U.S. patent application number 10/204639 was filed with the patent office on 2006-03-23 for novel gene and protein encoded by the gene.
Invention is credited to Takahiro Nagase, Daisuke Nakajima, Osamu Ohara.
Application Number | 20060063152 10/204639 |
Document ID | / |
Family ID | 18856231 |
Filed Date | 2006-03-23 |
United States Patent
Application |
20060063152 |
Kind Code |
A1 |
Ohara; Osamu ; et
al. |
March 23, 2006 |
Novel gene and protein encoded by the gene
Abstract
Novel DNAs containing the regions which encode proteins have
been directly cloned from cDNA libraries derived from the human
adult whole brain, the human adult hippocampus and the human
embryonic whole brain, the nucleotide sequences thereof have been
determined, and their functions have been identified. The present
invention provides DNA which comprises the nucleotide sequence
encoding the following polypeptide (a) or (b): (a) a polypeptide
comprising an amino acid sequence which is identical or
substantially identical to an amino acid sequence represented by
any one of SEQ ID NOS: 1 to 70; (b) a polypeptide comprising an
amino acid sequence derived from the amino acid sequence
represented by any one of SEQ ID NOS: 1 to 70 by deletion,
substitution or addition of a section of amino acids, and having
biological activity which is substantially the same characteristic
with the function of the polypeptide of (a); a recombinant
polypeptide, which is encoded by the above DNA; and a protein
containing the polypeptide.
Inventors: |
Ohara; Osamu; (Chiba,
JP) ; Nagase; Takahiro; (Chiba, JP) ;
Nakajima; Daisuke; (Chiba, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Family ID: |
18856231 |
Appl. No.: |
10/204639 |
Filed: |
December 20, 2001 |
PCT Filed: |
December 20, 2001 |
PCT NO: |
PCT/JP01/11199 |
371 Date: |
August 22, 2002 |
Current U.S.
Class: |
435/6.18 ;
435/287.2; 435/320.1; 435/325; 435/6.1; 435/69.1; 530/350;
530/388.1; 536/23.1 |
Current CPC
Class: |
A61K 2039/505 20130101;
C07K 14/47 20130101; A61P 15/00 20180101; A61P 13/08 20180101; A61P
35/00 20180101 |
Class at
Publication: |
435/006 ;
435/069.1; 435/320.1; 435/325; 435/287.2; 530/350; 530/388.1;
536/023.1 |
International
Class: |
C12Q 1/68 20060101
C12Q001/68; C07H 21/02 20060101 C07H021/02; C12P 21/06 20060101
C12P021/06; C12M 1/34 20060101 C12M001/34; C07K 14/47 20060101
C07K014/47; C07K 16/18 20060101 C07K016/18 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 22, 2000 |
JP |
2000-389742 |
Claims
1. DNA comprising a nucleotide sequence encoding a polypeptide (a)
or (b) as follows: (a) a polypeptide comprising an amino acid
sequence which is identical or substantially identical to an amino
acid sequence represented by any one of SEQ ID NOS: 1 to 70; (b) a
polypeptide which comprises an amino acid sequence derived from an
amino acid sequence represented by any one of SEQ ID NOS: 1 to 70
by deletion, substitution or addition of a section of amino
acid(s), and has biological activity which is substantially the
same characteristic with the function of the polypeptide of
(a).
2. DNA hybridizing to the DNA of claim 1 under stringent
conditions, and encoding a polypeptide having biological activity
which is substantially the same characteristic with the function of
the polypeptide of (a) of claim 1.
3. A gene construct containing the DNA of claim 1 or 2.
4. A polypeptide (a) or (b) as follows: (a) a polypeptide
comprising an amino acid sequence which is identical or
substantially identical to an amino acid sequence represented by
any one of SEQ ID NOS: 1 to 70; (b) a polypeptide comprising an
amino acid sequence derived from an amino acid sequence represented
by any one of SEQ ID NOS: 1 to 70 by deletion, substitution or
addition of a section of amino acids, and having biological
activity which is substantially the same characteristic with the
function of the polypeptide of (a).
5. A recombinant polypeptide, which is encoded by the gene
construct of claim 3.
6. An antibody against the polypeptide of claim 4 or 5.
7. A DNA chip, on which the DNAs of claim 1 or 2 are arrayed.
8. A polypeptide chip, on which the polypeptides of claim 4 or 5
are arrayed.
9. An antibody chip, on which the antibodies of claim 6 are
arrayed.
Description
TECHNICAL FIELD
[0001] The present invention relates to DNA and a gene containing
the DNA, and a recombinant polypeptide encoded by the DNA and a
novel recombinant protein containing the polypeptide.
BACKGROUND ART
[0002] An enormous amount of information on the nucleotide sequence
of the human genome has been obtained by large-scale sequencing in
the Human Genome Project and analysis of the information is
continuing on a daily basis.
[0003] The ultimate goal of the Human Genome Project is not just
simple determination of the entire nucleotide sequence of the
genome, but also the elucidation of various human life phenomena
based on the structural information, that is the nucleotide
sequence information of DNA.
[0004] Only limited regions of the human genome sequence encode
proteins. Currently, the coding regions are predicted by the neural
network or an information science technique, called the Hidden
Markov Model. However, these models' predictive abilities are not
yet sufficiently reliable.
DISCLOSURE OF THE INVENTION
[0005] For the purpose of finding novel genes, we have completed
the present invention by succeeding in directly cloning novel DNAs
comprising regions that encode proteins from cDNA libraries derived
from the human adult whole brain, the human adult hippocampus and
the human embryonic whole brain, and determining the nucleotide
sequences thereof.
[0006] In a first embodiment, the present invention relates to DNA
comprising a nucleotide sequence encoding the following (a) or (b):
[0007] (a) a polypeptide consisting of an amino acid sequence which
is identical or substantially identical to an amino acid sequence
represented by any one of SEQ ID NOS: 1 to 70; [0008] (b) a
polypeptide consisting of an amino acid sequence derived from an
amino acid sequence represented by any one of SEQ ID NOS: 1 to 70
by deletion, substitution or addition of a section of amino
acid(s), and having biological activity which is substantially the
same characteristic with the function of the polypeptide of (a).
Examples of such DNA include, but are not limited to, DNAs
comprising the nucleotide sequences of SEQ ID NOS: 71 to 140.
[0009] In a second embodiment, the present invention further
relates to a DNA hybridizing to the DNA of the first embodiment of
the present invention under stringent conditions, and encoding a
polypeptide having biological activity which is substantially the
same characteristic with the function of the polypeptide of (a)
above.
[0010] Hereinafter, the DNAs of the first and the second
embodiments of the present invention are together referred to as
"the DNA of the present invention." Further, the present invention
also relates to antisense DNA comprising a nucleotide sequence
which is substantially complementary to the DNA of the present
invention.
[0011] In a third embodiment, the present invention relates to a
gene construct containing the DNA of the present invention. The
term "gene construct" in the present specification refers to every
artificially-engineered gene. Examples of the gene construct
include, but are not limited to, a vector containing the DNA of the
present invention or the antisense DNA of the DNA of the present
invention, and an expression vector of the DNA of the present
invention.
[0012] In a fourth embodiment, the present invention relates to the
following (a) or (b): [0013] (a) a polypeptide, consisting of an
amino acid sequence which is identical or substantially identical
to an amino acid sequence represented by any one of SEQ ID NOS: 1
to 70; [0014] (b) a polypeptide, consisting of an amino acid
sequence derived from the amino acid sequence represented by any
one of SEQ ID NOS: 1 to 70 by deletion, substitution or addition of
a section of amino acids, and having biological activity which is
substantially the same characteristic with the function of the
polypeptide of (a).
[0015] In a fifth embodiment, the present invention relates to a
recombinant polypeptide encoded by the gene construct of the third
embodiment of the present invention.
[0016] Hereinafter, the above polypeptides are together also
referred to as "the polypeptide of the present invention." The term
"polypeptide" in the present specification refers to "polymers of
amino acids having every molecular weight." The present invention
also relates to a recombinant protein containing the polypeptide of
the present invention. As defined above, in the present
specification the term "polypeptide" is not to be limited by
molecular weight, and therefore the term "the polypeptide of the
present invention" also includes a recombinant protein containing
the polypeptide of the present invention.
[0017] In a sixth embodiment, the present invention relates to an
antibody against the polypeptide of the present invention.
[0018] In a seventh embodiment, the present invention relates to a
DNA chip on which the DNAs of the present invention are
arrayed.
[0019] In an eighth embodiment, the present invention relates to a
polypeptide chip on which the polypeptides of the present invention
are arrayed.
[0020] In a ninth embodiment, the present invention relates to an
antibody chip on which the antibodies of the sixth embodiment of
the present invention are arrayed.
[0021] Table 1 shows the names of clones having the DNA of the
present invention, lengths of the polypeptide of the present
invention, their putative functions and grounds for prediction.
[0022] The DNAs of the present invention are identified by
determining the nucleotide sequences after isolating them as cDNA
fragments from cDNA libraries that we have prepared using as a
starter material the commercially available (Clontech) mRNA of
human adult whole brain, the human adult hippocampus and the human
embryonic whole brain.
[0023] Specifically, clones are randomly isolated from cDNA
libraries derived from the human adult whole brain, the human adult
hippocampus and the human embryonic whole brain prepared according
to the method of Ohara et al. (DNA Research 4:53-59 (1997)).
[0024] Next, redundant clones (clones containing the same
sequences) are removed by hybridization, followed by in vitro
transcription and translation. Both termini of its nucleotide
sequence are determined for a clone that has been confirmed to have
products of 50 kDa or more.
[0025] Homology searches are performed with databases of known
genes using the thus obtained terminal nucleotide sequences as
queries. As a result, the full-length nucleotide sequence of a
clone that is shown to be new is determined.
[0026] As described above, unknown genes that cannot be obtained by
standard cloning techniques, which rely on known genes, can now be
cloned systematically.
[0027] Further, the entire region of a human-derived gene
containing the DNA of the present invention can also be prepared by
a PCR method, such as RACE, while exercising proper care so as not
to cause short fragments or any artificial mistakes in obtained
sequences.
[0028] Furthermore, the present invention provides a recombinant
vector which comprises the DNA of the present invention or a gene
construct containing the DNA of the present invention; a
transformant retaining the recombinant vector; a method for
producing the polypeptide of the present invention or a recombinant
protein containing the polypeptide, or salts thereof, which
comprises the steps of culturing the transformant, producing and
accumulating the polypeptide of the present invention or the
recombinant protein containing the polypeptide, and collecting
these products; and the thus produced polypeptide of the present
invention or the recombinant protein containing the polypeptide, or
salts thereof.
[0029] The present invention also relates to a pharmaceutical
preparation comprising the DNA of the present invention or the gene
construct; a pharmaceutical preparation comprising a polynucleotide
(DNA) comprising a nucleotide sequence which encodes the
polypeptide of the present invention or a partial polypeptide
thereof, or a recombinant protein containing the polypeptides, an
antisense nucleotide comprising a nucleotide sequence substantially
complementary to the nucleotide sequence which encodes the
polypeptide of the present invention or a partial polypeptide
thereof, or a recombinant protein containing the polypeptides; a
pharmaceutical preparation comprising the polynucleotide of the
present invention and the antisense nucleotide , and a
pharmaceutical preparation comprising the polypeptide of the
present invention or a partial polypeptide thereof, and a
recombinant protein containing the polypeptides.
[0030] The present invention further relates to a DNA chip, a
peptide chip and an antibody chip that are prepared by arraying the
DNAs of the present invention, the polypeptides of the present
invention and the antibodies against the polypeptide of the present
invention, respectively.
[0031] The present invention further relates to an antibody against
the polypeptide of the present invention or a partial polypeptide
thereof or a recombinant protein containing the polypeptides, or
against salts thereof, and a method for screening a substance which
specifically interacts with the polypeptide of the present
invention by using the polypeptide of the present invention, a
partial polypeptide thereof or a recombinant protein containing the
polypeptides, or salts thereof, or antibodies against these
substances; a kit for screening; and the substance (compound)
itself which is identified by the screening method.
[0032] Any DNA can be used as the DNA of the present invention, so
far as it comprises a nucleotide sequence encoding the
above-mentioned polypeptide of the present invention. Further, the
DNA of the present invention may be cDNA identified and isolated
from cDNA libraries or the like derived from the human brain, from
cells or tissues other than the brain, such as the heart, lung,
liver, spleen, kidney, and testicle, or synthetic DNA.
[0033] A vector used for constructing libraries may be a
bacteriophage, a plasmid, a cosmid, or a phagemid. In addition,
using total RNA fractions or mRNA fractions prepared from the above
cells or tissues, amplification can be performed directly by a
reverse transcriptase-polymerase chain reaction (hereinafter,
abbreviated as "RT-PCR method.").
[0034] Any antisense DNA may be used as an antisense
oligonucleotide (DNA) having a nucleotide sequence substantially
complementary to the DNA that encodes the polypeptide of the
present invention or a partial polypeptide thereof, so far as it
comprises a nucleotide sequence substantially complementary to the
nucleotide sequence of the DNA, and is capable of inhibiting the
expression of the DNA. A substantially complementary sequence is,
for example, a nucleotide sequence having preferably about 90% or
more, more preferably about 95% or more, and most preferably 100%
homology with the full-length or partial nucleotide sequence of the
nucleotide sequence complementary to the DNA of the present
invention. The antisense DNA of the present invention includes a
nucleic acid sequence (RNA or DNA modified) having a similar
function to that of the antisense DNA. These antisense DNAs can be
produced using a known DNA synthesizer or the like.
[0035] The term "an amino acid sequence substantially identical to
an amino acid sequence represented by any one of SEQ ID NOS: 1 to
70" refers to an amino acid sequence having on the overall average
about 70% or more, preferably about 80% or more, further preferably
about 90% or more, and particularly preferably about 95% or more
homology with each of all the amino acid sequences represented by
any one of SEQ ID NOS: 1 to 70.
[0036] An example of a polypeptide consisting of an amino acid
sequence substantially identical to an amino acid sequence
represented by any one of SEQ ID NOS: 1 to 70 of the present
invention is a polypeptide having the above homology with the amino
acid sequence represented by each of the above SEQ ID NOS, and
having biological activity (function) which is substantially the
same characteristic with the function of the polypeptide comprising
the amino acid sequence represented by each SEQ ID NO. The term
"substantially the same characteristic" refers to the activity
(function) having the same characteristics.
[0037] Further, the polypeptide of the present invention also
includes, for example, a polypeptide consisting of an amino acid
sequence derived from an amino acid sequence represented by any one
of SEQ ID NOS: 1 to 70 by deletion, substitution or addition of a
section of amino acids (preferably about 1 to 20, more preferably
about 1 to 10, and further preferably several amino acids) or by a
combination of these, and having biological activity (function)
which is substantially the same characteristic with the function of
a polypeptide comprising an amino acid sequence represented by any
one of SEQ ID NOS: 1 to 70.
[0038] The polypeptide consisting of an amino acid sequence which
is substantially identical to the above amino acid sequence
represented by any one of SEQ ID NOS: 1 to 70, or the polypeptide
comprising an amino acid sequence derived from the above amino acid
sequence by deletion, substitution or addition of a section of the
amino acids can be easily produced by, for example, an appropriate
combination of methods known by a person skilled in the art, such
as site-directed mutagenesis, homologous recombination of genes,
primer elongation and PCR.
[0039] For the polypeptide to have biological activity which is
substantially the same characteristics, a possible method is
substitution between homologous amino acids (polar or nonpolar
amino acids, hydrophobic or hydrophilic amino acids, positively or
negatively charged amino acids, aromatic amino acids and the like)
among amino acids composing the polypeptide. To maintain biological
activity that is substantially the same characteristics, it is
preferred to retain amino acids within functional domains contained
in each polypeptide of the present invention.
[0040] Further, the DNA of the present invention includes DNA
comprising a nucleotide sequence encoding an amino acid sequence
represented by any one of SEQ ID NOS: 1 to 70, and a DNA
hybridizing to the DNA under stringent conditions, and encoding a
polypeptide having biological activity (function) which is the same
characteristic with the function of a polypeptide consisting of an
amino acid sequence represented by each of the sequences.
[0041] Under such conditions, examples of DNA capable of
hybridizing to DNA comprising a nucleotide sequence encoding an
amino acid sequence represented by each of the nucleotide sequences
of SEQ ID NOS: 1 to 70 include DNA comprising a nucleotide sequence
having on the overall average about 80% or more, preferably about
90% or more, more preferably about 95% or more homology with each
of all the nucleotide sequences of the DNAs.
[0042] Hybridization can be performed by a method known in the art
or a method according to any known methods, such as a method
described in Current Protocols in Molecular Biology (edited by
Frederick M. Ausubel et al., 1987). When a commercially available
library is used, hybridization can also be performed by the method
described in the attached instructions.
[0043] The term "stringent conditions" means, for example,
conditions that allow hybridizing to the DNA probe of the present
invention by southern blot hybridization under conditions that
involve hybridization in an 7% SDS solution containing 1 mM sodium
EDTA and 0.5 M dibasic sodium phosphate (pH 7.2) at 65.degree. C.,
and washing membranes in a 1% SDS solution containing 1 mM sodium
EDTA and 40 mM dibasic sodium phosphate (pH 7.2) at 65.degree. C.
The same stringency can also be achieved by conditions other than
the above conditions.
[0044] To clone the DNA of the present invention, amplification is
performed by a PCR method using a synthetic DNA primer having an
appropriate nucleotide sequence of a part of the polypeptide of the
present invention or the like, or the DNA can be selected by
hybridization of DNA incorporated in an appropriate vector with DNA
labeled using a DNA fragment or synthetic DNA which encodes a
section or the full-length region of the polypeptide of the present
invention.
[0045] Hybridization can be performed according to, for example,
the above-described method in "Current Protocols in Molecular
Biology" (edited by Frederick M. Ausubel et al., 1987). In
addition, when commercially available libraries are used,
hybridization can be performed according to the method described in
the attached instructions.
[0046] Cloned DNA encoding a polypeptide can be used intact, or can
be used after digestion with restriction enzymes if necessary, or
after addition of linkers thereto, depending on the purposes. The
DNA may contain ATG as a translation initiating codon at the 5'
terminal side, or TAA, TGA or TAG as a translation termination
codon at the 3' terminal side. These translation initiating and
termination codons may be added using an appropriate synthetic DNA
adaptor.
[0047] An expression vector for the polypeptide of the present
invention can be produced according to any method known in the
technical field. For example, the vector can be produced by (1)
cleaving a DNA fragment containing the DNA of the present invention
or a gene having the DNA of the present invention, and (2) ligating
the DNA fragment downstream of a promoter in an appropriate
expression vector.
[0048] Examples of vectors that can be used herein include plasmids
derived from Escherichia coli, (for example, pBR322, pBR325, pUC18
and pUC118), plasmids derived from Bacillus subtilis (for example,
pUB110, pTP5 and pC194), plasmids derived from yeast (for example,
pSH19 and pSH15), bacteriophages, such as .lamda. phages, and
animal viruses, such as retrovirus, vaccinia virus, baculovirus and
the like.
[0049] Any promoter can be used in the present invention, so far as
it is appropriate for a host to be used for gene expression.
Preferred examples of promoters include, when the host is
Escherichia coli, trp promoters, lac promoters, recA promoters,
.lamda.PL promoters and lpp promoters; when the host is Bacillus
subtilis, SPO1 promoters, SPO2 promoters and penP promoters; and
when the host is yeast, PHO5 promoters, PGK promoters, GAP
promoters and ADH promoters. When animal cells are used as hosts,
examples of promoters include SR.alpha. promoters, SV40 promoters,
LTR promoters, CMV promoters and HSV-TK promoters.
[0050] In addition to the above substances, an enhancer, splicing
signal, polyA addition signal, a selection marker, SV40 replication
origin and the like that are known in the technical field can be
added to the expression vector, if desired. Further, if necessary,
a protein encoded by the DNA of the present invention can be
expressed as a fusion protein with another protein (for example,
glutathione S transferase and protein A). Such a fusion protein can
be cleaved with appropriate protease and then separated into each
protein.
[0051] Examples of host cells that are used herein include bacteria
of the genus Escherichia or the genus Bacillus, yeast, insect
cells, insects, and animal cells.
[0052] Specific examples of bacteria of the genus Escherichia that
are used herein include Escherichia coli K12/DH1 (Proc. Natl. Acad.
Sci. USA, 60:160 (1968)), JM103 (Nucleic Acids Research, 9:309
(1981)), JA221 (Journal of Molecular Biology, 120:517 (1978)), and
HB 101 (Journal of Molecular Biology, 41:459 (1969)).
[0053] Examples of bacteria of the genus Bacillus that are used
herein include Bacillus subtilis MI114 (Gene, 24:255(1983)) and
207-21 [Journal of Biochemistry, 95:87 (1984)].
[0054] Examples of yeast that are used herein include Saccaromyces,
such as Saccaromyces cerevisiae AH22, AH22R-, NA87-11A, DKD-5D and
20B-12; Schizosaccaromyces pombe NCYC1913 and NCYC2036; and Pichia
pastoris.
[0055] Examples of animal cells that are used herein include monkey
cells, such as COS-7 and Vero, Chinese hamster ovary cells, such as
CHO (hereinafter, abbreviated as CHO cells), dhfr gene-deficient
CHO cells; mouse L cells, mouse AtT-20, mouse myeloma cells, rat
GH3, and human FL cells.
[0056] These host cells can be transformed according to a method
known in the technical field. For example, transformation can be
performed by referring to Proc. Natl. Acad. Sci. USA, 69:2110
(1972); Gene, 17:107 (1982); Molecular & General Genetics,
168:111 (1979); "Methods in Enzymology," vol. 194, p 182-187
(1991); Proc. Natl. Acad. Sci. USA, 75:1929 (1978); A Separate
Volume 8 of Cell Technology, New Experimental Protocols in Cell
Technology, p 263-267 (1995) (issued by Shujunsha); and Virology,
52:456 (1973).
[0057] The thus obtained transformant, which has been transformed
with an expression vector containing the DNA of the present
invention or a gene containing the DNA of the present invention,
can be cultured according to a method known in the technical
field.
[0058] For example, when hosts are bacteria of the genus
Escherichia, culturing is performed normally at about 15.degree. C.
to 43.degree. C. for about 3 to 24 hours, and if necessary,
aeration and agitation may be performed. When hosts are bacteria of
the genus Bacillus, culturing is performed normally at about
30.degree. C. to 40.degree. C. for about 6 to 24 hours, and if
necessary, aeration and agitation may be performed.
[0059] A transformant whose host is yeast is normally cultured
using media adjusted to have pH of approximately 5 to 8, at about
20.degree. C. to 35.degree. C. for about 24 to 72 hours, and if
necessary, aeration and agitation may be performed.
[0060] A transformant whose host is an animal cell is normally
cultured using media adjusted to have pH of about 6 to 8, at about
30.degree. C. to 40.degree. C. for about 15 to 60 hours, and if
necessary, aeration and agitation may be performed.
[0061] To isolate and purify the polypeptide or the protein of the
present invention from the above culture product, for example,
bacteria or cells are collected by a known method after culturing,
suspended in an appropriate buffer, disrupted by ultrasonication,
lysozyme and/or freezing and thawing, and then centrifuged or
filtered, thereby obtaining a crude protein extract. The buffer may
contain a protein denaturing agent, such as urea or guanidine
hydrochloride, or a surfactant, such as Triton X-100 (trade-mark).
When the protein is secreted in a culture solution, bacteria or
cells are separated after culturing from the supernatant by a known
method, thereby collecting the supernatant. The thus obtained
culture supernatant or the protein contained in an extract can be
purified by an appropriate combination of known isolation and
purification methods.
[0062] The thus obtained polypeptide of the present invention can
be converted to a salt by a known method or a method according to
the known method. Conversely, when the polypeptide is obtained as a
salt, it can be converted to an educt or another salt by a known
method or a method according to the known method. Further before or
after purification, the protein produced by a recombinant can be
freely modified by allowing an appropriate protein modification
enzyme, such as trypsin and chymotrypsin, to act on the protein, or
polypeptides can be partially removed.
[0063] The presence of the polypeptide of the present invention or
its salt can be measured by various binding assays and enzyme
immunoassay using a specific antibody.
[0064] The C terminus of the polypeptide of the present invention
is normally a carboxyl group (--COOH) or a carboxylate (--COO--),
and the C terminus may be an amide (--CONH.sub.2) or ester
(--COOR). Here, examples of R in ester that are used herein include
a C1-6 alkyl group, such as methyl, ethyl, n-propyl, isopropyl or
n-butyl; a C3-8 cycloalkyl group, such as cyclopentyl or
cyclohexyl; a C6-12 aryl group, such as phenyl or .alpha.-naphthyl;
a phenyl-C1-2 alkyl group, such as benzyl or phenethyl; and a C7-14
aralkyl group, such as an .alpha.-naphthyl-C1-2 alkyl group, e.g.,
.alpha.-naphthyl methyl. Further, pivaloyl-oxymethylester which is
generally used as oral administration may also be used.
[0065] When the polypeptide of the present invention has a carboxyl
group (or carboxylate) at the terminus other than the C terminus,
the carboxyl group is amidated or esterified. The polypeptide of
the present invention encompasses such a polypeptide. An example of
ester that is used in this case is the above-mentioned ester at the
C-terminus. Moreover, the polypeptide of the present invention also
encompasses a polypeptide wherein an amino group of a methionine
residue at the N-terminus is protected with a protecting group (for
example, a C1-6 acyl group, such as a formyl group or an acetyl
group); a polypeptide wherein a glutamic acid residue at the
N-terminus which is generated by in vivo cleavage is
pyroglutamated; a polypeptide wherein OH, COOH, NH.sub.2, SH and
the like on the side chain of intramolecular amino acids are
protected with appropriate protecting groups (for example, a C1-6
acyl group, such as a formyl group and an acetyl group); or a
complex protein, such as a so-called glycoprotein formed by the
binding of sugar chains.
[0066] A partial polypeptide of the polypeptide of the present
invention may be any polypeptide which is a partial peptide of the
above-mentioned polypeptide of the present invention and has
activity which has substantially the same characteristics. For
example, a peptide that is used herein comprises a sequence of at
least 10 or more, preferably 50 or more, further preferably 70 or
more, further more preferably 100 or more, and most preferably 200
or more amino acids of the amino acid sequence composing the
polypeptide of the present invention, and, for example, has
biological activity substantially the same characteristic with the
function of the polypeptide of the present invention. An example of
a preferable partial polypeptide of the present invention contains
each functional domain. Further, the partial peptide of the present
invention normally has a carboxyl group (--COOH) or a carboxylate
(--COO--) at the C terminus, and it may also have an amide
(--CONH.sub.2) or an ester (--COOR) at the C terminus like the
above polypeptide of the present invention may have. Further,
examples of the partial peptide of the present invention, similar
to the polypeptide of the present invention described above,
include a peptide wherein an amino group of a methionine residue at
the N terminus is protected with a protecting group; a peptide
wherein a glutamyl residue at the N-terminus which is generated by
in vivo cleavage is pyroglutamated; a peptide wherein a substituent
on the side chain of intramolecular amino acids is protected with
an appropriate protecting group; a complex peptide, such as a
so-called glycopeptide formed by the binding of sugar chains, or
the like. The partial peptide of the present invention can be used
as, for example, a reagent, reference materials for experiments, or
an immunogen or a portion thereof.
[0067] Particularly preferred salts of the polypeptide of the
present invention or the partial peptide are physiologically
acceptable acid-added salts. Examples of such salts that are used
herein include a salt formed with inorganic acid (for example,
hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric
acid), and a salt formed with organic acid (for example, acetic
acid, formic acid, propionic acid, fumaric acid, maleic acid,
succinic acid, tartaric acid, citric acid, malic acid, oxalic acid,
benzoic acid, methane sulfonic acid and benzenesulfonic acid).
[0068] The polypeptide of the present invention, the partial
peptide thereof or salts thereof, or amides thereof can be prepared
by a chemical synthesis method known in the technical field.
[0069] For example, amino acids whose .alpha.-amino groups and side
chain functional groups are appropriately protected are condensed
on resin (which is commercially available resin for protein
synthesis) in accordance with the sequence of a target polypeptide,
according to various condensation methods known in the art. Various
protecting groups are then removed simultaneously with cleavage of
the polypeptide from the resin at the end of reaction. Further,
reaction for forming an intramolecular disulfide linkage is
conducted in a highly diluted solution, thereby obtaining a target
polypeptide, the partial peptide thereof or amides thereof.
Examples of activation reagents that can be used to condense the
above protected amino acids include those that can be used for
polypeptide synthesis and are represented by carbodiimides, such as
DCC, N,N'-diisopropylcarbodiimide and
N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide. For activation by
such reagents, both protected amino acids and a
racemization-suppressing additive (for example, HOBt or HOOBt) are
directly added to the resin; or protected amino acids can be
previously activated with acid anhydride as a control, or HOBt
ester or HOOBt ester, and then added to the resin.
[0070] Solvents used for activation of protected amino acids and
condensation with resin can be appropriately selected from solvents
known in the art as applicable to polypeptide condensation
reaction, such as acid amides, halogenated hydrocarbons, alcohols,
sulfoxides and ethers. A reaction temperature is appropriately
selected from a known range that can be used for reaction of
polypeptide linkage formation. Activated amino acid derivatives are
normally used in 1.5 to 4-fold excess. When condensation is
insufficient as a result of a test using ninhydrin reaction,
sufficient condensation can be performed by repeating condensation
reaction without eliminating protecting groups. When condensation
is still insufficient even when reaction is repeated, unreacted
amino acids are acetylated using acetic anhydride or
acetylimidazole so as not to affect the subsequent reaction.
[0071] Protecting groups which are normally employed in the
technical field can be used for raw materials, such as those for
each of amino groups, carboxyl groups and serine hydroxyl
groups.
[0072] The protection of functional groups that should not involve
the reaction of raw materials, protecting groups, and the
elimination of the protecting groups, and the activation of
functional groups that involve reaction and the like can be
appropriately selected from known groups or performed by known
measures.
[0073] The partial peptide of the present invention or a salt
thereof can be produced according to a peptide synthesis method
known in the technical field, or by cleaving the polypeptide of the
present invention with appropriate peptidase. For example, the
peptide synthesis method may be either a solid-phase synthesis
method or a liquid phase synthesis method. Examples of a known
condensation method and a method of elimination of protecting
groups are described in Nobuo IZUMIYA et al., Basics and Experiment
for Peptide Synthesis, Maruzen (1975); Haruaki YAJIMA and Shunpei
SAKAKIBARA, Experiment Course for Biochemistry 1, Protein Chemistry
IV, 205 (1977); and Development of Pharmaceutical Preparation 2,
vol. 14, Peptide Synthesis, under the editorship of Haruaki YAJIMA,
Hirokawa Publishing Co.
[0074] After reaction, the partial peptide of the present invention
can be purified and isolated using known methods, such as solvent
extraction, distillation, column chromatography, liquid
chromatography, recrystallization and the like in combination. When
the partial peptide obtained by the above methods is an educt, it
can be converted to an appropriate salt by a known method.
Conversely, when the peptide is obtained as a salt, it can be
converted to an educt by a known method.
[0075] The antibody for the polypeptide of the present invention,
the partial peptide thereof or salts thereof may be either a
polyclonal or a monoclonal antibody, so far as it can recognize
these substances. The antibody for the polypeptide of the present
invention, the partial peptide thereof or salts thereof can be
produced using as an antigen the polypeptide of the present
invention or the partial peptide thereof according to a known
method for producing antibodies or anti-serum.
[0076] The antibody of the present invention can be used to detect
the polypeptide of the present invention and the like which are
present in a specimen, such as body fluid, tissues or the like. In
addition, the antibody can be used for preparing an antibody column
to be used for purifying these substances; detecting the
polypeptide of the present invention in each fraction upon
purification; analyzing the behavior of the polypeptide of the
present invention within the cells of a specimen; and the like.
[0077] The use of the DNA, the polypeptide and the antibody of the
present invention will be further described below.
[0078] Using as a probe the DNA of the present invention, the
antisense DNA of the DNA of the present invention, or a gene
construct containing these DNAs, abnormalities (of the gene) in DNA
or mRNA encoding the polypeptide of the present invention or the
partial peptide thereof can be detected.
[0079] The DNA, the antisense DNA or the gene construct of the
present invention are useful as a genetic diagnostic agent for, for
example, damages, mutation or hypoexpression in the DNA or mRNA,
and an increase or hyperexpression of the DNA or mRNA. The above
gene diagnosis using the DNA of the present invention can be
performed by, for example, a known northern hybridization or a
PCR-SSCP method (Genomics, 5:874-879(1989), Proc. Natl. Acad. Sci.
USA, 86:2766-2770 (1989)).
[0080] Moreover, for patients who cannot exert normal in vivo
functions because of abnormalities or deletions in the DNA or the
gene of the present invention, or because the expression amount of
the DNA or the gene of the present invention is reduced, it is
effective that the DNA or the gene construct of the present
invention is introduced for expression into the bodies of the
patients by gene therapy using as vehicles appropriate vectors,
such as retrovirus vectors, adenovirus vectors and
adenovirus-associated virus vectors according to known techniques.
Further, when patients cannot exert normal functions because of an
increased expression amount, introduction of antisense can be
effective.
[0081] The DNA, the antisense DNA of the present invention, or the
gene construct thereof can be administered alone, or in combination
with an adjuvant to promote uptake using a gene gun or a catheter,
such as a hydrogel catheter.
[0082] In another example, injection of the polypeptide of the
present invention or the like into patients with the above diseases
also enables the polypeptide of the present invention or the like
to exert its function in the patients.
[0083] Furthermore, the antibody of the present invention can be
used for quantitatively determining the polypeptide of the present
invention in a test liquid by a known method. Specifically, the
antibody of the present invention can be used for quantitative
determination by a sandwich immuno-assay using monoclonal
antibodies, detection by tissue staining, and the like, by which,
for example, diseases that involve the polypeptide of the present
invention or the like can be diagnosed.
[0084] For these purposes, an antibody molecule itself can be used,
or the antibody molecules F(ab')2, Fab' or Fab fractions can be
used. Quantitative determination methods for the polypeptide of the
present invention using the antibody of the present invention are
not specifically limited. Any measurement method can be used, so
far as it involves detecting the amount of antibodies, antigens or
antibody-antigen complexes corresponding to the amount of antigens
(for example, protein amount) in a test liquid by chemical or
physical means, and calculating with a calibration curve which has
been prepared using a standardized solution containing a known
amount of antigens. For example, nephrometry, competitive assay,
immunometric assay and sandwich assay are preferably used, and a
later described sandwich assay is preferred in terms of sensitivity
and specificity. Examples of a labeling agent that can be used in a
measurement method using a labeling substance include a substance
known in the technical field, such as radioisotopes, enzymes,
fluorescent materials and light-emitting materials.
[0085] Details about the general technical procedures concerning
these measurement and detection methods can be referred to in a
review, reference book or the like, such as Radioimmunoassay 2
edited by Hiroshi IRIE, (Kodansha, issued in 1979); Enzyme
Immunoassay edited by Eiji ISHIKAWA et al., (3.sup.rd edition;
Igaku-Shoin, issued in 1987); and Methods in Enzymology (issued by
Academic Press), vol. 70, "Immunochemical Techniques (Part A),"
vol. 73, "Immunochemical Techniques (Part B)," vol. 74,
"Immunochemical Techniques (Part C)," vol. 84, "Immunochemical
Techniques (Part D: Selected Immunoassays)," vol. 92,
"Immunochemical Techniques (Part E: Monoclonal Antibodies and
General Immunoassay Methods)," and vol. 121, "Immunochemical
Techniques (Part I: Hybridoma Technology and Monoclonal
Antibodies)."
[0086] Moreover, DNA chips prepared by arraying the DNA of the
present invention are useful in detecting mutations and
polymorphism of the DNA of the present invention, and monitoring
the DNA dynamics. Regarding DNA array, which is a type of DNA chip,
see "DNA Microarray and Current PCR method" (a separate volume of
Cell Technology, Genome Science Series 1, under the editorship of
Masaaki MURAMATSU and Hiroyuki NABA, 1.sup.st impression of the
first edition, issued on Mar. 16, 2000) and the like.
[0087] Further, polypeptide chip prepared by arraying the
polypeptides of the present invention can be a strong tool for
functional analysis on the expression, interaction and
posttranslational modification of the polypeptides of the present
invention, and for identification and purification of proteins.
[0088] Antibody chip prepared by arraying antibodies against the
polypeptides of the present invention are very useful in analyzing
the correlation between the polypeptides of the present invention
and diseases, disorders, or other physiological phenomena.
[0089] Methods and materials for preparing the chip are known by
persons skilled in the art.
[0090] Furthermore, the polypeptides of the present invention or
the like are useful as reagents for screening compounds which
interact specifically with these substances. Specifically, the
present invention provides a method for screening compounds which
specifically interact with the polypeptide of the present
invention, a partial peptide thereof or salts thereof, or
antibodies against them by using these substances; and provides the
screening kit therefor.
[0091] Compounds or salts thereof that are identified using the
screening method or the screening kit of the present invention are
selected from the above test compounds. The compounds interact with
the polypeptide of the present invention or the like. For example,
the compounds regulate, inhibit, promote or antagonize the
biological activity of the polypeptide of the present invention or
the like. The compound or a salt thereof may directly act on the
activity of the polypeptide of the present invention or the like,
or indirectly act on the activity of the polypeptide of the present
invention or the like by acting on the expression of the
polypeptide of the present invention or the like. An example of the
salt of the compound that is used herein is a pharmaceutically
acceptable salt. Specific examples of such salts include a salt
formed with inorganic base, a salt formed with organic base, a salt
formed with inorganic acid, a salt formed with organic acid, and a
salt formed with basic or acidic amino acid. Compounds which
inhibit the biological activity of the polypeptide of the present
invention or the like can also be used as pharmaceutical
preparations, such as therapeutic agents and preventive agents for
each of the above-mentioned diseases.
[0092] When nucleotides (bases) and amino acids are indicated with
abbreviations in the present specification, the abbreviations
follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature,
or those commonly used in the art. Amino acids for which optical
isomerism is possible are, unless otherwise specified, in the L
form.
BEST MODE FOR CARRYING OUT THE INVENTION
[0093] The present invention will now be further described by means
of examples that are not intended to limit the present invention.
The various gene manipulations employed in the examples are
according to the methods described in the above Current Protocols
in Molecular Biology (edited by Frederick M. Ausubel et al.,
1987).
(1) Construction of cDNA Library Derived from Human Adult Whole
Brain, Human Adult Hippocampus and Human Embryonic Whole Brain
[0094] Double-stranded cDNA was synthesized using an
oligonucleotide having Not-I site
(GACTAGTTCTAGATCGCGAGCGGCCGCCC(T).sub.15) (Invitrogen) as a primer,
mRNAs (Clontech) derived from the human adult whole brain, the
human adult hippocampus and the human embryonic whole brain as
templates, and a SuperScriptII reverse transcriptase kit
(Invitrogen). Next, an adaptor (Invitrogen) having SalI site was
ligated to the cDNA, followed by digestion with NotI and 1%
low-melt agarose electrophoresis. Thus, DNA fragments of 3 kb or
more were purified.
[0095] The purified cDNA fragment was ligated to pBluescript IISK+
plasmid pre-treated with SalI-NotI restriction enzymes. The
recombinant plasmid was introduced into Escherichia coli strain
ElectroMax DH10B (Invitrogen) by electroporation.
(2) Screening
[0096] Subsequently, clones were randomly picked up from the
constructed cDNA library, and then spotted onto membranes. The
mixture of oligo DNAs (each comprising 21 nucleotides) was prepared
based on each of the full-length nucleotide sequences of
approximately 1300 clones that we had previously analyzed. Each 3'
terminus of the oligo DNAs was labeled with DIG using terminal
transferase. Using the DIG-labeled DNAs as probes, dot
hybridization (Current Protocols in Molecular Biology, edited by
Frederick M. Ausubel et al, 1987) was performed so as to remove
redundant clones (clones containing the same sequences).
[0097] Next, in vitro transcription and translation (Promega, TNT
T7 Quick Coupled Transcription/Translation System cat. No. L1107)
were performed, thereby selecting clones for which products of 50
kDa or more had been confirmed.
[0098] The terminal nucleotide sequences of the selected clones
were then determined. Using the obtained sequences as queries, a
homology search program BLASTN 2.0.14 (Stephen F. Altschul, Thomas
L. Madden, Alejandro A. Schaffer, Jinghui Zhang, Zheng Zhang, Webb
Miller, and David J. Lipman (1997), "Gapped BLAST and PSI-BLAST: a
new generation of protein database search programs," Nucleic Acids
Res. 25:3389-3402) was run on nr database (GenBank+EMBL+DDBJ+PDB
sequences which do not contain EST, STS, GSS or HTGS (phase 0, 1 or
2) sequences). As a result, the full-length nucleotide sequences of
novel genes, for which no homologous gene was present, were
determined.
[0099] For sequencing, a DNA sequencer (ABI PRISM377) and a
reaction kit which are manufactured by PE Applied Biosystems were
used. Most sequences were determined by a dye terminator method
using shotgun clones. Part of the nucleotide sequences was
determined by synthesizing oligonucleotides based on the determined
nucleotide sequences, and then performing a primer walking
method.
[0100] As described above, screening for novel DNAs or genes was
performed. As a result, a novel DNA or a gene represented by any
one of SEQ ID NOS: 71 to 140 in the sequence listing was
detected.
[0101] The nucleotide sequences of these novel DNAs or genes were
determined by the above sequencing method. Table 1 shows the names
of clones having the DNA or the gene of the present invention, the
length of a polypeptide encoded by the gene in the clone, its
putative function and the grounds for prediction. TABLE-US-00001
TABLE 1 Clone Name and Putative Function Clone SEQ Name/Protein
length/ ID Full length or partial Grounds for NO: sequence Putative
function prediction 1 fg01864 323 Partial Involved in mitoses, cell
motility Partially has a region sequence and phagocytosis through
the having 50% homology to regulation of the cytoskeleton.
coronin-, actin-binding Useful in therapy and diagnosis in protein
1C. the field of regulating the dynamic states of cells, such as
suppression of cancer metastasis and the action of immunocytes. 2
fg02011 314 Partial Regulates gene expression by binding Partially
has a region sequence of C2H2 type zinc finger motif to having 42%
homology to DNA, and interaction between zinc finger protein 91
Kruppel-associated box (KRAB) and has zf-C2H2 motifs. domain and
the other transcriptional apparatus. The deletion or the mutation
of the protein may cause abnormalities in morphogenesis or cell
proliferation. The detection of the mutation is useful in
diagnosing cancer and the introduction of the normal gene is useful
in treating cancer. 3 fg02301 187 Partial A molecule inferred to be
involved in Partially has a region sequence cell adhesion because
it has a having 39% homology to transmembrane domain and three the
immunoglobulin Ig-like C2-type domains, and shares superfamily, and
has ig high homology with NCAM1 and NCAM2. motifs and a sosui Since
the molecule regulates transmembrane domain. intercellular
adhesion, it is useful in diagnosing and treating canceration of
cells and cancer metastasis, and screening for the therapeutic
agent. 4 fg02936 1479 Partial A membrane protein expressed in the
Partially has a region sequence nerve system. Inferred to function
having 99% homology to as receptors for semaphorins, the
NOV/plexin-A1 protein guidance factor to elongate neural and has
the function axial filaments, thus regulating motifs of each of
Sema, neuron formation. With its Plexin_repeat, integrin.sub.--
function to regulate the growth of B, and TIG. neural axial
filaments, it is useful in diagnosing and treating a variety of
neuropsychiatric diseases, or screening for the therapeutic agent.
5 fg04068 258 Partial Encodes a guanine nucleotide Partially has a
region sequence exchange factor (GEF) whose target having 91%
homology to a is Rho-type GTPase. Activates Rho neuronal guanine
signal by converting Rho to GTP type. nucleotide exchange The
expression of the protein is high factor, and has a PH in the
brain, suggesting that it is domain motif. involved in brain
functions. Useful in diagnosing and treating cancer, and screening
for the therapeutic agent. Also inferred to be useful in improving
brain functions, since it is strongly expressed in the brain and is
thought to be involved in recognition functions. 6 fg05423 675
Partial A DNA-binding protein having a zinc Partially has a region
sequence finger motif, and is a having 51% homology to
transcriptional regulatory factor. EVI1 protein, and has Inferred
to be a protooncogene, zf-C2H2 motifs and a similar to EVI-1, or a
causative zf-BED motif. protein of osteomyelodysplasia syndrome.
Thus, it is thought to be useful in diagnosing and treating cancer
or osteomyelodysplasia, and in screening for the therapeutic agent.
7 fg06344 248 Partial Inferred to synthesize acetyl Partially has a
region sequence coenzyme A. The protein may be having 60% homology
to useful in screening for anticancer acetyl CoA synthetase. agents
and immunosuppressant agents. 8 fg06691 193 Partial Inferred to
have high homology with Partially has a region sequence an enzyme,
proline dehydrogenase, having 93% homology to and has functions
similar to proline proline dehydrogenase. dehydrogenase. Oxidizes
proline to 1-proline-5-carboxilic acid. The deletion of the enzyme
causes hyperprolinemia. Proline regulates transmission by
glutamate-operated synapses, and controls neurotransmission in the
brain. Elevated blood proline levels lead to abnormal sensory
motor. Thus, it is useful in diagnosing and treating mental
disorders due to hyperprolinemia and proline metabolic disorders. 9
fh02216 373 Partial Has .alpha.1,2-mannosidase activity to
Partially has a region sequence remove the terminal mannose of
having 100% homology to Man9GlcNac2-, the precursor, formed
.alpha.1,2-mannosidase, and in ER during the biosynthetic has a
Glyco_hydro_47 pathways of N-glycoside-binding motif and a sosui
sugar chain; and plays an important transmembrane domain. role in
sugar chain synthesis of N-glycoside-binding glycoprotein. The
N-glycoside-binding sugar chain functions everywhere in vivo. The
deletion of the protein may cause diseases induced by deficient
N-glycoside binding sugar chain. The protein is useful in treating
and diagnosing these diseases. 10 fh02982 215 Partial Regulates
exocytosis, triggered by Partially has a region sequence Ca2+, of
neurotransmitters in having 68% homology to synapse. Inferred to be
useful in NIM3, and has a C2 domain diagnosing and treating nervous
motif. diseases. 11 fh03203 1134 Partial An extracellular matrix
Partially has a region sequence glycoprotein which responds to
having 37% homology to pheromone and is transcribed.
hydroxyproline-rich Involved in biophylaxis. glycoprotein DZ-HRGP.
12 fh05673 438 Partial Expressed upon cephalization to be a
Partially has a region sequence guidance for the growth of neural
having 57% homology to axial filaments. Not a type which netrin-G1c
and has a acts by diffusion, but acts locally laminin_Nterm motif
and a on the surface of a cell membrane. laminin_EGF motif. Useful
in diagnosing and treating various neuropsychiatric diseases, or
screening for the therapeutic agents for these diseases, since the
protein regulates the growth of neural axial filaments. 13 fh06634
505 Partial One of the proteins forming an Partially has a region
sequence adaptor molecule complex which having 100% homology to
transduces a signal from tyrosine guanine kinase to Ras. Functions
as guanine nucleotide-releasing nucleotide-releasing factor 2 for
factor 2, and has a Ras. Since the protein is involved RasGEFN
motif and a in signal transduction from a RasGEF motif. receptor to
Ras, it is useful in diagnosing and treating cancer through the
regulation of cell proliferation, and screening for the therapeutic
agent. 14 fh08795 572 Partial Promotes GTPase activity of Partially
has a region sequence Ras-related nuclear protein Ran, having 100%
homology to which is involved in cell cycle; thus Ran GTPase
activating promotes conversion of active protein 1. GTP-Ran to
inactive GDP-Ran, thereby regulating initiation of cell mitosis.
Useful in diagnosing and treating cancer, and screening for the
therapeutic agent, since abnormalities in the protein can cause
canceration. 15 fh13310 1051 Partial Inferred to help the migration
of Partially has a region sequence hnRNPA1 from cytoplasms to
nuclei by having 98% homology to binding to hnRNPA1, which is a
karyopherin.beta.2b, protein controlling mRNA processing
transportin, and has and the transport of mRNA from nuclei
Armadillo_seg motifs and to cytoplasms. Useful in HEAT motifs.
diagnosing and treating cancer by regulating the gene. 16 fh18356
887 Partial Inferred to be a factor which is Partially has a region
sequence induced in blastocysts by having 94% homology to
parathyroid hormone, and involved in PTH-responsive the activation
of blastocysts by osteosarcome B1 protein. parathyroid hormone and
osteogenesis. Useful in diagnosing and treating bone diseases, such
as osteoporosis and a variety of cancers, and screening for the
therapeutic agent for these diseases. 17 fh18358 689 Partial
Promotes the formation of Partially has a region sequence
CDC25c/14-3-3 protein complex by having 64% homology to
phosphorylating Ser216 of Cdc25C associated CDC25c; and regulates
the initiation protein kinase C-TAK1, of cell mitosis through the
complex. and has a pkinase motif Useful in diagnosing and treating
and a UBA motif. cancer and screening for the therapeutic agent,
since it is involved in the regulation of cell division. 18 fh20539
1004 Partial Has the ankyrin repeat and is Partially has a region
sequence involved in protein interaction. having 35% homology to
Useful in treating cystic fibrosis, FRANK2 protein, and has since
it is involved in regulating ank repeat motifs. CFTR expression. 19
fh22167 761 Partial Serine/threonine kinase in the Partially has a
region sequence intracellular signal transduction having 30%
homology to system. Useful in screening a drug protein kinase WNK1.
for diseases which involve the signal transduction system. 20
fh23421 480 Partial A nuclear protein involved in mRNA Has 97%
homology to a sequence splicing. Concentrated in portions putative
splicing referred to as nuclear TY body, and factor, YT521-B.
inferred to provide a site for mRNA splicing. Useful in diagnosing
and treating cancer, and screening for the therapeutic agent, since
it is involved in regulating expression and cell proliferation.
Also useful in the field of regeneration medicine. 21 fh24594 762
Partial Involved in binding synaptosome Partially has a region
sequence binding protein (SNAP-25) to the having 94% homology to
cytoskeleton, and regulating SNAP-25-interacting exocytosis. Useful
in diagnosing, protein, and has a preventing and treating nervous
Troponin motif. diseases, since it is involved in regulating the
release of neurotransmitters. 22 fh26207 1094 Partial A GnRH-like
decapeptide precursor Partially has a region sequence acting as
gonadotropin releasing having 98% homology to hormone. Useful in
diagnosing, putative preoptic preventing and treating regulatory
factor-2 abnormalities in sex hormones, such precursor. as
infertility and cancer. 23 fj00154 388 Partial An enzyme which
substitutes Partially has a region sequence adenosine residue 37 of
alanine tRNA having 99% homology to with an inosine residue. Useful
in adenosine deaminase preventing, treating and diagnosing acting
on tRNA 1, and has diseases involved in modifying, such A_deamin
motifs. as tRNA.
24 fj00597s1 523 Full Inferred to transport iron or other Partially
has a region length divalent cations or to function as a having 39%
homology to membrane-binding receptor. For TTYH1, and has sosui
example, iron metabolic disorders transmembrane motifs. cause blood
diseases, such as anemia, the disease of nervous degeneration and
the like. Thus it is useful in diagnosing and treating such
diseases by detecting and regulating the expression and the
function of the protein. 25 fj03879s1 1653 Partial Acts on protein
interaction since it Partially has a region sequence has a PH
domain. Inferred to act on having 44% homology to the morphological
changes in P116 RHO-interacting neurons. Also inferred to inhibit
protein (P116RIP) cell expansion and the elongation of (RIP3), and
has a PH neurons by acting on Rho. Useful in domain motif.
diagnosing and treating nervous diseases and cancer, and screening
for the therapeutic agents for these diseases by regulating the
gene. 26 fj04226 959 Partial A microtubule-associated protein
Partially has a region sequence which regulates microtubule having
61% homology to kinetics and interaction between
microtubule-associated microtubules and other protein 4, and has
intracellular molecules. With the tubulin-binding motifs. strong
involvement of a microtubule-associated protein in cancer and
Alzheimer's disease, the protein, a putative member of the protein
family, is useful in diagnosing and treating these diseases. 27
fj04751 878 Full A protein which binds to oxysterol, Partially has
a region length and plays an important role in having 60% homology
to regulating cholesterol metabolism. oxysterol-binding Useful in
diagnosing and treating protein, and has a PH cardiovascular
diseases caused by domain and an abnormalities in cholesterol
Oxysterol_Bp motif. metabolism, and screening for the drug. 28
fj05456 281 Partial Inferred to act as a cytoskeleton Partially has
a region sequence factor in neurons of the brain. having 32%
homology to a This protein has 5 kelch motifs, ring canal protein,
and while Gigaxonin (mutated Gigaxonin has Kelch motifs. is found
in giant axonal neuropathy) has the BTB domain and 6 Kelch motifs.
The protein is useful in diagnosing and treating giant axonal
neuropathy and degenerative disorders in the nervous system (e.g.,
amyotrophic lateral sclerosis, amyotrophy, charcot-Marie-tooth
disease). 29 fj06918 707 Partial Present in neurons, and co-exists
Partially has a region sequence with ion channels. Involved in
having 46% homology to a differentiation of the functional cell
recognition domain of axial filaments. Useful molecule, Caspr2, and
has in treating, preventing, and laminin_G motifs and an diagnosing
nervous diseases, and EGF motif. screening for the therapeutic
agent. 30 fj08985 341 Partial A protein having a motif which binds
Partially has a region sequence to GTP-Rho, and which plays a role
in having 80% homology to transducing Rho signal to other GTP-rho
binding protein proteins. Involved in the regulation 1, and has a
BRO1 motif. of the cytoskeleton which is based on actin, the
contraction of the smooth muscle, transcription, cell
proliferation, and the regulation of cell cycle. Useful in
diagnosing and treating diseases caused by abnormalities in the
cytoskeleton and morphogenesis, and cancer, and screening for the
therapeutic agent. 31 fj10564 531 Partial An isozyme of
phosphoenzyme which Partially has a region sequence converts
inositol triphosphate to having 100% homology to inositol
tetraphosphate. inositol1, 4,5- Regulates intracellular calcium
triphosphate3-kinase levels and is involved in signal (IP3K).
transduction. Expressed in the hippocampus. Useful in screening for
an agent selectively acting on the inositol phosphate pathway. 32
fj11471 1199 Partial Has domains involved inhistogenesis Partially
has a region sequence and development of extremities. having 37%
homology to Possible involvement in cell FH1/FH2 localization, cell
division and the domain-containing regulation of the cytoskeleton.
protein FHOS, and has a High expression of this protein in FH2
motif. the spleen suggests its involvement in maturation and
development of B cells and erythrocytes. Useful in diagnosing and
treating diseases caused by cell or tissue development,
morphogenesis and maturation, and in regeneration medicine. 33
fj12188 449 Partial Regulates the binding and fusion of Partially
has a region sequence synaptic vesicles at the synaptic having 51%
homology to termini in the brain. Useful in serine/threonine-
treating and diagnosing diseases protein kinase DCAMKL1, with
abnormalities in neural and has a pkinase motif. transmission. 34
fj14406 1354 Partial A motor molecule which converts ATP Partially
has a region sequence (chemical energy) into physical having 37%
homology to 1 force so as to move along .beta. dynein heavy chain,
microtubules. While dyneins and has a Dynein_heavy involved in
mitosis, vesicle motif. transport, and the movement of cilia and
fragella exist as multisubunit complexes, the protein functions as
1.beta. dynein heavy chain which is a component of the complex.
Useful in diagnosing and treating cancer, and screening for the
therapeutic agent. Also useful in diagnosing cranial nerve
diseases, such as hydrencephaly, infertility and respiratory
apparatus-related diseases. 35 fj15278 966 Partial Involved in
regulation of binding Has 95% homology to Sequence and fusion of
synaptic vesicles to rsec8. pre-synaptic membranes. A component of
a complex involved in neural transmission. Useful in treating and
diagnosing diseases with abnormalities in neural transmission. 36
fj16085s1 1766 Partial Regulates cell differentiation and Partially
has a region sequence cell proliferation by interacting having 57%
homology to with proteins having the SET domain. nuclear
dual-specificity Useful in diagnosing and treating phosphatase, and
has a cancer, and screening for the DENN, a GRAM and a PH
therapeutic agent. domain motif. 37 fj17028 498 Partial Produces
phospholipids, the second Partially has a region sequence
messenger, and involved in having 95% homology to intracellular
reactions including phosphatidic production of hyperoxides in
acid-preferring neutrophils, actin polymerization phospholipase A1,
and has and the like. Useful in diagnosing a DDHD motif. and
treating infectious diseases, inflammation and immune diseases, and
screening for the drug. 38 fj17066 389 Full Regulates the
expression of homeotic Partially has a region length genes by
modifying the structure of having 87% homology to chromosomes, and
inhibits chromobox homolog 8, and (functions to perform silencing)
has a chromo motif. gene expression. Useful in diagnosing and
treating cancer, and screening for the therapeutic agent. Also
useful in gene diagnosis of malformation, teratogeny and the like,
and in the field of regeneration medicine. 39 gh01817b 380 Partial
Dissociates a transcribed complex Partially has a region sequence
from a template. Can be used for having 92% homology to analyzing
the transcriptional polymerase I and a mechanism. transcript
release factor. 40 gh13812 360 Partial A regulatory subunit of
phosphatase Partially has a region sequence which regulates the
activity of a having 93% homology to pyruvate dehydrogenase
complex. pyruvate dehydrogenase Useful in diagnosing and treating
phosphatase regulatory cancer, and screening for the subunit
precursor, and therapeutic agent. Also useful in has a GCV_T motif.
screening for an antiobestic drug. 41 hh05136b 832 Partial A
homologue of collagen V precursor. Partially has a region sequence
Collagen V plays an important role in having 46% homology to
forming extracellular matrix. collagen .alpha.1 (V) chain Useful in
diagnosing cirrhosis, and precursor, and has as biological base
materials in Collagen motifs and COLFI regeneration medicine.
motifs. 42 hh05356 370 Partial Forms a spindle during cell
Partially has a region sequence division, and delivers chromosomes
having 97% homology to to daughter cells. Involved in tubulin
.beta.-5 chain (.beta.- constructing and maintaining the tubulin
class-V). three-dimensional structure of a cytoplasm together with
actin fibers and intermediate filaments. Useful in diagnosing and
treating cancer, and screening for the therapeutic agent. 43
hh10052 412 Partial Inferred to be the gene product of a Partially
has a region sequence novel human cartilage link protein having 49%
homology to family, which is important in proteoglycan link
differentiation and proliferation protein precursor of cartilage
cells. Useful in (cartilage link regeneration of the cartilage.
protein), and has an ig motif and Xlink motifs. 44 hh13045 803
Partial Inferred to be novel cadherin Partially has a region
sequence molecules, since they have cadherin having 30% homology to
repeats. Involved in cell FAT tumor suppressor, and adhesion.
Possible involvement in has cadherin motifs. segregation of cancer
cells from primary layers and infiltrationwith cancer cells. Useful
in diagnosing and treating cancer, and screening for the
therapeutic agent. Also useful as a marker for renal diseases,
because of its high expression in kidney. 45 hh14180 1036 Full
(Threonin)-0-binding Has a region having 99% length
N-acetylglucosamine transferase, homology to which controls
activities of various N-acetylglucosaminyl proteins including a
transcription transferase 110 KDA factor, a nuclear membrane
protein, subunit, and has TPR a cytoskeletal protein and a motifs.
cancer-related protein within the nucleus and cytoplasm. Useful in
diagnosing and treating various diseases, such as cancer, and
screening for the therapeutic agent. 46 hj02562 277 Partial A
protein which may function as a Has a region having 88% sequence
co-activator in RNA polymerase II homology to PC2 glutamine
complexes. Possible involvement in rich binding protein. cranial
nerve diseases, such as Alzheimer's disease and Parkinson's
disease, because they have glutamate repeats. Useful in diagnosing
cranial nerve diseases, such as Alzheimer's disease and Parkinson's
disease, and as a target therapeutic agent to be developed. 47
hj03865 1115 Partial Has 98% homology to a Partially has a region
sequence huntingtin-associated protein having 98% homology to
interacting protein (HAPIP) which huntingtin-associated binds to a
protein (Duo) binding to protein interacting huntingtin, the cause
of protein, and has a RhoGEF Huntington's chorea. High and a PH
domain motif.
expression in the brain. UNC-73, the C. elegans homologue of HAPIP,
has been shown to involve axonal guidance. Suggested to be involved
in signal transduction, because it has the RhoGEF motif. Inferred
to be useful in diagnosing and treating Huntington's chorea. Useful
as a target gene for developing an agent for nerve regeneration
because of the involvement in axonal guidance. 48 hj05256 783
Partial Inferred to be a transcription Partially has a region
sequence factor, since the protein has the having 48% homology to
zinc finger motif. A deletion or a zinc finger protein 91, mutation
in the protein may cause and has zf-C2H2 motifs. abnormalities in
morphogenesis and cell proliferation. Detection of a mutation in
the gene is useful in diagnosing cancer, and introduction of the
normal gene is useful in treating cancer. 49 hk02174 797 Partial A
protein, which is accumulated in Partially has a region sequence
significant amount in the having 94% homology to post-synaptic
density of excitable proline rich synapse synapses. Inferred to be
a gene associated protein 2, and encoding a protein which anchors
has a SAM motif. SAP90/PSD-95, the scaffold for a membrane
receptor, to the cytoskeleton in synapses using glutamate in the
central nerve system. The protein may have influence on the
generation of the neural network, and establishment of memory and
learning. Useful in diagnosing various neuropsychiatric disorders,
and screening for the therapeutic agent. 50 pf00330s1 1043 Full A
protein, the scaffold for ephr in B, Partially has a region length
which plays an important role by having 87% homology to guiding
axial filaments in the glutamate receptor embryogenesis, to form a
complex interacting protein 2, that transduces signal. Inferred and
has PDZ motifs. to involve neural circuit formation. Useful in gene
diagnosis and the field of regeneration medicine. 51 pf00447 421
Partial It may bind to a protein having the Partially has a region
sequence SH3 domain, because the protein is having 41% homology to
homologous to SH3-domain binding SH3-domain binding protein. Since
the protein having protein 5 the SH3-domain is often involved in
(BTK-associated). intracellular signal transduction, it can be
inferred that the protein has similar functions. Useful in
diagnosing and treating cancer, and screening for the therapeutic
agent. 52 pg00239 1644 Partial Inferred to perform protein
Partially has a region sequence interaction, since the protein has
having 30% homology to the ankyrin repeat. Possible ankyrin 3, and
has ank involvement in signal transduction repeat motifs. and
transcriptional control. Useful in diagnosing and treating cancer,
and screening for the therapeutic agent. 53 pg00264 534 Partial
Inferred to be sialyltransferase, Partially has a region sequence
and involve post-translational having 54% homology to modification
of protein. Useful in CMP-N-acetylneuraminate- treating, preventing
and diagnosing .beta.-galactosamide-.alpha.-2, cancer, and
screening for the drug. 6-siaryltransferase, and Also useful in
modifying the sugar has a sosui transmembrane chain of a
recombinant protein, motif and a similar to a human type.
Glyco_transf_29 motif. 54 pg00933 1768 Partial A motor molecule
which converts ATP Partially has a region sequence (chemical
energy) into physical having 98% homology to force so as to move
along ubiqutinating enzyme microtubules. While dyneins E2-230 kDa.
involved in mitosis, vesicle transport, and the movement of cilia
and fragella exist as multisubunit complexes, the protein functions
as 1.beta. dynein heavy chain which is a component of the complex.
Useful in diagnosing and treating cancer, and screening for the
therapeutic agent. Also useful in diagnosing cranial nerve
diseases, such as hydrencephaly, infertility and respiratory
apparatus-related diseases. 55 ph00331 1313 Partial Inferred to be
ubiquitin-binding Partially has a region sequence enzyme. It is
known that with an having 73% homology to abnormal ubiquitinating
process, dynein heavy chain cells are unable to differentiate
isotype 6. and proliferate, inducing various diseases including
cancer and Parkinson's disease. Useful in screening for the
therapeutic agent of these diseases. 56 pj01645 765 Partial
Inferred to be a gene involved in Partially has a region sequence
cilia formation. Useful in having 76% homology to diagnosing and
treating respiratory KPL2. diseases and cilia dysfunction. 57
pj01649 439 Full Many microtubule-binding proteins Partially has a
region length are present in neurons, and involve having 58%
homology to neural axial filament formation. putative Therefore
abnormal microtubule-associated microtubule-binding proteins affect
protein. neurogenesis and cause malformation and teratogeny. Useful
in diagnosing and treating cancer, and screening for the
therapeutic agent. Also useful in gene diagnosis of congenital
diseases and the field of nerve regeneration medicine. 58 bf00083
879 Full A pyruvate dehydrogenase Has a region having 91% length
phosphatase activity regulatory homology to pyruvate subunit.
Inferred to involve dehydrogenase regulating sugar metabolism.
phosphatase regulatory Useful in diagnosing and treating subunit
precursor, and cancer, and screening for the has a DAO, a
Phytoene_dh therapeutic agent. Also useful in and a GCV_T motifs.
screening for an antiobestic agent. 59 bf00135 699 Partial Kinesin
light chain, the motor Partially has a region sequence protein
which moves along having 36% homology to microtubules. Inferred to
involve kinesin light chain, and the intracellular transport of has
TPR motifs. substances. Directly binds amyloid protein precursor
(APP), the causative agent of Alzheimer with substances, so as to
transport the substances along neural axial filaments in neurons.
Useful in preventing diseases involved in the intracellular
transport of substances; and diagnosing and treating Alzheimer, and
screening for the therapeutic agent. 60 bg00184 1179 Partial A
novel transcription factor. Many Partially has a region sequence of
them are present as a nuclear having 99% homology to protein in the
cerebellum. Useful TFNR. in diagnosing and treating cancer, and
screening for the therapeutic agent. 61 bj00061 802 -- A protein
analogous to endozepine, Partially has a region the ligand of the
receptor of having 80% homology to benzodiazepine which is
classified endodiazepine-related as an antianxiety agent or
sedative protein precursor, and drug/hypnotics. Useful as an has an
ACBP motif and a analgesic agent, antianxiety agent sosui
transmembrane and anticonvulsant in diagnosing, motif. preventing
and treating nervous diseases. 62 bj00195 1194 Partial Type 1
hexokinase, which is Partially has a region sequence transcribed
upon spermatogenesis. having 94% homology to The protein is present
in the cytoplasmic dynein heavy acrosome of a sperm, and functions
as chain 2. a receptor for ZP3 protein, the pellucid zone of an
egg, upon fertilization. Useful in discriminating the maturity of
sperms and suppressing the function of sperm. Also useful in
diagnosing and treating infertility, and contraception. 63 fg01285
1560 Partial A protein analogous to myosin, which Partially has a
region sequence is involved in intracellular having 35% homology to
transport and induces dysgenic myosin XV, and has a congenital
asymptomatic auditory myosin_head motif and a disorder DFNB3.
Useful in MyTH4 motif. preventing, diagnosing and treating nervous
diseases involving intracellular transport. Also useful in the
filed of medicine of nerve regeneration. 64 fh17057 958 Partial
Inferred to be breakpoint cluster Present on chromosome 14,
sequence region protein 2, the product of a partially has a region
house keeping gene which encodes a having 99% homology to protein
necessary for cell breakpoint cluster survival. Useful in
diagnosing region protein 2, and has and treating cancer, and
screening WD40 motifs. for the therapeutic agent. 65 ha06731 715
Partial An analogous protein of HrPOPK-1, Partially has a region
sequence which is inferred to have having 51% homology to
serine/threonine kinase activity, HrPOPK-1, and has a sosui and
have regulatory functions in transmembrane motif.
generation/differentiation, such as determination of the embryonic
axis. Useful in gene diagnosis of congenital abnormalities and
teratogeny, and in the field of regeneration medicine. Further,
useful in diagnosing and treating cancer, and screening for the
therapeutic agent. 66 hj05226 105 -- Homologous to a part of
EGF-like Partially has a region domains in a protein (MEGF) having
having 52% homology to many EGF-like domains. It is known MEGF6,
and has EGF that mutations in the domains affect motifs.
cell-to-cell interaction in the brain and ligand-receptor
interaction, so as to cause auxesis of the nerve system or
disorganization of the brain cortex, thus induces dementia or the
like. Useful in diagnosing and treating diseases of the brain and
the nervous system. 67 pf01012 1192 -- Homologous to a part of
EGF-like Partially has a region domains in a protein (MEGF) having
having 32% homology to many EGF-like domains. It is known MEGF6,
and has EGF that mutations in the domains affect motifs.
cell-to-cell interaction in the brain and ligand-receptor
interaction, so as to cause auxesis of the nerve system or
disorganization of the brain cortex, thus induces dementia or the
like. Useful in diagnosing and treating diseases of the brain and
the nervous system. 68 fg02852 350 Partial An analogous protein of
p150-Spir Partially has a region sequence protein which regulates
having 42% homology to reconstruction of actin by being p150-Spir
protein. phosphorylated with stress-responsive phosphoenzyme JNK.
Useful in diagnosing and treating cancer, and screening for the
therapeutic agent. 69 fh21913a 244 Partial A protein analogous to
fibrillin Partially has a region sequence which is a major
component of a thin having 74% homology to fiber network formed by
assembly of fibrillin 5, and has EGF
elastin proteins and is present motifs and a TB motif. extensively
over the connective tissue. With its possible involvement in a
hereditary disease, Marfans syndrome, associated with
cardiovascular and visual disorders, it is useful in the diagnosis
and the treatment. 70 fj22564 1299 -- A protein having C2H2 type
zinc Partially has a region finger motifs. One of intranuclear
having 96% homology to proteins expressed in embryonic stem zinc
finger protein and cells. Inferred to involve has zf-C2H2 motifs.
development, differentiation and proliferation. With possible
involvement in development of early embryos, it is inferred to
involve cell proliferation or differentiation. Thus it is useful in
diagnosing and treating cancer, and screening for the therapeutic
agent. Also it is useful in regeneration medicine or gene diagnosis
of congenital abnormalities and teratogeny.
(3) Homology Search for the DNA of the Present Invention
[0102] Next, based on the thus obtained full-length nucleotide
sequences, the amino acid sequences of the clones were searched on
the library of known sequences, nr release 122, using an analysis
program BLASTP 2.0.14 (the above-mentioned "Gapped BLAST and
PSI-BLAST: a new generation of protein database search programs").
Thus, it was shown that the clones were homologous to each
homologous genes listed in Table 2. Table 2 shows the information
on these homologous genes, specifically, the name, database ID,
biological species, nomenclature, protein length and the literature
containing the information. TABLE-US-00002 TABLE 2 Homologous Gene
of Each Gene and Biological Species SEQ Homologous gene ID Database
Biological Protein NO: Name ID species.sup..asterisk-pseud. length
Literature 1 coronin, actin binding protein gi|6753496 Mouse 474
DNA Cell Biol. 17 (9), 1C 779-787 (1998) 2 zinc finger protein 91
gi|4508041 Human 1191 Proc. Natl. Acad. Sci. U.S.A. 88 (9),
3608-3612 (1991) 3 immunoglobulin superfamily gi|7657226 Human 442
Genomics 62 (2), 139-146 (1999) 4 NOV/plexin-A1 protein
emb|CAB57274.1| Human 1754 Proc. Natl. Acad. Sci. U.S.A. 93 (2),
674-678 (1996) 5 neuronal guanine nucleotide gi|9845277 Mouse 554
Genomics 65 (1), 53-61 exchange factor (2000) 6 EVI1 protein
pir||S41705 Human 1042 EMBO J. 13 (3), 504-510 (1994) 7
acetyl-coenzyme A synthetase gb|AAG08119.1|AE004887_3 Bacillus of
green pus 645 Nature 406 (6799), 959-964 (2000) 8 proline
dehydrogenase gb|AAD24775.1|AF120278_1 Human 516 Nat. Genet. 21
(4), 434-439 (1999) 9 alpha 1,2-mannosidase gi|7706437 Human 699
Glycobiology 9 (10), 1073-1078 (1999) 10 NIM3
gb|AAF81657.1|AF199335_1 Rat 285 J. Biol. Chem. 275 (26),
20033-20044 (2000) 11 hydroxyproline-rich emb|CAB62280.1| Volvox
409 J. Biol. Chem. 274 glycoprotein DZ-HRGP (49), 35023-35028
(1999) 12 Netrin-G1c dbj|BAB12008.1| Mouse 438 J. Neurosci. 20
(17), 6540-6550 (2000) 13 guanine nucleotide-releasing gi|4885357
Human 1077 Proc. Natl. Acad. Sci. factor 2 U.S.A. 91 (8), 3443-3447
(1994) 14 Ran GTPase activating protein 1 gi|4506411 Human 587
Proc. Natl. Acad. Sci. U.S.A. 91 (7), 2587-2591 (1994) 15
karyopherin beta 2b, gi|7305595 Human 887 J. Cell Biol. 138
transportin (6), 1181-1192 (1997) 16 PTH-responsive osteosarcoma
gb|AAD25981.1|AF095771_1 Human 802 Bone 24 (4), 305-313 B1 protein
(1999) 17 Cdc25C associated protein gb|AAC15093.1| Human 729 Cell
Growth Differ. 9 kinase C-TAK1 (3), 197-208 (1998) 18 FRANK2
protein emb|CAB96906.1| Hawaii's 1596 Genome Res. 10 (8), sea
urchin 1194-1203 (2000) 19 protein kinase WNK1
gb|AAF74258.1|AF227741_1 Rat 2126 J. Biol. Chem. 275 (22),
16795-16801 (2000) 20 putative splicing factor
gb|AAD55973.1|AF144731_1 Rat 738 Mol. Biol. Cell 10 YT521-B (11),
3909-3926 (1999) 21 SNAP-25-interacting protein gi|9507127 Rat 1197
J. Biol. Chem. 275 (2), 1191-1200 (2000) 22 PUTATIVE PREOPTIC
REGULATORY sp|P18890|PRF2.sub.-- Rat 75 Mol. Endocrinol. 4 FACTOR-2
PRECURSOR (8), 1205-1210 (1990) 23 adenosine deaminase acting on
gi|6912230 Human 502 Proc. Natl. Acad. Sci. tRNA 1 U.S.A. 96 (16),
8895-8900 (1999) 24 TTYH1 gb|AAG02580.1|AF177909_1 Human 450
Genomics 68 (1), 89-92 (2000) 25 P116 RHO-INTERACTING PROTEIN
sp|P97434|RIP3 Mouse 1024 J. Cell Biol. 137 (7), (P116RIP) (RIP3)
1603-1613 (1997) 26 microtubule-associated gi|4505099 Human 1152
Cell Motil. protein 4 Cytoskeleton 23 (4), 236-243 (1992) 27
OXYSTEROL-BINDING PROTEIN sp|P16258|OXYB Rabbit 809 J. Biol. Chem.
264 (28), 16798-16803 (1989) 28 ring canal protein gb|AAA53472.2|
Fruit fly 1477 Cell 72 (5), 681-693 (1993) 29 cell recognition
molecule gi|7662350 Human 1331 Neuron 24 (4), Caspr2 1037-1047
(1999) 30 GTP-rho binding protein 1 gi|6680085 Mouse 643 Science
271 (5249), 645-648 (1996) 31 INOSITOL 1,4,5-TRISPHOSPHATE
sp|P27987|IP3L Human 505 Biochem. J. 278 (Pt 3-KINASE (IP3K) 3),
883-886 (1991) 32 FH1/FH2 domain-containing gi|7019375 Human 1164
Gene 232 (2), 173-182 protein FHOS (1999) 33
SERINE/THREONINE-PROTEIN sp|008875|DCK1 Rat 433 J. Mol. Neurosci.
10 KINASE DCAMKL1 (2), 75-98 (1998) 34 1 beta dynein heavy chain
emb|CAB99316.1| Chlamydomonas 4513 Mol. Biol. Cell 11 (7),
2297-2313 (2000) 35 rsec8 pir||I59422 Rat 975 Proc. Natl. Acad.
Sci. U.S.A. 92 (21), 9613-9617 (1995) 36 nuclear dual-specificity
gb|AAC39675.1| Human 1697 Nature Genet. 18 (4), phosphatase 331-337
(1998) 37 phosphatidic acid-preferring gb|AAC03019.1| Bovine 875 J.
Biol. Chem. 273 phospholipase A1 (1998) 5468-5477 38 chromobox
homolog 8 gi|7304947 Mouse 362 Gene 242 (1-2), 31-40 (2000) 39
polymerase I and transcript gi|6679567 Mouse 392 EMBO J. 17 (10),
release factor 2855-2864 (1998) 40 pyruvate dehydrogenase
gb|AAC48785.1| Bovine 878 J. Biol. Chem. 272 phosphatase regulatory
(50), 31625-31629 subunit precursor (1997) 41 collagen alpha 1(V)
chain pir||CGHU1V Human 1838 J. Biol. Chem. 261 precursor (11),
5034-5040 (1986) 42 TUBULIN BETA-5 CHAIN sp|P09653|TBB5.sub.--
Gallus 446 Mol. Cell. Biol. 6 (BETA-TUBULIN CLASS-V) CHICK (12),
4409-4418 (1986) 43 PROTEOGLYCAN LINK PROTEIN sp|P07354|PLK_CHICK
Gallus 355 Proc. Natl. Acad. Sci. PRECURSOR (CARTILAGE LINK U.S.A.
83 (11), PROTEIN) 3766-3770 (1986) 44 FAT tumor suppressor
gi|4885229 Human 4590 Genomics 30 (2), 207-223 (1995) 45
N-ACETYLGLUCOSAMINYLTRANSFERASE sp|P56558|OGT1 Rat 1036 J. Biol.
Chem. 272 110 KDA SUBUNIT (14), 9308-9315 (1997) 46 OPA-containing
protein 1 gb|AAC83164.1| Mouse 2074 Mol. Psych. 3 (4), 303-309
(1998) 47 huntingtin-associated protein gi|4504335 Human 1663 Hum.
Mol. Genet. 6 interacting protein (9), 1519-1525 (1997) 48 zinc
finger protein 91 gi|4508041 Human 1191 Proc. Natl. Acad. Sci.
U.S.A. 88 (9), 3608-3612 (1991) 49 Proline rich synapse
emb|CAB45688.1| Rat 1806 Biochem. Biophys. associated protein 2
Res. Commun. 264, 2476-2528 (1999) 50 glutamate receptor
gb|AAD25916.1|AF072509_1 Rat 1043 Neuron 22, 511-524 interacting
protein 2 (1999) 51 SH3-domain binding protein 5 gi|4759058 Human
425 Biochem. Biophys. (BTK-associated) Res. Commun. 245 (2),
337-343 (1998) 52 ankyrin 3 gb|AAB01607.1| Mouse 1961 J. Cell Biol.
130 (2), 313-330 (1995) 53 CMP-N-ACETYLNEURAMINATE-BETA-
sp|Q92182|CAG1.sub.-- Gallus 413 Eur. J. Biochem. 219
GALACTOSAMIDE-ALPHA-2, CHICK (1-2), 375-381 (1994)
6-SIALYLTRANSFERASE 54 dynein heavy chain isotype 6 pir||T30298
Globe fish 1125 Mol. Biol. Cell 5 (1), 57-70 (1994) 55
ubiquitinating enzyme E2-230 kDa pir||I49264 Mouse 299 Proc. Natl.
Acad. Sci. U.S.A. 92 (11), 4982-4986 (1995) 56 KPL2
gb|AAD56310.1|AF102129_1 Rat 1744 Am. J. Respir. Cell Mol. Biol. 20
(4), 675-683 (1999) 57 putative microtubule gb|AAC79958.1| Gallus
369 J. Med. Dent. Sci. 45, associated protein 123-133 (1998) 58
pyruvate dehydrogenase gb|AAC48785.1| Bovine 878 J. Biol. Chem. 272
phosphatase regulatory (50), 31625-31629 subunit precursor (1997)
59 kinesin light chain gb|AAB87735.1| Plectonema 490 DNA Cell Biol.
16 (6), 787-795 (1997) 60 TFNR emb|CAC21448.1| Human 2187 Genomics
70, 315-326 (2000) 61 ENDOZEPINE-RELATED PROTEIN sp|P07106|ENDR
Bovine 533 DNA 6 (1), 71-79 PRECURSOR (1987) 62 cytoplasmic dynein
heavy chain 2 gi|12711694 Rat 4306 Mol. Biol. Cell 9, 276 (1998) 63
Myosin XV gi|6754780 Mouse 3511 Genomics 61 (3), 243-258 (1999) 64
breakpoint cluster region gb|AAC08965.1| Human 510 Genomics 52 (1),
17-26 protein 2 (1998) 65 HrPOPK-1 dbj|BAA28663.1| Ascidian 698
Mech. Dev. 76 (1-2), 161-163 (1998) 66 MEGF6 gi|12621134 Rat 1574
Genomics 51 (1), 27-34 (1998) 67 MEGF6 gi|12621134 Rat 1574
Genomics 51 (1), 27-34 (1998) 68 p150-Spir protein emb|CAB62901.1|
Fruit fly 1020 Curr. Biol. 10 (6), 345-348 (2000) 69 fibrillin 5
emb|CAB56757.1| Human 754 Nature 352 (6333), 330-334 (1991) 70 zinc
finger protein pir||B38203 Mouse 191 Genes Dev. 6 (6), 903-918
(1992) .sup..asterisk-pseud.Nomenclature of each biological species
is as follows: mouse = Mus musculus; human = Homo sapiens; bacillus
of green pus = Pseudomonas aeruginosa; rat = Rattus norvegicus;
volvox = Volvox carteri f. nagariensis; Hawaii's sea urchin =
Tripneustes gratilla; rabbit = Oryctolagus cuniculus; fruit fly =
Drosophila melanogaster; chlamydomonas = Chlamydomonas reinhardtii;
# bovine = Bos taurus; gallus = Gallus gallus; globe fish =
Takifugu rubripes; plectonema = Plectonema boryanum; ascidian =
Halocynthia roretzi.
[0103] Table 3 summarizes a variety of data concerning homology
between the DNA or the gene of the present invention contained in
each clone and each homologous gene listed in Table 2. The meaning
of each item in Table 3 is as follows: [0104] Score: the higher the
value, the higher the reliability [0105] E-value: the closer this
value to 0, the higher the reliability [0106] Starting point: an
amino acid position as a starting point of the homologous region
[0107] End point: an amino acid position as an end point of the
homologous region [0108] Homology: the proportion (degree) of amino
acid residues that are identical in a homologous region.
[0109] Homologous region %: the proportion (%) of a homologous
region in a homologous gene. TABLE-US-00003 TABLE 3 Homology
between each gene and homologous gene Homologous region Homologous
SEQ clone gene Homology value ID Starting End Starting End
Homologous NO: point point point point Score E-value Homology
region % 1 20 318 211 472 295 4e-79 50% (155/310) 55% 2 1 183 975
1166 156 3e-37 42% (81/192) 16% 3 20 187 259 442 122 3e-27 39%
(74/187) 42% 4 1 1324 278 1601 2708 0 99% (1321/1324) 75% 5 71 217
322 468 266 2e-70 91% (135/147) 27% 6 4 653 294 923 599 e-170 51%
(343/661) 60% 7 1 235 303 534 325 3e-88 60% (142/235) 36% 8 51 193
283 425 275 3e-73 93% (134/143) 28% 9 92 373 418 699 591 e-168 100%
(282/282) 40% 10 6 215 76 285 303 9e-82 68% (143/210) 74% 11 875
1130 27 277 144 6e-33 37% (96/256) 61% 12 36 380 28 372 444 e-124
57% (199/346) 79% 13 47 505 619 1077 928 0 100% (459/459) 43% 14 37
530 1 494 963 0 100% (494/494) 84% 15 165 1051 1 887 1794 0 98%
(874/887) 100% 16 62 856 1 755 1499 0 94% (753/795) 94% 17 2 669 1
655 816 0 64% (435/674) 90% 18 2 998 515 1592 593 e-168 35%
(398/1127) 68% 19 187 748 739 1328 189 9e-47 30% (188/625) 28% 20 1
480 251 738 1001 0 97% (476/488) 66% 21 1 718 457 1173 1364 0 94%
(683/719) 60% 22 1020 1094 1 75 152 1e-35 98% (74/75) 100% 23 26
388 97 459 738 0 99% (360/363) 72% 24 6 413 7 417 306 3e-82 39%
(163/411) 91% 25 1063 1644 383 975 452 e-125 44% (273/611) 58% 26
140 913 332 1089 835 0 61% (491/793) 66% 27 54 878 20 809 965 0 60%
(498/830) 98% 28 1 278 408 684 136 3e-31 32% (91/284) 19% 29 1 705
597 1329 663 0 46% (343/736) 55% 30 94 259 160 325 267 1e-70 80%
(133/166) 26% 31 319 519 3 203 419 e-116 100% (201/201) 40% 32 2
361 216 569 182 2e-44 37% (142/379) 30% 33 308 445 75 212 152 7e-36
51% (71/138) 32% 34 1 1353 3205 4512 966 0 37% (515/1363) 29% 35 1
966 9 975 1816 0 95% (921/967) 99% 36 110 1762 5 1630 1828 0 57%
(957/1674) 96% 37 4 498 381 875 979 0 95% (475/495) 57% 38 1 389 1
362 667 0 87% (341/389) 100% 39 1 380 11 392 682 0 92% (355/382)
97% 40 1 360 519 878 715 0 93% (336/360) 41% 41 2 592 634 1274 545
e-154 46% (304/647) 35% 42 14 369 90 445 720 0 97% (346/356) 80% 43
36 376 19 353 361 7e-99 49% (171/345) 94% 44 3 615 2979 3576 255
1e-66 30% (189/618) 13% 45 1 1036 1 1036 2117 0 99% (1030/1036)
100% 46 129 263 1911 2052 101 7e-21 50% (72/144) 7% 47 53 1115 588
1663 2132 0 98% (1063/1076) 65% 48 66 760 425 1157 744 0 48%
(365/758) 62% 49 1 797 1010 1806 1504 0 94% (754/799) 44% 50 4 1043
11 1043 1814 0 87% (912/1040) 99% 51 80 365 7 269 213 2e-54 41%
(120/287) 62% 52 658 1057 213 611 149 2e-34 30% (126/413) 20% 53
211 524 100 413 371 e-102 54% (172/315) 76% 54 717 1768 1 1047 1570
0 73% (774/1060) 93% 55 129 368 1 240 497 e-139 98% (236/240) 80%
56 6 735 965 1715 1195 0 76% (579/753) 43% 57 1 439 1 369 472 e-132
58% (258/440) 100% 58 1 879 1 878 1680 0 91% (804/878) 100% 59 264
557 179 446 153 5e-36 36% (108/294) 55% 60 1 742 1446 2187 1463 0
99% (741/742) 34% 61 6 437 93 533 722 0 80% (357/443) 83% 62 1 1194
3113 4306 2274 0 94% (1126/1194) 28% 63 146 965 1653 2499 494 e-138
35% (319/888) 24% 64 278 787 1 510 1048 0 99% (508/510) 100% 65 1
650 44 647 611 e-174 51% (346/678) 87% 66 4 94 330 419 117 5e-26
52% (48/91) 6% 67 74 892 32 1002 499 e-139 32% (315/982) 62% 68 62
318 213 456 189 6e-47 42% (109/259) 24% 69 1 242 163 405 435 e-121
74% (181/243) 32% 70 798 988 1 191 389 e-106 96% (185/191) 100%
(4) Search for Each Domain
[0110] Using as queries the amino acid sequence encoded by DNAs
contained in the clones, functional domains were searched with a
search tool contained in Pfam 6.0 (Pfam HMM ver. 2.1 Search
(HMMPFAM), Sonnhammer, E. L. L., Eddy, S. R., Birney, E., Bateman,
A., and Durbin, R. (1998) "Pfam: multiple sequence alignments and
HMM-profiles of protein domains" Nucleic Acids Res.
26:320-322).
[0111] Further, transmembrane domains were searched with a
prediction program for membrane proteins, the SOSUI system (ver.
1.0/10, March, 1996) (Takatsugu Hirokawa, Seah Chieng and Shigeki
Mitaku, SOSUI: Classification and Secondary Structure Prediction
System for Membrane Proteins), Bioinformatics (formerly CABIOS)
1998 May; 14(4):378-379).
[0112] Table 4 shows the detected functional domains and
transmembrane domains for each clone.
[0113] The meaning of each item in Table 4 is as follows: [0114]
Functional domain: a domain detected by Pfam or SOSUI [0115]
Starting point: an amino acid position as a starting point of a
functional domain [0116] End point: an amino acid position as an
end point of a functional domain. [0117] Score (Pfam only): the
higher the value, the higher the reliability [0118] Exp (Pfam
only): the closer the value to 0, the higher the reliability
[0119] Table 5 shows the complete notation of each functional
domain. TABLE-US-00004 TABLE 4 Functional domain SEQ Clone
Homologous gene ID Functional Starting End Functional Starting End
NO: domain point point Score Exp domain point point Score Exp 1
WD40 72 109 33.1 6.2e-06 WD40 122 159 28.6 0.00015 WD40 166 202
21.4 0.022 2 zf-C2H2 45 67 31.2 2.4e-05 KRAB 13 75 159.5 5.6e-44
zf-C2H2 73 95 37.1 3.9e-07 zf-C2H2 182 200 -1.9 1.3e+02 zf-C2H2 123
145 23.2 0.0063 zf-C2H2 210 232 21.8 0.017 zf-C2H2 151 173 31.3
2.2e-05 zf-C2H2 238 260 33.1 6.3e-06 zf-C2H2 179 201 27.7 0.00026
zf-C2H2 266 288 34 3.4e-06 zf-C2H2 261 283 31.3 2.3e-05 zf-C2H2 294
316 37.9 2.3e-07 zf-C2H2 289 311 38.4 1.6e-07 zf-C2H2 322 344 37.9
2.2e-07 zf-C2H2 350 372 36.1 7.8e-07 zf-C2H2 378 400 34.9 1.8e-06
zf-C2H2 406 428 35.3 1.4e-06 zf-C2H2 434 456 35.3 1.4e-06 zf-C2H2
462 484 33.8 3.9e-06 zf-C2H2 490 512 37.1 4e-07 zf-C2H2 518 540
15.7 1.1 zf-C2H2 546 568 32.4 1.1e-05 zf-C2H2 574 596 34 3.4e-06
zf-C2H2 602 624 34.2 3.1e-06 zf-C2H2 630 652 37.9 2.2e-07 zf-C2H2
658 680 36.1 7.8e-07 zf-C2H2 686 708 34.9 1.8e-06 zf-C2H2 714 736
35.3 1.4e-06 zf-C2H2 742 764 36.8 5e-07 zf-C2H2 770 792 35 1.7e-06
zf-C2H2 798 820 37.3 3.4e-07 zf-C2H2 826 848 34.8 2e-06 zf-C2H2 854
876 37 4.2e-07 zf-C2H2 885 904 11.3 6.3 zf-C2H2 910 932 38.2
1.9e-07 zf-C2H2 938 960 36.5 5.9e-07 zf-C2H2 966 988 34.3 2.8e-06
zf-C2H2 994 1016 39 1.1e-07 zf-C2H2 1022 1044 35.1 1.6e-06 zf-C2H2
1050 1072 33.8 3.8e-06 zf-C2H2 1078 1100 39 1.1e-07 zf-C2H2 1106
1128 32.9 7.5e-06 zf-C2H2 1134 1156 19.5 0.081 3 ig 21 87 16.9
0.0012 sosui 16 38 -- -- sosui 120 142 -- -- ig 57 126 23.3 1.1e-05
ig 159 222 9.6 0.21 ig 260 315 36.6 8.6e-10 sosui 374 396 -- -- 4
Sema 14 196 78.3 2.9e-20 Sema 29 473 198.8 8.3e-56 Plexin_repeat
215 265 58.1 1.9e-13 Plexin_repeat 492 542 58.1 1.9e-13 integrin_B
221 237 5.1 0.18 integrin_B 498 514 5.1 0.18 Plexin_repeat 361 408
59.8 5.7e-14 Plexin_repeat 638 685 59.8 5.7e-14 Plexin_repeat 509
563 50.7 3.3e-11 Plexin_repeat 786 840 50.7 3.3e-11 integrin_B 516
535 9.4 0.006 integrin_B 793 812 9.4 0.006 TIG 565 660 75.5 1.1e-18
TIG 842 937 75.5 1.1e-18 TIG 662 746 86.3 6.3e-22 TIG 939 1023 86.3
6.3e-22 TIG 749 848 71.3 2e-17 TIG 1026 1125 71.3 2e-17 TIG 851 937
42.9 7.2e-09 TIG 1128 1214 42.9 7.2e-09 sosui 943 965 -- -- 5 PH 83
194 43.6 7.7e-11 RhoGEF 121 297 71.2 2.2e-17 PH 334 445 42.8
1.3e-10 SH3 459 515 47.3 3.3e-10 6 zf-C2H2 449 471 37.3 3.4e-07
zf-C2H2 21 44 26.3 0.00074 zf-BED 462 501 11.3 0.073 zf-C2H2 75 97
26.5 0.00061 zf-C2H2 477 500 33.5 4.8e-06 zf-C2H2 103 125 35.1
1.6e-06 zf-C2H2 506 528 26.5 0.00061 zf-BED 116 155 -0.3 1.5
zf-C2H2 131 154 37.2 3.8e-07 zf-C2H2 160 182 32 1.4e-05 zf-C2H2 188
210 26.5 0.00064 zf-C2H2 217 239 29.5 7.8e-05 zf-C2H2 724 746 37.3
3.4e-07 zf-BED 737 776 11.3 0.073 zf-C2H2 752 775 33.5 4.8e-06
zf-C2H2 781 803 27.5 0.0003 7 AMP-binding 108 544 446.8 1.8e-130 8
Pro_dh 143 498 582.7 2.4e-171 9 Glyco_hydro_47 2 369 205 1.2e-57
sosui 83 105 -- -- sosui 17 39 -- -- Glyco_hydro_47 256 695 696
1.9e-205 10 C2 76 163 45.6 1.1e-09 C2 146 233 61.9 1.4e-14 12 BNR
44 55 9.4 34 sosui 1 23 -- -- laminin_Nterm 58 304 30 5.4e-12
laminin_Nterm 50 295 37.3 1.6e-12 BNR 171 182 11.7 16 laminin_EGF
297 341 33.3 5.4e-06 laminin_EGF 306 363 35.2 1.5e-06 sosui 419 438
-- -- 13 RasGEFN 114 170 36.7 5.3e-07 RasGEFN 686 742 36.7 5.3e-07
RasGEF 265 442 206.6 3.8e-58 RasGEF 837 1014 206.6 3.8e-58 15
Armadillo_seg 281 319 13.4 2.6 Armadillo_seg 117 155 13.4 2.6
Armadillo_seg 364 406 0.4 84 Armadillo_seg 200 242 0.4 84 HEAT 373
408 10.9 9 HEAT 209 244 10.9 9 HEAT 551 589 10.3 11 HEAT 387 425
10.3 11 Armadillo_seg 590 628 19.8 0.064 Armadillo_seg 426 464 19.8
0.064 HEAT 592 630 1.4 1.1e+02 HEAT 428 466 1.4 1.1e+02 HEAT 718
758 1.7 1e+02 HEAT 554 594 1.7 1e+02 Armadillo_seg 819 857 1.2 68
HEAT 657 695 11.7 7.3 HEAT 821 859 11.6 7.6 Armadillo_seg 695 734
17.3 0.37 Armadillo_seg 859 898 11.4 4.5 17 pkinase 60 311 351.3
1.1e-101 pkinase 56 307 345.6 5.3e-100 UBA 331 370 30.8 3.1e-05 UBA
327 366 31.1 2.6e-05 18 ank 50 83 6.3 36 ank 563 594 4.6 58 ank 84
116 42.3 1.1e-08 ank 627 659 18.1 0.2 ank 117 149 39.4 8.3e-08 ank
660 692 42.8 7.6e-09 ank 150 182 40.1 5e-08 ank 693 725 39.8 6e-08
ank 183 217 18.5 0.16 ank 726 760 25.9 0.00094 ank 253 286 23.4
0.0053 19 Pkinase 221 479 215.7 7e-61 21 Troponin 230 378 -18.4
0.97 Troponin 685 833 -17.8 0.87 22 WW 37 67 4.5 2.3 Sosui 1 23 --
-- WW 76 106 23.4 0.0054 MyTH4 772 890 78.5 1.4e-19 RhoGAP 920 1067
76.1 7.3e-19 23 A_deamin 27 76 17.7 0.0003 A_deamin 63 147 86.3
3.9e-24 A_deamin 220 295 76.3 3.2e-21 A_deamin 431 497 16.1 0.00084
24 sosui 1 19 -- -- sosui 46 68 -- -- sosui 43 65 -- -- sosui 87
108 -- -- sosui 83 104 -- -- sosui 214 236 -- -- sosui 175 197 --
-- sosui 247 269 -- -- sosui 209 231 -- -- sosui 390 412 -- --
sosui 240 262 -- -- sosui 388 410 -- -- 25 PH 1067 1175 77.3
2.6e-20 PH 44 145 49.8 1.4e-12 PH 387 482 75.2 9.6e-20 26
tubulin-binding 747 777 54.8 1.1e-14 tubulin-binding 923 953 54.8
1.1e-14 tubulin-binding 816 846 61.8 9.4e-17 tubulin-binding 992
1022 61.8 9.4e-17 tubulin-binding 847 877 61 1.6e-16
tubulin-binding 1023 1053 61 1.6e-16 tubulin-binding 878 909 36.5
3.2e-09 tubulin-binding 1054 1085 36.5 3.2e-09 27 PH 145 236 78.7
1e-20 PH 91 183 87.8 2.8e-23 Oxysterol_BP 446 868 506.2 2.4e-148
Oxysterol_BP 383 799 770.3 7.5e-228 28 Kelch 32 79 30 5.5e-05 BTB
141 253 127.6 2.3e-34 Kelch 81 126 43.2 6e-09 Kelch 392 436 20.4
0.042 Kelch 128 176 30.1 5.1e-05 Kelch 438 483 44.6 2.3e-09 Kelch
178 218 42.8 7.5e-09 Kelch 485 530 52.7 8.3e-12 Kelch 220 267 48.3
1.7e-10 Kelch 532 579 49.9 5.5e-11 Kelch 581 626 49 1.1e-10 Kelch
628 673 48.9 1.1e-10 29 laminin_G 220 342 76.1 1.6e-20 sosui 7 29
-- -- EGF 361 395 19.3 0.089 F5_F8_type_C 38 178 216.5 4e-61 TSPN
380 577 -42.4 0.71 laminin_G 216 348 62.2 1.5e-16 laminin_G 472 530
8.4 0.37 laminin_G 401 532 48.5 1.3e-12 sosui 639 661 -- -- EGF 558
590 30.3 4.4e-05 laminin_G 827 948 53.8 3.8e-14 EGF 967 1001 18.2
0.19 Laminin_G 1055 1185 15.6 0.0032 30 BR01 66 201 123.2 4.7e-33
HR1 42 114 89.2 8.4e-23 BR01 115 267 276.1 4.6e-79 PDZ 500 577 45
1.6e-09 32 FH2 661 1157 178.1 1.5e-49 FH2 594 1069 187.1 2.7e-52 33
pkinase 316 445 170.2 3.4e-47 pkinase 83 340 326.3 3.5e-94 34
Dynein_heavy 597 1351 920 6.8e-273 Dynein_heavy 3804 4510 910.4
5.1e-270 36 DENN 44 183 111.1 7e-30 DENN 5 78 70 2.2e-18 GRAM 756
842 46.6 3.8e-12 GRAM 650 736 62.4 9.1e-17 PH 1661 1764 68 1e-17 PH
1529 1632 63.6 1.8e-16 37 DDHD 237 484 401.4 8.6e-117 DDHD 614 861
431.3 8.9e-126 38 chromo 8 48 67.7 2.1e-18 chromo 8 48 67.7 2.1e-18
40 GCV_T 4 344 556.6 1.6e-163 DAO 42 403 -70.5 0.0014 Phytoene_dh
44 405 -327.7 0.14 UPF0079 52 149 -47.5 0.26 GCV_T 522 862 593.6
1.2e-174 41 Collagen 5 64 46.8 4.9e-10 TSPN 39 230 289.8 3.3e-83
Collagen 65 124 50.1 5.1e-11 Collagen 469 528 23.8 0.00018 Collagen
125 184 52.1 1.2e-11 Collagen 554 612 27.7 0.00011 Collagen 188 247
48.8 1.2e-10 Collagen 613 672 61.8 1.5e-14 Collagen 251 310 53.8
3.7e-12 Collagen 673 732 60.8 3e-14 Collagen 312 371 58.4 1.5e-13
Collagen 733 792 42.8 7.5e-09 Collagen 384 443 48.5 1.5e-10
Collagen 793 852 37.7 2.7e-07 Collagen 450 509 50.8 3e-11 Collagen
853 912 43.9 3.6e-09 Collagen 534 593 44.8 1.9e-09 Collagen 913 972
59.9 5.4e-14 COLFI 648 706 92.7 1e-35 Collagen 985 1044 54.4
2.5e-12 COLFI 715 831 56.7 1.1e-21 Collagen 1045 1104 55.2 1.5e-12
Collagen 1105 1164 55.7 9.9e-13 Collagen 1165 1224 49.5 7.2e-11
Collagen 1225 1284 46.7 5.3e-10 Collagen 1285 1344 48.9 1.1e-10
Collagen 1345 1404 43.5 4.7e-09 Collagen 1405 1464 46.4 6.3e-10
Collagen 1465 1524 55.9 9.1e-13 Collagen 1525 1584 18.9 0.00032
COLFI 1625 1836 484.1 1.1e-188 42 tubulin 14 347 737 8e-218 43
sosui 16 36 -- -- ig 54 142 25.8 2e-06 ig 71 155 23.8 8e-06 Xlink
159 254 220.3 7.1e-95 Xlink 172 277 162 1.2e-69 Xlink 260 351 196
2.3e-84 Xlink 283 374 132 1.3e-56 44 cadherin 56 143 86.5 5.3e-22
sosui 4 26 -- -- cadherin 157 253 81.7 1.5e-20 cadherin 39 140 14.8
0.04 cadherin 267 360 69.7 6.2e-17 cadherin 154 248 70.4 3.8e-17
cadherin 374 470 50.8 3.1e-11 cadherin 372 454 20.6 0.013 cadherin
486 577 94.6 1.9e-24 cadherin 468 560 69.2 8.8e-17 cadherin 591 682
72.4 9.5e-18 cadherin 574 664 24.7 0.0022 cadherin 722 813 68.8
1.1e-16 cadherin 827 918 98.3 1.5e-25 cadherin 932 1023 96.9
3.9e-25 cadherin 1039 1130 83.9 3.3e-21 cadherin 1144 1236 105.7
8.8e-28 cadherin 1250 1346 41 2.7e-08 cadherin 1363 1447 46.3
6.6e-10 cadherin 1461 1553 53.5 4.7e-12 cadherin 1567 1661 89.5
6.6e-23 cadherin 1675 1759 69.7 6e-17 cadherin 1773 1871 47.7
2.7e-10 cadherin 1887 1973 36.7 5.4e-07 cadherin 1987 2073 29.5
7.9e-05 cadherin 2089 2178 43.9 3.6e-09 cadherin 2190 2277 53.8
3.9e-12 cadherin 2291 2384 96.1 7e-25 cadherin 2398 2486 44.1
3.1e-09 cadherin 2500 2590 48.6 1.4e-10 cadherin 2604 2696 47.1
3.9e-10 cadherin 2710 2802 35.4 1.3e-06 cadherin 2816 2911 81.5
1.8e-20 cadherin 2925 3016 68.3 1.7e-16 cadherin 3030 3118 94.1
2.8e-24 cadherin 3132 3223 99.9 5e-26 cadherin 3237 3328 104.8
1.7e-27 cadherin 3342 3433 106.6 4.8e-28 cadherin 3447 3538 47.2
3.7e-10 cadherin 3553 3634 11.5 0.077 EGF 3796 3828 19.5 0.077
laminin_G 3861 3990 75.5 2.3e-20 EGF 4019 4051 36.8 4.9e-07 EGF
4058 4089 31.7 1.7e-05 EGF 4095 4126 35.6 1.1e-06 EGF 4133 4164
32.9 7.2e-06 45 TPR 11 44 1.6 31 TPR 11 44 1.6 31 TPR 79 112 50.7
3.3e-11 TPR 79 112 50.7 3.3e-11 TPR 113 146 26.3 0.00073 TPR 113
146 26.3 0.00073 TPR 147 180 31 2.8e-05 TPR 147 180 31 2.8e-05 TPR
181 214 39.8 6.1e-08 TPR 181 214 39.8 6.1e-08 TPR 215 248 31.9
1.5e-05 TPR 215 248 31.9 1.5e-05 TPR 249 282 38.8 1.3e-07 TPR 249
282 38.8 1.3e-07 TPR 283 316 39.5 7.4e-08 TPR 283 316 39.5 7.4e-08
TPR 317 350 40.1 5e-08 TPR 317 350 40.1 5e-08 TPR 351 384 39.7
6.4e-08 TPR 351 384 39.7 6.4e-08 TPR 385 418 41.4 2e-08 TPR 385 418
41.4 2e-08 TPR 419 452 38.2 1.9e-07 TPR 419 452 38.2 1.9e-07 46
sosui 179 200 -- -- sosui 266 288 -- -- 47 RhoGEF 737 907 120.3
3.6e-32 spectrin 188 235 12 0.074 PH 921 1032 45.6 2.1e-11 spectrin
279 308 9.6 0.34 spectrin 310 416 23.7 4.2e-05 spectrin 536 642
20.1 0.00043 spectrin 803 877 -9.2 3.5e+04 spectrin 890 937 7
1.8
spectrin 958 1004 7.8 1.1 spectrin 1130 1222 17.6 0.0021 RhoGEF
1285 1455 120.3 3.6e-32 PH 1469 1580 45.6 2.1e-11 48 zf-C2H2 103
125 38.1 1.9e-07 KRAB 13 75 159.5 5.6e-44 zf-C2H2 131 153 31.8
1.6e-05 zf-C2H2 182 200 -1.9 1.3e+02 zf-C2H2 159 181 34.5 2.4e-06
zf-C2H2 210 232 21.8 0.017 zf-C2H2 187 209 35.5 1.2e-06 zf-C2H2 238
260 33.1 6.3e-06 zf-C2H2 215 237 30.8 3.2e-05 zf-C2H2 266 288 34
3.4e-06 zf-C2H2 243 265 30.1 5.2e-05 zf-C2H2 294 316 37.9 2.3e-07
zf-C2H2 271 293 28.6 0.00015 zf-C2H2 322 344 37.9 2.2e-07 zf-C2H2
299 321 29.6 7.4e-05 zf-C2H2 350 372 36.1 7.8e-07 zf-C2H2 352 374
20.2 0.051 zf-C2H2 378 400 34.9 1.8e-06 zf-C2H2 380 402 37.2
3.7e-07 zf-C2H2 406 428 35.3 1.4e-06 zf-BED 393 431 5.6 0.32
zf-C2H2 434 456 35.3 1.4e-06 zf-C2H2 408 430 30.2 4.7e-05 zf-C2H2
462 484 33.8 3.9e-06 zf-C2H2 436 458 38.1 2e-07 zf-C2H2 490 512
37.1 4e-07 zf-C2H2 464 486 37.6 2.9e-07 zf-C2H2 518 540 15.7 1.1
zf-C2H2 492 514 25.4 0.0013 zf-C2H2 546 568 32.4 1.1e-05 zf-C2H2
544 566 22.8 0.0079 zf-C2H2 574 596 34 3.4e-06 zf-C2H2 572 594 37.2
3.7e-07 zf-C2H2 602 624 34.2 3.1e-06 zf-BED 585 623 3.9 0.5 zf-C2H2
630 652 37.9 2.2e-07 zf-C2H2 600 622 34.9 1.9e-06 zf-C2H2 658 680
36.1 7.8e-07 zf-C2H2 628 650 38.2 1.9e-07 zf-C2H2 686 708 34.9
1.8e-06 zf-C2H2 656 678 32.6 9.3e-06 zf-C2H2 714 736 35.3 1.4e-06
zf-C2H2 684 706 24.4 0.0026 zf-C2H2 742 764 36.8 5e-07 zf-C2H2 737
759 20.9 0.03 zf-C2H2 770 792 35 1.7e-06 zf-C2H2 798 820 37.3
3.4e-07 zf-C2H2 826 848 34.8 2e-06 zf-C2H2 854 876 37 4.2e-07
zf-C2H2 885 904 11.3 6.3 zf-C2H2 910 932 38.2 1.9e-07 zf-C2H2 938
960 36.5 5.9e-07 zf-C2H2 966 988 34.3 2.8e-06 zf-C2H2 994 1016 39
1.1e-07 zf-C2H2 1022 1044 35.1 1.6e-06 zf-C2H2 1050 1072 33.8
3.8e-06 zf-C2H2 1078 1100 39 1.1e-07 zf-C2H2 1106 1128 32.9 7.5e-06
zf-C2H2 1134 1156 19.5 0.081 49 SAM 732 795 79.8 5.7e-20 ank 223
256 12.3 6.6 ank 257 289 28 0.00022 ank 290 323 12.6 6 ank 324 356
21.5 0.021 ank 357 389 37.1 4.1e-07 SH3 548 602 36.5 6.2e-07 PDZ
645 738 22.2 0.007 SAM 1741 1804 80.5 3.5e-20 50 PDZ 48 130 51.2
2.3e-11 PDZ 53 135 48.8 1.2e-10 PDZ 148 233 54.1 3e-12 PDZ 153 238
53.5 4.7e-12 PDZ 248 331 42.3 1.1e-08 PDZ 253 336 46.7 5.3e-10 PDZ
456 544 42.5 9.2e-09 PDZ 458 546 39 1.1e-07 PDZ 557 640 62 1.3e-14
PDZ 559 642 55.7 1e-12 PDZ 656 737 69.4 7.5e-17 PDZ 658 739 65.6
1e-15 PDZ 941 1022 36.4 6.5e-07 PDZ 942 1023 26.6 0.0006 52 ank 679
714 6.6 33 ank 23 55 3.5 80 ank 717 749 6.1 38 ank 56 88 43.2
5.7e-09 ank 750 782 33.2 6.2e-06 ank 89 121 45.3 1.4e-09 ank 783
815 4.8 55 ank 122 154 42.7 8.4e-09 ank 823 859 4.1 67 ank 155 183
14.3 2.9 ank 861 893 31.5 1.9e-05 ank 184 216 18.6 0.15 ank 894 926
40 5.4e-08 ank 217 249 36.1 8e-07 ank 927 959 42.3 1.1e-08 ank 250
282 45.6 1.1e-09 ank 960 992 35.7 1.1e-06 ank 283 315 39.3 8.4e-08
ank 993 1025 38.1 2e-07 ank 316 348 39.3 8.8e-08 ank 1026 1058 12.9
5.5 ank 349 381 39.1 9.7e-08 TPR 1072 1105 0.2 43 ank 382 414 46.6
5.5e-10 TPR 1119 1152 16.4 0.7 ank 415 447 39.7 6.7e-08 TPR 1153
1186 25.6 0.0012 ank 448 480 42.6 9.1e-09 ank 481 513 40.2 4.7e-08
ank 514 546 49.7 6.5e-11 ank 547 579 43.6 4.5e-09 ank 580 612 38.3
1.7e-07 ank 613 645 47.2 3.6e-10 ank 646 678 36.3 7e-07 ank 679 711
42.7 8e-09 ank 712 744 43.8 3.9e-09 ank 745 777 41 2.8e-08 ank 778
810 2.2 1.1e+02 ZU5 983 1087 229.6 4.4e-65 death 1479 1562 111.4
1.8e-29 53 sosui 16 38 -- -- sosui 9 30 -- -- Glyco_transf_29 218
512 243.2 3.6e-69 Glyco_transf_29 107 401 448 8.2e-131 54 GSPII_E
1032 1046 8.6 0.092 55 UQ_con 971 1136 0.9 2.6e-06 57 Ca_channel_B
17 75 6.5 0.07 58 DAO 43 404 -61.8 0.00044 DAO 42 403 -70.5 0.0014
Phytoene_dh 45 406 -331.1 0.19 Phytoene_dh 44 405 -327.7 0.14 GCV_T
523 863 556.6 1.6e-163 UPF0079 52 149 -47.5 0.26 GCV_T 522 862
593.6 1.2e-174 59 TPR 285 318 9.6 4.2 TPR 155 189 10.7 3.2 TPR 327
360 21.6 0.018 TPR 198 231 30.9 3e-05 TPR 369 402 8.6 5.4 TPR 240
273 31.3 2.2e-05 TPR 435 468 19.9 0.06 TPR 282 315 15.1 1.1 TPR 477
510 28.8 0.00013 TPR 324 357 30.1 5.3e-05 TPR 519 552 23.6 0.0046
TPR 366 399 18.5 0.16 TPR 561 594 36.5 6.1e-07 TPR 408 441 10.6 3.3
TPR 603 636 19.7 0.071 60 Myb_DNA-binding 300 345 18.8 0.0011 61
ACBP 5 43 -18.1 0.014 ACBP 42 130 199.3 5.9e-56 sosui 405 427 -- --
sosui 503 524 -- -- 62 Dynein_heavy 494 1192 444.2 1.1e-129 63
myosin_head 147 282 81.9 3.4e-23 myosin_head 1208 1871 946.2
8.7e-281 MyTH4 561 673 33.9 2.1e-06 IQ 1887 1907 22.5 0.0097 SH3
1455 1511 8 0.013 IQ 1910 1930 26.1 0.00081 MyTH4 2088 2195 71.8
1.4e-17 MyTH4 3071 3185 108.4 1.4e-28 64 WD40 61 98 22.4 0.011 WD40
12 47 13.6 3.4 WD40 110 145 12.9 4.7 WD40 64 100 19.9 0.059 WD40
150 187 25.3 0.0014 WD40 289 324 13.6 3.4 WD40 341 377 19.9 0.059
65 sosui 152 174 -- -- pkinase 14 265 330.4 2e-95 sosui 193 215 --
-- 66 EGF 12 47 20.7 0.035 EGF 127 162 25.5 0.0013 EGF 53 86 10.6
2.5 EGF 168 203 43.5 4.6e-09 EGF 209 245 27.2 0.00038 EGF 251 286
29.2 9.5e-05 EGF 292 327 30.5 4e-05 EGF 338 373 27.2 0.0004 EGF 379
413 8.6 3.8 EGF 419 454 29.3 9e-05 EGF 524 555 21.3 0.022 EGF 568
598 23.2 0.0061 EGF 611 641 12.3 1.7 EGF 645 686 8.2 4.1 EGF 699
731 2.2 14 EGF 735 773 4.3 9.2 EGF 786 817 21.5 0.02 EGF 830 860
21.4 0.022 EGF 873 904 7.1 5.1 EGF 917 947 17.7 0.27 EGF 960 990
11.4 2.1 EGF 1003 1033 22.8 0.0079 EGF 1046 1076 21.6 0.018 EGF
1089 1119 28.6 0.00015 EGF 1132 1162 18.1 0.21 EGF 1175 1205 21.8
0.017 EGF 1209 1249 0.6 20 EGF 1262 1292 14.5 1.1 EGF 1305 1335 15
1 EGF 1348 1378 22.5 0.0099 EGF 1391 1421 19 0.12 EGF 1434 1464
16.5 0.62 EGF 1477 1507 9.2 3.3 EGF 1520 1550 14.2 1.2 67 EGF 157
187 10.9 2.3 EGF 127 162 25.5 0.0013 EGF 200 230 15.6 0.88 EGF 168
203 43.5 4.6e-09 EGF 243 273 27 0.00045 EGF 209 245 27.2 0.00038
EGF 286 316 25.5 0.0012 EGF 251 286 29.2 9.5e-05 EGF 329 359 26.1
0.0008 EGF 292 327 30.5 4e-05 EGF 372 402 20 0.056 EGF 338 373 27.2
0.0004 EGF 416 448 11.8 1.9 EGF 379 413 8.6 3.8 EGF 461 491 23.2
0.006 EGF 419 454 29.3 9e-05 EGF 504 534 24.9 0.0019 EGF 524 555
21.3 0.022 EGF 547 577 23.9 0.0038 EGF 568 598 23.2 0.0061 EGF 590
620 12.6 1.6 EGF 611 641 12.3 1.7 EGF 633 663 21.6 0.019 EGF 645
686 8.2 4.1 EGF 676 708 9.9 2.9 EGF 699 731 2.2 14 EGF 721 751 15.8
0.84 EGF 735 773 4.3 9.2 EGF 764 794 22 0.014 EGF 786 817 21.5 0.02
EGF 807 837 18.6 0.15 EGF 830 860 21.4 0.022 EGF 850 880 18.2 0.19
EGF 873 904 7.1 5.1 sosui 909 930 -- -- EGF 917 947 17.7 0.27 EGF
960 990 11.4 2.1 EGF 1003 1033 22.8 0.0079 EGF 1046 1076 21.6 0.018
EGF 1089 1119 28.6 0.00015 EGF 1132 1162 18.1 0.21 EGF 1175 1205
21.8 0.017 EGF 1209 1249 0.6 20 EGF 1262 1292 14.5 1.1 EGF 1305
1335 15 1 EGF 1348 1378 22.5 0.0099 EGF 1391 1421 19 0.12 EGF 1434
1464 16.5 0.62 EGF 1477 1507 9.2 3.3 EGF 1520 1550 14.2 1.2 68 WH2
399 417 8.5 22 WH2 463 480 17.2 0.38 69 EGF 45 81 43.6 4.4e-09 EGF
20 56 36.8 4.9e-07 TB 96 137 42.8 7.5e-09 EGF 62 98 37.7 2.6e-07
EGF 162 198 26.5 0.00063 EGF 104 138 31.9 1.5e-05 EGF 204 241 19.5
0.078 TB 153 194 56.9 4.5e-13 EGF 207 243 39.4 8e-08 TB 258 299
74.2 2.8e-18 EGF 325 361 23.4 0.0055 EGF 367 404 18.3 0.18 EGF 410
446 35.7 1e-06 EGF 452 488 24.6 0.0024 EGF 494 529 27.7 0.00027 EGF
535 571 28.8 0.00013 EGF 577 613 17.4 0.33 EGF 619 654 26.5 0.00061
Plexin_repeat 625 674 4.9 0.73 EGF 660 695 31.8 1.5e-05 EGF 701 737
34.8 2e-06 70 zf-C2H2 44 67 6.3 19 zf-C2H2 21 43 20.9 0.031 zf-C2H2
101 124 4.3 31 zf-C2H2 50 73 17.6 0.3 zf-C2H2 202 225 16.1 0.87
zf-C2H2 79 102 15 1.8 zf-C2H2 247 270 5.6 23 zf-C2H2 309 332 15.5
1.3 zf-C2H2 392 415 16.1 0.84 zf-C2H2 429 452 6.3 20 zf-C2H2 499
522 1.8 55 zf-C2H2 578 601 4.5 29 zf-C2H2 624 646 18.9 0.12 zf-C2H2
700 722 11 6.7 zf-C2H2 784 806 19.1 0.1 zf-C2H2 818 840 20.9 0.031
zf-C2H2 847 870 17.6 0.3 zf-C2H2 876 899 15 1.8 zf-C2H2 984 1007
3.8 35 zf-C2H2 1013 1036 15.4 1.4 zf-C2H2 1047 1069 12.8 4.4
zf-C2H2 1093 1115 20.5 0.039 zf-C2H2 1121 1144 16.6 0.58 zf-C2H2
1207 1229 27.4 0.00034
[0120] TABLE-US-00005 TABLE 5 Complete notation of each functional
domain Abbreviated notation Complete notation A_deamin
Adenosine-deaminase (editase) domain ACBP Acetyl CoA binding
protein AMP-binding AMP-binding enzyme ank Ank repeat
Armadillo.sub.-- Armadillo/beta-catenin-like repeat seg BNR BNR
repeat BR01 BR01-like domain BTB BTB/POZ domain C2 C2 domain
Ca_channel_B Dihydropyridine sensitive L-type calcium channel (Beta
subunit) cadherin Cadherin domain chromo `chromo` (CHRomatin
Organization MOdifier) domain COLFI Fibrillar collagen C-terminal
domain Collagen Collagen triple helix repeat (20 copies) DAO FAD
dependent oxidoreductase DDHD DDHD domain death Death domain DENN
DENN (AEX-3) domain Dynein_heavy Dynein heavy chain EGF EGF-like
domain F5_F8_type_C F5/8 type C domain FH2 Formin Homology 2 Domain
GCV_T Glycine cleavage T-protein (aminomethyl transferase)
Glyco_hydro_47 Glycosyl hydrolase family 47 Glyco_transf_29
Glycosyltransferase family 29 (sialyltransferase) GRAM GRAM domain
GSPII_E Bacterial type II secretion system protein HEAT HEAT repeat
HR1 Hr1 repeat motif integrin_B Integrins, beta chain IQ IQ
calmodulin-binding motif Kelch Kelch motif KRAB KRAB box
Laminin_EGF Laminin EGF-like (Domains III and V) laminin_G Laminin
G domain Laminin_Nterm Laminin N-terminal (Domain VI)
myb_DNA-binding Myb-like DNA-binding domain myosin_head Myosin head
(motor domain) MyTH4 MyTH4 domain Oxysterol_BP Oxysterol-binding
protein PDZ PDZ domain (Also known as DHR or GLGF). PH PH domain
Phytoene_dh Phytoene dehydrogenase related enzyme pkinase Protein
kinase domain Plexin_repeat Plexin repeat Pro_dh Proline
dehydrogenase RasGEF RasGEF domain RasGEFN Guanine nucleotide
exchange factor for Ras-like GTPases; N-terminal motif RhoGAP
RhoGAP domain RhoGEF RhoGEF domain SAM SAM domain (Sterile alpha
motif) Sema Sema domain SH3 SH3 domain spectrin Spectrin repeat TB
TB domain TIG IPT/TIG domain TPR TPR Domain Troponin Troponin TSPN
Thrombospondin N-terminal-like domain tubulin Tubulin/FtsZ family
tubulin-binding Tau and MAP protein, Tubulin-binding repeat UBA
UBA/TS-N domain UPF0079 Uncharacterised P-loop hydrolase UPF0079
UQ_con Ubiquitin-conjugating enzyme WD40 WD domain, G-beta repeat
WH2 WH2 motif WW WW domain Xlink Extracellular link domain zf-BED
BED zinc finger zf-C2H2 Zinc finger, C2H2 type ZU5 ZU5 domain
(5) Expression Site
[0121] Expressions in the tissue and the sites of the brain were
examined by RT-PCR ELISA. Table 6 lists the sites showing the
strongest expression.
(6) Chromosome Position
[0122] Using the DNA nucleotide sequences of the clones as queries,
an analysis program BLASTN 2.0.14 (the above-mentioned "Gapped
BLAST and PSI-BLAST: a new generation of protein database search
programs") was run on human genome sequences corresponding to the
library of known sequences, Genbank release 119. The description of
the chromosome number from which the clone had been derived was
extracted from the definitions for the matched clones as listed in
Table 6. TABLE-US-00006 TABLE 6 Expression site of each gene and
chromosome position of homologous gene Chromosome Expression site
position SEQ ID NO: Tissue Brain Position 1 Brain Caudate nucleus
-- 2 Ovary Cerebellum -- 3 Brain -- -- 4 Brain Nucleus of
hypothalamus -- 5 Brain Caudate nucleus 2 6 Kidney Caudate nucleus
-- 7 Ovary Spinal cord 20 8 Brain Substantia nigra 7 9 Ovary
Amygdaloid body -- 10 Brain Caudate nucleus 20 11 Ovary Thalamus 7
12 Brain Amygdaloid body -- 13 Ovary Substantia nigra 9 14 Brain
Caudate nucleus 22 15 Brain Thalamus 19 16 Kidney Spinal cord 7 17
Skeletal muscle Caudate nucleus 19 18 Brain Spinal cord 7 19 Heart
Amygdaloid body 9 20 -- -- -- 21 Brain Hippocampus 17 22 Brain
Spinal cord -- 23 Orchis Corpus callosum -- 24 Kidney Thalamus 7 25
-- Nucleus of hypothalamus 22 26 -- -- 3 27 Brain Thalamus 22 28
Brain Cerebellum 2 29 Brain Spinal cord 16 30 Brain Caudate nucleus
8 31 Ovary Nucleus of hypothalamus 1 32 Heart Amygdaloid body 18 33
Brain Caudate nucleus 3 34 Ovary Caudate nucleus 2 35 Ovary
Thalamus 7 36 Ovary Spinal cord 11 37 Brain Cerebellum 14 38 Brain
Cerebellum -- 39 Ovary Spinal cord 17 40 Ovary Corpus callosum 16
41 Ovary Cerebellum -- 42 Kidney Spinal cord -- 43 Brain Thalamus
19 44 Brain Corpus callosum -- 45 Kidney Cerebellum X 46 Brain
Spinal cord 22 47 Brain Amygdaloid body 3 48 Ovary Spinal cord 17
49 Skeletal muscle Amygdaloid body 22 50 Skeletal muscle Thalamus 3
51 Skeletal muscle Spinal cord -- 52 Ovary Hippocampus -- 53 Brain
Cerebellum 2 54 -- -- 3 55 Brain Thalamus -- 56 Kidney Spinal cord
5 57 Brain Caudate nucleus 11 58 -- -- 16 59 Kidney Spinal cord 3
60 -- -- 5 61 Brain Substantia nigra 10 62 Ovary Caudate nucleus 11
63 -- -- 17 64 Skeletal muscle Spinal cord 14 65 Brain Substantia
nigra 19 66 Brain Caudate nucleus 3 67 Brain Hippocampus 5 68 -- --
16 69 -- -- 19 70 Brain Caudate nucleus 19
[0123] According to the above information on homology, homologous
genes, each domain, expression sites, chromosome positions and the
like, a person skilled in the art can predict based on the grounds
shown in Table 1 that the DNAs or the genes of the present
invention respectively have each function described in Table 1.
INDUSTRIAL APPLICABILITY
[0124] A single nucleotide polymorphism, SNP, which is a change in
one base (nucleotide) among individuals in the DNA or the gene of
the present invention, can be found by performing PCR using
synthetic DNA primers prepared based on the nucleotide sequence of
the DNA or the gene of the present invention or a part thereof, and
using chromosome DNA extracted from human blood or tissue so as to
determine the nucleotide sequence of the product. Therefore,
individual constitution or the like can be predicted, which enables
the development of a pharmaceutical preparation suitable for each
individual.
[0125] Further, when ortholog (homolog, counterpart) genes for the
DNA or the gene of the present invention in model organisms, such
as mice, are isolated with cross hybridization, for example, these
genes are knocked out to produce human disease model animals, so
that the causative genes which cause human diseases can be searched
and identified.
[0126] DNA chip, polypeptide chip and antibody chip can be
respectively prepared by arraying the DNAs and the polypeptides of
the present invention, and antibodies for the polypeptides of the
present invention. Specifically, novel DNAs or genes obtained by
the present invention are assembled on a so-called DNA chip, and
then probes prepared using blood or tissue derived from patients
with diseases that relate to the brain, such as mental disease, or
as a control using blood or tissue from healthy individuals are
hybridized to the chip, so that the chip can be applied to
diagnosis and treatment for the diseases. Moreover, antibody chip,
on which the antibodies against the polypeptides of the present
invention are thoroughly prepared and arrayed, can be applied to
diagnosis, treatment of diseases and the like through proteome
analysis, such as detection of a difference in expression amount of
a protein between a patient and a healthy individual.
[0127] The present application asserts priority based on the three
specifications of Japanese Patent Application Nos. 2000-389742,
2001-95524 and 2001-127066, and includes by reference all of the
contents as disclosed in these specifications.
Sequence CWU 0 SQTB SEQUENCE LISTING The patent application
contains a lengthy "Sequence Listing" section. A copy of the
"Sequence Listing" is available in electronic form from the USPTO
web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20060063152A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
0 SQTB SEQUENCE LISTING The patent application contains a lengthy
"Sequence Listing" section. A copy of the "Sequence Listing" is
available in electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20060063152A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
* * * * *
References