 Lys Ala Leu Ser Asn Leu Ser Cys Ser Val Ser Gly Asn Val Ile Asp 320 325 330 335 tgg cac aat gac ttt tgg agc atc tca acc caa gct ctg aaa gcc gag 1175 Trp His Asn Asp Phe Trp Ser Ile Ser Thr Gln Ala Leu Lys Ala Glu 340 345 350 ggc aac ctg agc tgt ggt tcc tac ctg atc cag ctt cct gca gca gag 1223 Gly Asn Leu Ser Cys Gly Ser Tyr Leu Ile Gln Leu Pro Ala Ala Glu 355 360 365 ctg aca aac tgt tca gaa ctg ggg act ctc tgt caa gac gga ata atg 1271 Leu Thr Asn Cys Ser Glu Leu Gly Thr Leu Cys Gln Asp Gly Ile Met 370 375 380 tat cga ata tct gtt gtg att cac aat gac ttt aat cac cct gaa gta 1319 Tyr Arg Ile Ser Val Val Ile His Asn Asp Phe Asn His Pro Glu Val 385 390 395 aaa gtg cag acc aaa gta gca gaa tgg ctc aat tca acc ttt cag aat 1367 Lys Val Gln Thr Lys Val Ala Glu Trp Leu Asn Ser Thr Phe Gln Asn 400 405 410 415 tgg aac tac act gtt tat gtg gtt aat ata agt ttt cat caa aaa gta 1415 Trp Asn Tyr Thr Val Val Tyr Val Val As n Ile Ser Phe His Gln Lys Val 420 425 430 gga gag gac agg atg aaa gtc aag aga gac atc atg gac gat gac aaa 1463 Gly Glu Asp Arg Met Lys Val Lys Arg Asp Ile Met Asp Asp Asp Lys 435 440 445 agg ttg gtg ctc tgg gcc ctt cta gtc tac aat gct acc aat aac gtc 1511 Arg Leu Val Leu Trp Ala Leu Leu Val Tyr Asn Ala Thr Asn Asn Val 450 455 460 agc ctg aat gaa gag aag att aaa caa aag ctt atg aca aat aatca Ser Leu Asn Glu Glu Lys Ile Lys Gln Lys Leu Met Thr Asn Asn Ala 465 470 475 tca cta gag gat gga ctg agg ctg tgt gaa gtc gac gtg aac cag ctg 1607 Ser Leu Glu Asp Gly Leu Arg Leu Cys Glu Val Asp Gln Leu 480 485 490 495 ggt atg tgt agc gcc ttg gag gat cca gac ggc ttt agt tgg cca gcc 1655 Gly Met Cys Ser Ala Leu Glu Asp Pro Asp Gly Phe Ser Trp Pro Ala 500 505 510 acc tta ccc tct gtc tac aaa ca cca tgt cca aac aag cct ggc ttt 1703 Thr Leu Pro Ser Val Tyr Lys Gln Pro Cys Pro Asn Lys Pro Gly Phe 515 520 525 ttt atg act cga gcg tgc ctt tct aat gga aca tca acc ttc tgg ggc 1751 Phe Met Thr Arg Ala Cys Leu Ser Asn Gly Thr Ser Thr Phe Trp Gly 530 535 540 cct gtt gac act tcc aac tgt tca aga caa tca aat gaa gtg gcc aat 1799 Pro Val Asp Thr Ser Sern Cys Ser Arg Gln Ser Asn Glu Val Ala Asn 545 550 555 gag att tta aac caa act ggt gat ggg cag aac ctc acc tcg gct aat 1847 Glu Ile Leu Asn Gln Thr Gly Asp Gly Gln Asn Leu Thr Ser Ala Asn 560 565 570 570 575 atc aac agc att gta gaa aag gtc gt c gg atg aac aaa gaa gaa 1895 Ile Asn Ser Ile Val Glu Lys Val Lys Arg Ile Val Asn Lys Glu Glu 580 585 590 aac att gac atc acc ctc ggc tcc act cta atg aat ata ttt tct aat 1943 Asn Ile Asp Ile Thr Leu Gly Ser Thr Leu Met Asn Ile Phe Ser Asn 595 600 605 atc tta agc agt tca gat agc gat ttg ctt gag tct tct act gaa gct 1991 Ile Leu Ser Ser Ser Asp Ser Asp Leu Leu Glu Ser Ser Thr Glu Ala 610 615 620 620 tta aaa aca att gac gag cta gcc ttc aaa ata gac ctg aat agc acc 2039 Leu Lys Thr Ile Asp Glu Leu Ala Phe Lys Ile Asp Leu Asn Ser Thr 625 630 635 cca cat gtg aac att gag aca cag aat ttg gcc ctt gga gtc tca tcc 087 Pro His Val Asn Ile Glu Thr Gln Asn Leu Ala Leu Gly Val Ser Ser 640 645 650 655 cta att cca gga aca aat gca cct tca aat ttt agc att ggc ctt cca 2135 Leu Ile Pro Gly Thr Asn Ala Pro Ser Asn Phe Ser Ile Gly Leu Pro 660 665 670 agc aat aat gaa tcg tac ttc cag atg gac ttc ggg aac gga cag aca 2183 Ser Asn Asn Glu Ser Tyr Phe Gln Met Asp Phe Gly Asn Gly Gln Thr 675 680 685 gat cca ctg gcat ttg cct cca aat ttg ctt gag aat tta 2231 Asp Pro Leu Ala Ser Val Ile Leu Pro Pro Asn Leu Leu Glu Asn Leu 690 695 700 agc ccc gaa gat tct gta ttg gtc agg aga gca cag ttc act ttc ttc 2p Ser Glu Ser Val Leu Val Arg Arg Ala Gln Phe Thr Phe Phe 705 710 715 aac aaa acc gga ctt ttc cag gat gtt gga tct caa aga aaa gtc ctc 2327 Asn Lys Thr Gly Leu Phe Gln Asp Val Gly Ser Gln Arg Lys Val Leu 720 725 730 735 gtg agt tat gtg atg gcg tgc agc att gga aac att act atc cag aat 2375 Val Ser Tyr Val Met Ala Cys Ser Ile Gly Asn Ile Thr Ile Gln Asn 740 745 750 ctg aaa gat ccg gtt caa atc aaa atcaaa c acc aga aca cag gaa 2423 Leu Lys Asp Pro Val Gln Ile Lys Ile Lys His Thr Arg Thr Gln Glu 755 760 765 gtg cat cat cct atc tgt gcc ttc tgg gat atg aac aaa aac aaa agt 2471 Val His His Pro Ile Cys Ala Phe Trp Asp Met Asn Lys Asn Lys Ser 770 775 780 ttc ggg ggg tgg aac acc tca gga tgt gtt gcc cac tct gat ttg gac 2519 Phe Gly Gly Gly Trp Asn Thr Ser Gly Cys Val Ala His Ser Asp Leu Asp 785 790 795 gct ggt gag acc att tgt ctg tgc agc cac ttc act cac ttt gga gtt 2567 Ala Gly Glu Thr Ile Cys Leu Cys Ser His Phe Thr His Phe Gly Val 800 805 810 815 ctg atg gat ctt cca agg agt gcc tca caa ata gat gga aga aac aca 2615 Leu Met Asp Leu Pro Arg Ser Ala Ser Gln Ile Asp Gly Arg Asn Thr 820 825 830 aaa gtc ctc acg ttc att acc tat att ggg tgc gga ata tct gcc att 2663 Lys Val Leu Thr Phe Ile Thr Tyr Ile Gly Cys Gly Ile Ser Ala Ile 835 840 845 ttc tca gct gca act ctc ctg aca tat gtt gct ttt gag aag ctg cgc 2711 Phe Ser Ala Ala Thr Leu Leu Thr Tyr Val Ala Phe Glu Lys Leu Arg 850 855 860 860 agg gat tat ccc tccaaa atc ctg atg aat ctg agc tcg gcc ttg ctc 2759 Arg Asp Tyr Pro Ser Lys Ile Leu Met Asn Leu Ser Ser Ala Leu Leu 865 870 875 ttc ctg aat ctc atc ttc ctc ctg gat ggc tgg gtc tcc ncc Leu Ile Phe Leu Leu Asp Gly Trp Val Thr Ser Phe Gly 880 885 890 895 gtg gct gga ctc tgc acg gct gtg gct gcc ctg ttg cac ttc ttc ctc 2855 Val Ala Gly Leu Cys Thr Ala Val Ala Ala Leu Leu His Phe 900 905 910 ctg gct acc ttc acc tgg atg ggg ctg gaa gcc atc cac atg tac att 2903 Leu Ala Thr Phe Thr Trp Met Gly Leu Glu Ala Ile His Met Tyr Ile 915 920 925 gct ctt gtg aaa gtg ttt cac act tac atc cgc tat att cta aaa 2951 Ala Leu Val Lys Val Phe Asn Thr Tyr Ile His Arg Tyr Ile Leu Lys 930 935 940 ttc tgc atc ata ggc tgg ggt ctg cca gcc ttg gtg gtg tca att att 2999 Phe Cys Ile Gle Gly Pro Ala Leu Val Val Ser Ile Ile 945 950 955 cta gtg agc aga aga caa aat gaa gta tat gga aaa gaa agt tat ggg 3047 Leu Val Ser Arg Arg Gln Asn Glu Val Tyr Gly Lys Glu Ser Tyr Gly 960 965 970 975 975 aaa gat cag gat gat gaa ttc tgc tgg att cag gat cct gtg gtg ttt 3095 Lys Asp Gln Asp Asp Glu Phe Cys Trp Ile Gln Asp Pro Val Val Phe 980 985 990 tat gtg agc tgt gcc ggg tc ttc ggac tc ttc ggagt aat gtc 3143 Tyr Val Ser Cys Ala Gly Tyr Phe Gly Val Met Phe Phe Leu Asn Val 995 1000 1005 gcc atg ttc att gtg gtc atg gtg cag atc tgt ggg agg aat gga aag 3191 Ala Met Phe Ile Val Val Met Val Gln Ile Cys Gly Arg Asn Gly Lys 1010 1015 1020 aga agc aac cgg acc ctg aga gaa gag gtt tta aga aac ctg cgc agt 3239 Arg Ser Asn Arg Thr Leu Arg Glu Glu Val Leu Arg Asn Leu Arg Ser 1025 1030 1035 gtg gtc accc ctg ctt ggc atg acg tgg ggg ttt gct ttc 3287 Val Val Ser Leu Thr Phe Leu Leu Gly Met Thr Trp Gly Phe Ala Phe 1040 1045 1050 1055 ttt gcc tgg gga ccc tta aat att cct ttc atg tac ctc ttc tcc atla 335 Trp Gly Pro Leu Asn Ile Pro Phe Met Tyr Leu Phe Ser Ile 1060 1065 1070 ttc aat tca tta caa ggt tta ttt ata ttc atc ttc cac tgt gcg atg 3383 Phe Asn Ser Leu Gln Gly Leu Phe Ile Phe I le Phe His Cys Ala Met 1075 1080 1085 aag gag aat gtt cag aaa cag tgg agg cgt cac ctc tgc tgt ggc agg 3431 Lys Glu Asn Val Gln Lys Gln Trp Arg Arg His Leu Cys Cys Gly Arg 1090 1095 1100 ttt cgg cta gac aac tca gat tgg agt aag aca gct acc aat atc 3479 Phe Arg Leu Ala Asp Asn Ser Asp Trp Ser Lys Thr Ala Thr Asn Ile 1105 1110 1115 atc aag aag ag agc tcc gat aac ctg ggg aaa tct ttg tct tca agc tcc 3527 Ile Lys Ser Ser Asp Asn Leu Gly Lys Ser Leu Ser Ser Ser Ser 1120 1125 1130 1135 att ggc tcc aat tca aca tat ctc aca tcc aaa tca aag tcc agc tcc 3575 Ile Gly Ser Asn Ser Thr Tyr Leu Thr Ser Lys Ser Lys Ser Ser Ser 1140 1145 1150 act acc tat ttc aaa aga aac agc cac tcg gat aat ttc tcc 3617 Thr Thr Tyr Phe Lys Arg Asn Ser His Ser Asp Asn Phe Ser 1155 1160 1165 taagagaatt ccttcacacaa aagtggatca ctccccgcag ctccccgcagcag gtcaggag actg tgataaggtc aagggttact gtaatgccca ttccgataac ttctataaaa atatcatcct 3797 gtcagatgcc ttcagccac a gcacaaagtt ttaatgtcat tgagagggga aacaaaggga 3857 aaagaaagcc tgtctggaga agtgtgatgc ccaagaagca cggaaagcta cgccggtgga 3917 atgtcagtgt gctgctctgt agggaactgc agagcttaga ggactgactg catcttgtta 3977 gggaagcatc tttgagatgc agaattcatc ttttttggaa tatttccatg gtggagctca 4037 gtcatcacac ttcaagagct gagaacactc tgagcccggc aagaatacag gacttcttaa 4097 ctgtaattga atcaaactca tcagaatcgg gggggggggg ggaaggcgtt aaaattatag 4157 gccttgagag gagaacccca agaagaaatt tgagtttagc tctcatatac cacacctcat 4217 agttaggctc ggcagtggcc tgactcttgt aaagacaatg tagaaaacac actaattact 4277 gtttgtagtg tctttggatg ctcacgggtt ctgttccagt gctattttct atgaatatag 4337 cagcatcgtt tcctttttca gtgaaatttc aaccataagt agaaaagaat tgtttactat 4397 ttgacccaca tattaaacat gctttttttc tctattatgg caaatattga atattcatga 4457 acataacttg ctaaacaagt attccaaaaa tttgatctag tcaatccatt gtgtgaatct 4517 caaatatctc aagacacgca gcctaagcat ctccattatc ccgtgcacat aagccaatcc 4577 agttgaatgt ggacattacg ttcaagtggg cctcctggaa cttaagaaca agcacctctc 4637 ctgtcccctt ctgtgtgcac atag gtccat aggctcatta gagggatgag agttcccatt 4697 aagcactcca tgcaatggcc tctcactgtt taaagaacac acttttgaga ttatgtggtc 4757 ctatccttgt tttaatgatt aaaaaaaaaa aaaagacatt ccaaatcaca taaacttcag 4817 aggcctctgg ctccctctag tgacaagttt gttccaaggg acatacactg aaacatacag 4877 ctgtctaggt tataaatgtg taggtctaca actgctagtc taaaaactgt ttgcaccgag 4937 ccctctgatc agagtggatg agaccctaca gagggctggc aggatttact aatctagtgg 4997 aatatgcatg gatcagactg tggcatacaa gtcgtgcaga gcatgaagca gcttacctaa 5057 ctcttaaact atcctaagca atgtgtgctt gcctgttaat gagggtgtag gttgagccca 5117 agtggtggag tcctattcat gggcctcagt gcatgctggc tttagcccca tgctcagggt 5177 tctctgggaa gtttcaggtt tccaagatag cacagtgacc acaaagggag attttagcag 5237 agccagcctg ctagaaggca ggagtagcca gaatggaaca tctgtgcaga aagtaggcca 5297 ttctcagcta ggatgtagaa gaacttgcag gctttgaaac agccaacaga tccccttagc 5357 tctctgtcag tcacgaagct atatgccagg ctgcaaagga tgtcaatagc atgtggcaat 5417 gggggttttt attgccattc attctttagc aacctggact gccatcttgg cagacctgaa 5477 ctttgctgag cctgattttc acaaaggag g aggccatgta ggagaaaggg atagtgactt 5537 antcttaagg tgactaagat tcacctcagc agagccaatc tttttggggg gatgggaggg 5597 agacttatat tagcaggctg ctcattgtac cacaggatac atataggtag aatataatct 5657 cgatagacac tgactattga tatacacccc caaacttaag gtgttcatgg tagattttaa 5717 ttagctgtga gatttatgca caaagtgaat atttagctga tagaaattat gattttgttt 5777 caaatgtggc tttgcttttg ttttgttttg ttttttctta ctagcattga gatctgagaa 5837 agatcttttt ttattttttt catatttggc aatgatgtca gctccattta aaaaatctcc 5897 aataaccagg taagaaaaga aagaaaaaaa ttaagaaaca acaggccaaa catatttgca 5957 agtggattta aacgactggt ccaaattttg ccttcagtta caagtctgtg gctctcattt 6017 gcctcctcag aagagtggga cagggctcca tgggagaccc agagttcagg ctacacacag 6077 ctgtaaaaca gccccaatcc tgactctggc tattcgcttc ccaccctctc ctttcactgt 6137 gatgtgttcc aggtttagcc tagggtccat tcttgtcact gtttcttact gtgtagagta 6197 cctttggcaa tgtctcttct gtacatattt atttatttgt gttcacgtca gtttgtttca 6257 tatcttagtt ttctttcacc cagctttgtt gttttaatta actgcccatt agagagactg 6317 tacctttttt ctagaaaaaa tattgtgaaa cagt tttctg tagtgatatt gttgaatatg 6377 acaggtaaag caactgtgag ggcgaactag aattagtagt gagaaactgc taaagctgat 6437 ttgccatttt actgaaatgg aaaatgattt ttttcaaata aatacttata ttgttcatgt 6497 tccaaaaaaa aaaaaaaaaa aaaaaaaagg gcggcc 6533 <210> 10 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 10 atgatgtttc gctcagatcg 20 <210> 11 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 11 gcatgggcca gttttgacaa 20 <210> 12 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 12 atgatgtttc gctcagatcg 20 <210> 13 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 13 attaaaactt tgtgctgtgg 20 <210> 14 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 14 atgatgtttg acactctcgg 20 <210> 15 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 15 ggagaaatta tccgagtggc 20 <210> 16 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 16 cacaagagca atgtacatgt gg 22 <210> 17 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 17 ctgtgtctca atgttcacat g 21 <210> 18 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 18 tattgcttgg aagaccaatg c 21 <210> 19 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> Description of Artificial Sequence: synthetic DNA <400> 19 gacacatgca tctcattcgc ac 22

[0065]

[Sequence list free text] SEQ ID NO: 10: Synthetic DNA SEQ ID NO: 11: Synthetic DNA SEQ ID NO: 13: Synthetic DNA SEQ ID NO: 14: Synthetic DNA SEQ ID NO: 15: Synthetic DNA SEQ ID NO: 16: Synthetic DNA SEQ ID NO: 17: Synthetic DNA SEQ ID NO: 18: Synthetic DNA SEQ ID NO: 19: Synthetic DNA

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 105 C07K 16/28 4C084 C07K 14/705 C12N 1/15 4C085 16/28 1/19 4H045 C12N 1/15 1/21 1/19 C12P 21/02 C 1/21 C12Q 1/68 A 5/10 G01N 33/15 Z C12P 21/02 33/50 Z C12Q 1/68 33/53 D G01N 33/15 M 33/50 33/566 33/53 C12N 15/00 ZNAA 5/00 A 33/566 A61K 37/02 (72) Inventor Toshio Furuya 1-11-23 Higashicho, Koganei-shi, Tokyo F-term (reference) 2G045 AA40 DA12 DA13 DA14 DA36 FB02 FB03 4B024 AA01 AA11 BA43 BA63 CA01 GA11 HA12 HA15 4B063 QA01 QQ02 QQ08 QQ43 QR32 QR55 QS34 QX01 4B064 AG20 AG27 CA19 CC24 DA01 DA13 4B065 AB01 AC14 BA02 CA24 A07A04 A07A08 BA22 CA53 CA56 NA14 ZC012 ZC422 ZC522 4C085 AA13 AA14 BB11 CC05 DD22 DD23 DD35 DD37 EE01 4H045 AA10 AA11 BA10 CA40 DA50 DA76 EA20 EA50 FA74

Claims (26)

[Claims] 1. SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6
Or a salt thereof comprising an amino acid sequence identical or substantially identical to the amino acid sequence represented by: 2. A peptide or a salt thereof comprising a partial amino acid sequence of the G protein-coupled receptor protein according to claim 1. 3. A polynucleotide comprising a base sequence encoding the G protein-coupled receptor protein according to claim 1 or the peptide according to claim 2. 4. The polynucleotide according to claim 3, wherein the polynucleotide is DNA. 5. The polynucleotide according to claim 3, comprising the nucleotide sequence represented by SEQ ID NO: 1, SEQ ID NO: 3, or SEQ ID NO: 5, or a part of the nucleotide sequence. 6. A recombinant vector containing the polynucleotide according to claim 3. 7. A transformant transformed with the recombinant vector according to claim 6. 8. The G protein according to claim 1, wherein the transformant according to claim 7 is cultured in a medium, and the G protein-coupled receptor protein according to claim 1 is collected from the obtained culture. A method for producing a protein-coupled receptor protein or a salt thereof. 9. An antibody against the G protein-coupled receptor protein according to claim 1 or a salt thereof, or the peptide according to claim 2 or a salt thereof. 10. The antibody according to claim 9, wherein the antibody has an activity of inhibiting signal transduction of the G protein-coupled receptor protein according to claim 1. 11. A pharmaceutical composition comprising the antibody according to claim 9 as an active ingredient. 12. A ligand for the G protein-coupled receptor protein according to claim 1. 13. A pharmaceutical composition comprising the ligand according to claim 12 as an active ingredient. 14. A method comprising the step of examining the specific binding ability of a candidate ligand substance to the G protein-coupled receptor protein according to claim 1 or a salt thereof, or the peptide according to claim 2 or a salt thereof. A method for determining a ligand for the receptor protein. 15. A G protein-coupled receptor according to claim 1, wherein the G protein-coupled receptor protein according to claim 1 or a salt thereof, or the peptide according to claim 2 or a salt thereof is used. A method for screening a substance that changes the binding to a type receptor protein or a salt thereof. 16. The G according to claim 1, comprising the G protein-coupled receptor protein according to claim 1 or a salt thereof, and / or the peptide according to claim 2 or a salt thereof as a component. A screening kit for a substance that changes the binding between a protein-coupled receptor protein and a ligand of the receptor protein. 17. The method according to claim 1, wherein the G protein-coupled receptor protein and the ligand for the receptor protein are obtained by using the screening method according to claim 15 or the screening kit according to claim 16. A substance that changes the binding properties of 18. A pharmaceutical composition comprising the substance according to claim 17. (19) a polynucleotide which hybridizes with the polynucleotide of (3) under stringent conditions; 20. A polynucleotide comprising a nucleotide sequence complementary to the polynucleotide according to claim 3, or a part of said nucleotide sequence. 21. The G protein-coupled receptor protein according to claim 1, further comprising a step of measuring the intensity of hybridization between mRNA in the subject and the polynucleotide according to claim 20. MRNA quantification method. 22. The method for quantifying a G protein-coupled receptor protein according to claim 1, further comprising the step of measuring the strength of binding between the protein in the sample and the antibody according to claim 9. Method. 23. The receptor protein mR according to claim 21.
The method for testing a disease associated with the function of a G protein-coupled receptor according to claim 1, wherein the method for quantifying NA or the method for quantifying a receptor protein according to claim 22 is used. 24. The expression level of the G protein-coupled receptor protein according to claim 1 in a test cell or a test animal to which a candidate substance has been administered or exposed, and the mRNA level using the quantification method according to claim 21. Or 22.
The method for screening a substance that alters the expression of a G protein-coupled receptor according to claim 1, comprising a step of measuring at the protein level using the quantification method according to claim. 25. A substance that alters the expression of the G protein-coupled receptor according to claim 1, which is obtained by using the screening method according to claim 24. 26. A pharmaceutical composition comprising the substance according to claim 25 as an active ingredient.