Homo sapiens Protein: MSH6
InnateDB Protein IDBP-51048.6
Last Modified 2014-10-13 [Report errors or provide feedback]
Gene Symbol MSH6
Protein Name mutS homolog 6 (E. coli)
Synonyms GTBP; GTMBP; HNPCC5; HSAP; p160;
Species Homo sapiens
Ensembl Protein ENSP00000234420
InnateDB Gene IDBG-51044 (MSH6)
Protein Structure
UniProt Annotation
Function Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. Recruited on chromatin in G1 and early S phase via its PWWP domain that specifically binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early recruitment to chromatin to be replicated allowing a quick identification of mismatch repair to initiate the DNA mismatch repair reaction. {ECO:0000269PubMed:10078208, ECO:0000269PubMed:10660545, ECO:0000269PubMed:15064730, ECO:0000269PubMed:23622243, ECO:0000269PubMed:9564049, ECO:0000269PubMed:9822679, ECO:0000269PubMed:9822680}.
Subcellular Localization Nucleus {ECO:0000269PubMed:23622243}. Chromosome {ECO:0000269PubMed:23622243}. Note=Associates with H3K36me3 via its PWWP domain.
Disease Associations Hereditary non-polyposis colorectal cancer 5 (HNPCC5) [MIM:614350]: An autosomal dominant disease associated with marked increase in cancer susceptibility. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra-colonic tumors 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. Clinically, HNPCC is often divided into two subgroups. Type I is characterized by hereditary predisposition to colorectal cancer, a young age of onset, and carcinoma observed in the proximal colon. Type II is characterized by 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. The term 'suspected HNPCC' or 'incomplete HNPCC' can be used to describe families who do not or only partially fulfill the Amsterdam criteria, but in whom a genetic basis for colon cancer is strongly suspected. {ECO:0000269PubMed:10480359, ECO:0000269PubMed:10521294, ECO:0000269PubMed:11586295, ECO:0000269PubMed:12658575, ECO:0000269PubMed:14974087, ECO:0000269PubMed:15365995, ECO:0000269PubMed:9354786}. Note=The disease is caused by mutations affecting the gene represented in this entry.Endometrial cancer (ENDMC) [MIM:608089]: A malignancy of endometrium, the mucous lining of the uterus. Most endometrial cancers are adenocarcinomas, cancers that begin in cells that make and release mucus and other fluids. {ECO:0000269PubMed:11153917, ECO:0000269PubMed:14961575}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.Mismatch repair cancer syndrome (MMRCS) [MIM:276300]: An autosomal recessive, rare, childhood cancer predisposition syndrome encompassing a broad tumor spectrum. This includes hematological malignancies, central nervous system tumors, Lynch syndrome-associated malignancies such as colorectal tumors as well as multiple intestinal polyps, embryonic tumors and rhabdomyosarcoma. Multiple cafe-au-lait macules, a feature reminiscent of neurofibromatosis type 1, are often found as first manifestation of the underlying cancer. Areas of skin hypopigmentation have also been reported in MMRCS patients. {ECO:0000269PubMed:17557300}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Tissue Specificity
Number of Interactions This gene and/or its encoded proteins are associated with 86 experimentally validated interaction(s) in this database.
They are also associated with 5 interaction(s) predicted by orthology.
Experimentally validated
Total 88 [view]
Protein-Protein 85 [view]
Protein-DNA 3 [view]
Protein-RNA 0
Predicted by orthology
Total 5 [view]
Gene Ontology

Molecular Function
Accession GO Term
GO:0000287 magnesium ion binding
GO:0000400 four-way junction DNA binding
GO:0003677 DNA binding
GO:0003682 chromatin binding
GO:0003684 damaged DNA binding
GO:0003690 double-stranded DNA binding
GO:0005515 protein binding
GO:0005524 ATP binding
GO:0008094 DNA-dependent ATPase activity
GO:0016887 ATPase activity
GO:0030983 mismatched DNA binding
GO:0032137 guanine/thymine mispair binding
GO:0032142 single guanine insertion binding
GO:0032143 single thymine insertion binding
GO:0032357 oxidized purine DNA binding
GO:0032405 MutLalpha complex binding
GO:0035064 methylated histone binding
GO:0043531 ADP binding
Biological Process
GO:0000710 meiotic mismatch repair
GO:0006200 ATP catabolic process
GO:0006281 DNA repair
GO:0006298 mismatch repair
GO:0007131 reciprocal meiotic recombination
GO:0008340 determination of adult lifespan
GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage
GO:0009411 response to UV
GO:0016446 somatic hypermutation of immunoglobulin genes
GO:0016447 somatic recombination of immunoglobulin gene segments
GO:0045190 isotype switching
GO:0045910 negative regulation of DNA recombination
GO:0051096 positive regulation of helicase activity
GO:0097193 intrinsic apoptotic signaling pathway
Cellular Component
GO:0000228 nuclear chromosome
GO:0000790 nuclear chromatin
GO:0005634 nucleus
GO:0005737 cytoplasm
GO:0005794 Golgi apparatus
GO:0005886 plasma membrane
GO:0032301 MutSalpha complex
GO:0043231 intracellular membrane-bounded organelle
Protein Structure and Domains
InterPro IPR000313 PWWP domain
IPR000432 DNA mismatch repair protein MutS, C-terminal
IPR007695 DNA mismatch repair protein MutS-like, N-terminal
IPR007696 DNA mismatch repair protein MutS, core
IPR007860 DNA mismatch repair protein MutS, connector domain
IPR007861 DNA mismatch repair protein MutS, clamp
IPR016151 DNA mismatch repair protein MutS, N-terminal
IPR017261 DNA mismatch repair protein Msh6
IPR027417 P-loop containing nucleoside triphosphate hydrolase
PFAM PF00855
Post-translational Modifications
SwissProt P52701
PhosphoSite PhosphoSite-P52701
UniProt Splice Variant
Entrez Gene 2956
UniGene Hs.733502
RefSeq NP_000170
OMIM 600678
HPRD 07202
EMBL AC006509 AK293921 AK304735 AY082894 BC004246 D89645 D89646 U28946 U54777 U73732 U73733 U73734 U73736 U73737
GenPept AAB39212 AAB47425 AAC50461 AAH04246 AAL87401 BAA23674 BAA23675 BAG57302 BAG65496