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Description:
DNA mismatch repair protein MSH6 (MutS-alpha 160 kDa subunit) (G/Tmismatch binding protein) (GTBP) (GTMBP) (p160).
Molecular weight: 1527
View which proteins in this organism that is involved with DNA Repair;
classified after biological processes (using data from the GOA project):
DNA repair( GO:0006281 ) mismatch repair( GO:0006298 )
Important dates:
01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
21-JUN-2005, sequence version 2.
07-FEB-2006, entry version 58.
Phylogenetic order:
Eukaryota Metazoa Chordata Craniata Vertebrata Euteleostomi Mammalia Eutheria Euarchontoglires Primates Catarrhini Hominidae Homo.
To calculate the pI (Isoelectric point - the pH where a protein has a neutral charge),
go to this page and enter the protein ID (e.g 3MG_ECOLI): http://us.expasy.org/tools/pi_tool.html
Links to references in other databases for protein MSH6_HUMAN:
| Database | Pointer | Add. info#1 | Add. info#2 |
| EMBL | U73737 | AAB47425.1 | - |
| EMBL | U73732 | AAB47425.1 | JOINED |
| EMBL | U73733 | AAB47425.1 | JOINED |
| EMBL | U73734 | AAB47425.1 | JOINED |
| EMBL | U73736 | AAB47425.1 | JOINED |
| EMBL | D89645 | BAA23674.1 | - |
| EMBL | D89646 | BAA23675.1 | - |
| EMBL | AY082894 | AAL87401.1 | - |
| EMBL | BC004246 | AAH04246.1 | - |
| EMBL | U54777 | AAB39212.2.1 | - |
| EMBL | U28946 | AAC50461.1 | - |
| PIR | JC5839 | JC5839. | |
| HSSP | P23909 | 1OH6 | |
| IntAct | P52701 | -.1 | |
| H-InvDB | HIX0002043 | -.1 | |
| HGNC | HGNC:7329 | MSH6.1 | |
| MIM | 600678 | gene+phenotype. | |
| MIM | 608089 | phenotype. | |
| GO | GO:0003684 | F:damaged DNA binding | TAS. |
| GO | GO:0006298 | P:mismatch repair | TAS. |
| InterPro | IPR000432 | MutS_C. | |
| InterPro | IPR007860 | MutS_II. | |
| InterPro | IPR007696 | MutS_III. | |
| InterPro | IPR007861 | MutS_IV. | |
| InterPro | IPR007695 | MutS_N. | |
| InterPro | IPR000313 | PWWP. | |
| Pfam | PF01624 | MutS_I | 1. |
| Pfam | PF05188 | MutS_II | 1. |
| Pfam | PF05192 | MutS_III | 1. |
| Pfam | PF05190 | MutS_IV | 1. |
| Pfam | PF00488 | MutS_V | 1. |
| Pfam | PF00855 | PWWP | 1. |
| ProDom | PD001263 | MutS_C | 1. |
| SMART | SM00534 | MUTSac | 1. |
| SMART | SM00533 | MUTSd | 1. |
| SMART | SM00293 | PWWP | 1. |
| PROSITE | PS00486 | DNA_MISMATCH_REPAIR_2 | 1. |
| PROSITE | PS50812 | PWWP | 1. |
Keywords:
Alternative splicing; ATP-binding; Direct protein sequencing; Disease mutation; DNA damage; DNA repair; DNA-binding; Hereditary nonpolyposis colorectal cancer; Nuclear protein; Nucleotide-binding; Phosphorylation; Polymorphism.
References:
RN [1]
RP NUCLEOTIDE SEQUENCE, AND VARIANT GLU-39.
RX MEDLINE=97098445; PubMed=8942985; DOI=10.1073/pnas.93.24.13629;
RA Acharya S., Wilson T., Gradia S., Kane M.F., Guerrette S.,
RA Marsischky G.T., Kolodner R.D., Fishel R.;
RT "hMSH2 forms specific mispair-binding complexes with hMSH3 and
RT hMSH6.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:13629-13634(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE, AND ALTERNATIVE SPLICING.
RX MEDLINE=98116665; PubMed=9455487; DOI=10.1093/dnares/4.5.359;
RA Shiwaku H.O., Wakatsuki S., Mori Y., Fukushige S., Horii A.;
RT "Alternative splicing of GTBP in normal human tissues.";
RL DNA Res. 4:359-362(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Rieder M.J., Braun A.C., Montoya M.A., Chung M.-W., Nguyen C.P.,
RA Nguyen D.A., Livingston R.J., Poel C.L., Robertson P.D.,
RA Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A.;
RT "NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department
RT of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu).";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX MEDLINE=22388257; PubMed=12477932; DOI=10.1073/pnas.242603899;
RA Strausberg R.L., Feingold E.A., Grouse L.H., Derge J.G.,
RA Klausner R.D., Collins F.S., Wagner L., Shenmen C.M., Schuler G.D.,
RA Altschul S.F., Zeeberg B., Buetow K.H., Schaefer C.F., Bhat N.K.,
RA Hopkins R.F., Jordan H., Moore T., Max S.I., Wang J., Hsieh F.,
RA Diatchenko L., Marusina K., Farmer A.A., Rubin G.M., Hong L.,
RA Stapleton M., Soares M.B., Bonaldo M.F., Casavant T.L., Scheetz T.E.,
RA Brownstein M.J., Usdin T.B., Toshiyuki S., Carninci P., Prange C.,
RA Raha S.S., Loquellano N.A., Peters G.J., Abramson R.D., Mullahy S.J.,
RA Bosak S.A., McEwan P.J., McKernan K.J., Malek J.A., Gunaratne P.H.,
RA Richards S., Worley K.C., Hale S., Garcia A.M., Gay L.J., Hulyk S.W.,
RA Villalon D.K., Muzny D.M., Sodergren E.J., Lu X., Gibbs R.A.,
RA Fahey J., Helton E., Ketteman M., Madan A., Rodrigues S., Sanchez A.,
RA Whiting M., Madan A., Young A.C., Shevchenko Y., Bouffard G.G.,
RA Blakesley R.W., Touchman J.W., Green E.D., Dickson M.C.,
RA Rodriguez A.C., Grimwood J., Schmutz J., Myers R.M.,
RA Butterfield Y.S.N., Krzywinski M.I., Skalska U., Smailus D.E.,
RA Schnerch A., Schein J.E., Jones S.J.M., Marra M.A.;
RT "Generation and initial analysis of more than 15,000 full-length human
RT and mouse cDNA sequences.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903(2002).
RN [5]
RP NUCLEOTIDE SEQUENCE OF 69-1360, AND PARTIAL PROTEIN SEQUENCE.
RX MEDLINE=95327934; PubMed=7604265;
RA Palombo F., Gallinari P., Iaccarino I., Lettieri T., Hughes M.,
RA D'Arrigo A., Truong O., Hsuan J.J., Jiricny J.;
RT "GTBP, a 160-kilodalton protein essential for mismatch-binding
RT activity in human cells.";
RL Science 268:1912-1914(1995).
RN [6]
RP NUCLEOTIDE SEQUENCE OF 1-116.
RX MEDLINE=96435440; PubMed=8838326; DOI=10.1006/geno.1996.0067;
RA Nicolaides N.C., Palombo F., Kinzler K.W., Vogelstein B., Jiricny J.;
RT "Molecular cloning of the N-terminus of GTBP.";
RL Genomics 31:395-397(1996).
RN [7]
RP CHARACTERIZATION, AND PARTIAL PROTEIN SEQUENCE.
RX MEDLINE=95327933; PubMed=7604264;
RA Drummond J.T., Li G.-M., Longley M.J., Modrich P.;
RT "Isolation of an hMSH2-p160 heterodimer that restores DNA mismatch
RT repair to tumor cells.";
RL Science 268:1909-1912(1995).
RN [8]
RP IDENTIFICATION OF MSH6 AS MEMBER OF BASC.
RX MEDLINE=20245492; PubMed=10783165; DOI=10.1101/gad.827000;
RA Wang Y., Cortez D., Yazdi P., Neff N., Elledge S.J., Qin J.;
RT "BASC, a super complex of BRCA1-associated proteins involved in the
RT recognition and repair of aberrant DNA structures.";
RL Genes Dev. 14:927-939(2000).
RN [9]
RP DISEASE.
RX MEDLINE=98016406; PubMed=9354786;
RA Miyaki M., Konishi M., Tanaka K., Kikuchi-Yanoshita R., Muraoka M.,
RA Yasuno M., Igari T., Koike M., Chiba M., Mori T.;
RT "Germline mutation of MSH6 as the cause of hereditary nonpolyposis
RT colorectal cancer.";
RL Nat. Genet. 17:271-272(1997).
RN [10]
RP PHOSPHORYLATION SITES SER-227; SER-252; SER-254; SER-256; SER-261 AND
RP SER-830.
RX PubMed=15302935; DOI=10.1073/pnas.0404720101;
RA Beausoleil S.A., Jedrychowski M., Schwartz D., Elias J.E., Villen J.,
RA Li J., Cohn M.A., Cantley L.C., Gygi S.P.;
RT "Large-scale characterization of HeLa cell nuclear phosphoproteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:12130-12135(2004).
RN [11]
RP VARIANTS VAL-1213 AND ILE-1260.
RX MEDLINE=95327935; PubMed=7604266;
RA Papadopoulos N., Nicolaides N.C., Liu B., Parsons R., Lengauer C.,
RA Palombo F., D'Arrigo A., Markowitz S., Willson J.K.V., Kinzler K.W.,
RA Jiricny J., Vogelstein B.;
RT "Mutations of GTBP in genetically unstable cells.";
RL Science 268:1915-1917(1995).
RN [12]
RP VARIANTS HNPCC5 ILE-144 AND CYS-850.
RX MEDLINE=99452590; PubMed=10521294;
RA Wu Y., Berends M.J.W., Mensink R.G.J., Kempinga C., Sijmons R.H.,
RA van Der Zee A.G.J., Hollema H., Kleibeuker J.H., Buys C.H.C.M.,
RA Hofstra R.M.W.;
RT "Association of hereditary nonpolyposis colorectal cancer-related
RT tumors displaying low microsatellite instability with MSH6 germline
RT mutations.";
RL Am. J. Hum. Genet. 65:1291-1298(1999).
RN [13]
RP VARIANTS CRC ILE-285; ARG-566; GLY-803 AND THR-1087, AND VARIANTS
RP GLU-39; ASP-220; VAL-396 AND LEU-800.
RX MEDLINE=20005667; PubMed=10537275;
RA Kolodner R.D., Tytell J.D., Schmeits J.L., Kane M.F., Gupta R.D.,
RA Weger J., Wahlberg S., Fox E.A., Peel D., Ziogas A., Garber J.E.,
RA Syngal S., Anton-Culver H., Li F.P.;
RT "Germ-line msh6 mutations in colorectal cancer families.";
RL Cancer Res. 59:5068-5074(1999).
RN [14]
RP VARIANT HNPCC5 GLU-698.
RX MEDLINE=99408236; PubMed=10480359; DOI=10.1007/s004390051067;
RA Wang Q., Lasset C., Desseigne F., Saurin J.-C., Maugard C.,
RA Navarro C., Ruano E., Descos L., Trillet-Lenoir V., Bosset J.-F.,
RA Puisieux A.;
RT "Prevalence of germline mutations of hMLH1, hMSH2, hPMS1, hPMS2, and
RT hMSH6 genes in 75 French kindreds with nonpolyposis colorectal
RT cancer.";
RL Hum. Genet. 105:79-85(1999).
RN [15]
RP VARIANT HNPCC5 ALA-878.
RX MEDLINE=21470348; PubMed=11586295; DOI=10.1038/ng1001-137;
RA Wu Y., Berends M.J.W., Sijmons R.H., Mensink R.G.J., Verlind E.,
RA Kooi K.A., van der Sluis T., Kempinga C., van der Zee A.G.J.,
RA Hollema H., Buys C.H.C.M., Kleibeuker J.H., Hofstra R.M.W.;
RT "A role for MLH3 in hereditary nonpolyposis colorectal cancer.";
RL Nat. Genet. 29:137-138(2001).
RN [16]
RP VARIANT CRC HIS-976.
RX MEDLINE=21666030; PubMed=11807791; DOI=10.1002/ijc.10097;
RA Plaschke J., Krueger S., Pistorius S., Theissig F., Saeger H.D.,
RA Schackert H.K.;
RT "Involvement of hMSH6 in the development of hereditary and sporadic
RT colorectal cancer revealed by immunostaining is based on germline
RT mutations, but rarely on somatic inactivation.";
RL Int. J. Cancer 97:643-648(2002).
Feature:
CHAIN 1 1360 DNA mismatch repair protein MSH6.
/FTId=PRO_0000115207.
DOMAIN 92 154 PWWP.
NP_BIND 1134 1141 ATP (Potential).
COMPBIAS 34 37 Poly-Ala.
COMPBIAS 201 209 Poly-Glu.
COMPBIAS 1118 1123 Poly-Glu.
MOD_RES 227 227 Phosphoserine.
MOD_RES 252 252 Phosphoserine.
MOD_RES 254 254 Phosphoserine.
MOD_RES 256 256 Phosphoserine.
MOD_RES 261 261 Phosphoserine.
MOD_RES 830 830 Phosphoserine.
VARSPLIC 1058 1068 DVLLCLANYSR -> GKTLNKLVLRL (in isoform
GTBP-alt).
/FTId=VSP_003291.
VARSPLIC 1069 1360 Missing (in isoform GTBP-alt).
/FTId=VSP_003292.
VARIANT 39 39 G -> E (in dbSNP:1042821).
/FTId=VAR_004490.
VARIANT 144 144 S -> I (in suspected HNPCC5).
/FTId=VAR_012955.
VARIANT 220 220 E -> D (in dbSNP:1800938).
/FTId=VAR_012956.
VARIANT 285 285 S -> I (in CRC).
/FTId=VAR_012957.
VARIANT 396 396 L -> V (rare polymorphism;
dbSNP:2020908).
/FTId=VAR_012958.
VARIANT 566 566 G -> R (in CRC; partial functional loss).
/FTId=VAR_012959.
VARIANT 698 698 Q -> E (in suspected HNPCC; could be a
polymorphism).
/FTId=VAR_012960.
VARIANT 800 800 V -> L (may be a rare polymorphism).
/FTId=VAR_012961.
VARIANT 803 803 D -> G (in CRC).
/FTId=VAR_012962.
VARIANT 850 850 Y -> C (in suspected HNPCC5).
/FTId=VAR_012963.
VARIANT 878 878 V -> A (in suspected HNPCC5;
dbSNP:2020912).
/FTId=VAR_012964.
VARIANT 886 886 I -> V (in dbSNP:2020914).
/FTId=VAR_014902.
VARIANT 976 976 R -> H (in CRC; sporadic).
/FTId=VAR_012965.
VARIANT 1087 1087 P -> T (in CRC).
/FTId=VAR_012966.
VARIANT 1213 1213 D -> V.
/FTId=VAR_004491.
VARIANT 1260 1260 V -> I.
/FTId=VAR_004492.
CONFLICT 36 57 AAPGASPSPGGDAAWSEAGPGP -> GCPRGLSFPRRGCGL
ERGWAWA (in Ref. 2).
CONFLICT 1358 1360 KEL -> D (in Ref. 3).
Comments:
-!- FUNCTION: Restores repair of base-base and single- nucleotide
insertion-deletion mismatches, and increases the proficiency to
process heteroduplexes with two-, three-, or four- nucleotide
insertion-deletion mismatches. GTBP binds covalently to G/T
mismatches.
-!- SUBUNIT: Heterodimer of MSH2 and MSH6 (GTBP). Part of the BRCA1-
associated genome surveillance complex (BASC), which contains
BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1
protein complex. This association could be a dynamic process
changing throughout the cell cycle and within subnuclear domains.
-!- SUBCELLULAR LOCATION: Nucleus.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=2;
Name=GTBP-N;
IsoId=P52701-1; Sequence=Displayed;
Name=GTBP-alt;
IsoId=P52701-2; Sequence=VSP_003291, VSP_003292;
-!- PTM: The N-terminus is blocked.
-!- DISEASE: Defects in MSH6 are the cause of hereditary non-polyposis
colorectal cancer type 5 (HNPCC5) [MIM:600678]. Mutations in more
than one gene locus can be involved alone or in combination in the
production of the HNPCC phenotype (also called Lynch syndrome).
Most families with clinically recognized HNPCC have mutations in
either MLH1 or MSH2 genes. HNPCC is an autosomal, dominantly
inherited disease associated with marked increase in cancer
susceptibility. It is characterized by a familial predisposition
to early onset colorectal carcinoma (CRC) and extra-colonic
cancers of the gastrointestinal, urological and female
reproductive tracts. HNPCC is reported to be the most common form
of inherited colorectal cancer in the Western world. Cancers in
HNPCC originate within benign neoplastic polyps termed adenomas.
Clinically, HNPCC is often divided into two subgroups. Type I:
hereditary predisposition to colorectal cancer, a young age of
onset, and carcinoma observed in the proximal colon. Type II:
patients have an increased risk for cancers in certain tissues
such as the uterus, ovary, breast, stomach, small intestine, skin,
and larynx in addition to the colon. Diagnosis of classical HNPCC
is based on the Amsterdam criteria: 3 or more relatives affected
by colorectal cancer, one a first degree relative of the other
two; 2 or more generation affected; 1 or more colorectal cancers
presenting before 50 years of age; exclusion of hereditary
polyposis syndromes. MSH6 mutations appear to be associated with
atypical HNPCC and in particular with development of endometrial
carcinoma or atypical endometrial hyperplasia, the presumed
precursor of endometrial cancer. Defects in MSH6 are also found in
familial colorectal cancers (suspected or incomplete HNPCC) that
do not fulfill the Amsterdam criteria for HNPCC.
-!- DISEASE: Defects in MSH6 are a cause of susceptibility to
endometrial cancer [MIM:608089].
-!- SIMILARITY: Belongs to the DNA mismatch repair mutS family.
-!- SIMILARITY: Contains 1 PWWP domain.
-!- DATABASE: NAME=Hereditary non-polyposis colorectal cancer db;
WWW="http://www.nfdht.nl/".
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Sequence length: 1360
MSRQSTLYSF FPKSPALSDA NKASARASRE GGRAAAAPGA SPSPGGDAAW SEAGPGPRPL
ARSASPPKAK NLNGGLRRSV APAAPTSCDF SPGDLVWAKM EGYPWWPCLV YNHPFDGTFI
REKGKSVRVH VQFFDDSPTR GWVSKRLLKP YTGSKSKEAQ KGGHFYSAKP EILRAMQRAD
EALNKDKIKR LELAVCDEPS EPEEEEEMEV GTTYVTDKSE EDNEIESEEE VQPKTQGSRR
SSRQIKKRRV ISDSESDIGG SDVEFKPDTK EEGSSDEISS GVGDSESEGL NSPVKVARKR
KRMVTGNGSL KRKSSRKETP SATKQATSIS SETKNTLRAF SAPQNSESQA HVSGGGDDSS
RPTVWYHETL EWLKEEKRRD EHRRRPDHPD FDASTLYVPE DFLNSCTPGM RKWWQIKSQN
FDLVICYKVG KFYELYHMDA LIGVSELGLV FMKGNWAHSG FPEIAFGRYS DSLVQKGYKV
ARVEQTETPE MMEARCRKMA HISKYDRVVR REICRIITKG TQTYSVLEGD PSENYSKYLL
SLKEKEEDSS GHTRAYGVCF VDTSLGKFFI GQFSDDRHCS RFRTLVAHYP PVQVLFEKGN
LSKETKTILK SSLSCSLQEG LIPGSQFWDA SKTLRTLLEE EYFREKLSDG IGVMLPQVLK
GMTSESDSIG LTPGEKSELA LSALGGCVFY LKKCLIDQEL LSMANFEEYI PLDSDTVSTT
RSGAIFTKAY QRMVLDAVTL NNLEIFLNGT NGSTEGTLLE RVDTCHTPFG KRLLKQWLCA
PLCNHYAIND RLDAIEDLMV VPDKISEVVE LLKKLPDLER LLSKIHNVGS PLKSQNHPDS
RAIMYEETTY SKKKIIDFLS ALEGFKVMCK IIGIMEEVAD GFKSKILKQV ISLQTKNPEG
RFPDLTVELN RWDTAFDHEK ARKTGLITPK AGFDSDYDQA LADIRENEQS LLEYLEKQRN
RIGCRTIVYW GIGRNRYQLE IPENFTTRNL PEEYELKSTK KGCKRYWTKT IEKKLANLIN
AEERRDVSLK DCMRRLFYNF DKNYKDWQSA VECIAVLDVL LCLANYSRGG DGPMCRPVIL
LPEDTPPFLE LKGSRHPCIT KTFFGDDFIP NDILIGCEEE EQENGKAYCV LVTGPNMGGK
STLMRQAGLL AVMAQMGCYV PAEVCRLTPI DRVFTRLGAS DRIMSGESTF FVELSETASI
LMHATAHSLV LVDELGRGTA TFDGTAIANA VVKELAETIK CRTLFSTHYH SLVEDYSQNV
AVRLGHMACM VENECEDPSQ ETITFLYKFI KGACPKSYGF NAARLANLPE EVIQKGHRKA
REFEKMNQSL RLFREVCLAS ERSTVDAEAV HKLLTLIKEL