Reviewed,
UniProtKB/Swiss-Prot P52701 (MSH6_HUMAN)
Last modified
November 25, 2008.
Version 107.
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Names and origin
| Protein names | Recommended name: DNA mismatch repair protein Msh6 Alternative name(s): MutS-alpha 160 kDa subunit G/T mismatch-binding protein Short name=GTMBP Short name=GTBP p160 | ||||
| Gene names |
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| Organism | Homo sapiens (Human) | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 1360 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| 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. |
| Subunit structure | Heterodimer consisting of MSH2-MSH6 (MutS alpha). Forms a ternary complex with MutL alpha (MLH1-PMS1). Interacts with EXO1. 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. Interacts with ATR. |
| Subcellular location | |
| Post-translational modification | The N-terminus is blocked. Phosphorylated upon DNA damage, probably by ATM or ATR. Phosphorylated by PRKCZ, which may prevent MutS alpha degradation by the ubiquitin-proteasome pathway. |
| Involvement in 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. Defects in MSH6 are a cause of susceptibility to endometrial cancer [MIM:608089]. |
| Sequence similarities | Belongs to the DNA mismatch repair mutS family. Contains 1 PWWP domain. |
Ontologies
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| CASP4 | P49662 | 1 | EBI-395529,EBI-1057327 | |
| MSH2 | P43246 | 1 | EBI-395529,EBI-355888 |
Alternative products
| This entry describes 2 isoforms produced by alternative splicing. [Align] [Select] | ||||||
| Isoform GTBP-N (identifier: P52701-1) This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. | ||||||
| Isoform GTBP-alt (identifier: P52701-2) The sequence of this isoform differs from the canonical sequence as follows: 1058-1068: DVLLCLANYSR → GKTLNKLVLRL 1069-1360: Missing. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 1360 | 1360 | DNA mismatch repair protein Msh6 | PRO_0000115207 | |||||
Regions | |||||||||
| Domain | 92 – 154 | 63 | PWWP | ||||||
| Nucleotide binding | 1134 – 1141 | 8 | ATP Potential | ||||||
| Compositional bias | 34 – 37 | 4 | Poly-Ala | ||||||
| Compositional bias | 201 – 209 | 9 | Poly-Glu | ||||||
| Compositional bias | 1118 – 1123 | 6 | Poly-Glu | ||||||
Amino acid modifications | |||||||||
| Modified residue | 14 | 1 | Phosphoserine | ||||||
| Modified residue | 41 | 1 | Phosphoserine | ||||||
| Modified residue | 43 | 1 | Phosphoserine | ||||||
| Modified residue | 79 | 1 | Phosphoserine | ||||||
| Modified residue | 91 | 1 | Phosphoserine | ||||||
| Modified residue | 137 | 1 | Phosphoserine | ||||||
| Modified residue | 139 | 1 | Phosphothreonine | ||||||
| Modified residue | 200 | 1 | Phosphoserine | ||||||
| Modified residue | 219 | 1 | Phosphoserine | ||||||
| Modified residue | 227 | 1 | Phosphoserine | ||||||
| Modified residue | 252 | 1 | Phosphoserine | ||||||
| Modified residue | 254 | 1 | Phosphoserine | ||||||
| Modified residue | 256 | 1 | Phosphoserine | ||||||
| Modified residue | 261 | 1 | Phosphoserine | ||||||
| Modified residue | 348 | 1 | Phosphoserine | ||||||
| Modified residue | 830 | 1 | Phosphoserine | ||||||
| Modified residue | 924 | 1 | Phosphothreonine | ||||||
Natural variations | |||||||||
| Alternative sequence | 1058 – 1068 | 11 | DVLLCLANYSR → GKTLNKLVLRL in isoform GTBP-alt. | VSP_003291 | |||||
| Alternative sequence | 1069 – 1360 | 292 | Missing in isoform GTBP-alt. | VSP_003292 | |||||
| Natural variant | 13 | 1 | K → T: dbSNP rs41294988. | VAR_038032 | |||||
| Natural variant | 20 | 1 | A → V in colorectal/endometrial cancer. | VAR_043943 | |||||
| Natural variant | 25 | 1 | A → V: dbSNP rs35462442. | VAR_038033 | |||||
| Natural variant | 39 | 1 | G → E: dbSNP rs1042821. | VAR_004490 | |||||
| Natural variant | 54 | 1 | G → A in CRC; uncertain pathogenicity. | VAR_043944 | |||||
| Natural variant | 65 | 1 | S → L: dbSNP rs41294984. | VAR_038034 | |||||
| Natural variant | 99 | 1 | K → N in CRC; uncertain pathogenicity. | VAR_043945 | |||||
| Natural variant | 128 | 1 | R → L No impairment of heterodimerization with MSH2 and of in vitro mismatch repair capacity. | VAR_043946 | |||||
| Natural variant | 144 | 1 | S → I in suspected HNPCC5 and CRC. dbSNP rs3211299. | VAR_012955 | |||||
| Natural variant | 220 | 1 | E → D: dbSNP rs1800938. | VAR_012956 | |||||
| Natural variant | 221 | 1 | E → D: dbSNP rs41557217 and dbSNP rs61748079. | VAR_042274 | |||||
| Natural variant | 285 | 1 | S → I in CRC. | VAR_012957 | |||||
| Natural variant | 295 | 1 | K → R in multiple colorectal adenoma. | VAR_043947 | |||||
| Natural variant | 340 | 1 | F → S in CRC, breast cancer and leukemia. | VAR_043948 | |||||
| Natural variant | 396 | 1 | L → V Rare polymorphism. dbSNP rs2020908. | VAR_012958 | |||||
| Natural variant | 449 | 1 | L → P in colorectal/endometrial cancer; uncertain pathogenicity. | VAR_043949 | |||||
| Natural variant | 468 | 1 | R → H: dbSNP rs41295268. | VAR_038035 | |||||
| Natural variant | 492 | 1 | M → V in HNPCC5. | VAR_042275 | |||||
| Natural variant | 503 | 1 | S → C | VAR_038036 | |||||
| Natural variant | 509 | 1 | V → A | VAR_043950 | |||||
| Natural variant | 522 | 1 | Q → R in CRC; uncertain pathogenicity. | VAR_043951 | |||||
| Natural variant | 538 | 1 | Y → S: dbSNP rs728619. | VAR_038037 | |||||
| Natural variant | 566 | 1 | G → R in CRC; partial functional loss. | VAR_012959 | |||||
| Natural variant | 580 | 1 | S → L: dbSNP rs41295270. | VAR_038038 | |||||
| Natural variant | 619 | 1 | E → D in CRC; uncertain pathogenicity. | VAR_043952 | |||||
| Natural variant | 623 | 1 | P → A: dbSNP rs3136334. | VAR_029244 | |||||
| Natural variant | 623 | 1 | P → L No impairment of heterodimerization with MSH2 and of in vitro mismatch repair capacity. | VAR_043953 | |||||
| Natural variant | 685 | 1 | G → A in CRC. | VAR_043954 | |||||
| Natural variant | 698 | 1 | Q → E in suspected HNPCC; could be a polymorphism. | VAR_012960 | |||||
| Natural variant | 725 | 1 | I → M in CRC; uncertain pathogenicity. | VAR_043955 | |||||
| Natural variant | 728 | 1 | K → T No impairment of heterodimerization with MSH2 and of in vitro mismatch repair capacity. dbSNP rs35552856. | VAR_043956 | |||||
| Natural variant | 772 | 1 | R → Q in CRC. | VAR_043957 | |||||
| Natural variant | 772 | 1 | R → W in HNPCC5. | VAR_043958 | |||||
| Natural variant | 787 | 1 | A → V in CRC; uncertain pathogenicity. | VAR_043959 | |||||
| Natural variant | 800 | 1 | V → A in CRC; somatic mutation. | VAR_043960 | |||||
| Natural variant | 800 | 1 | V → L May be a rare polymorphism. | VAR_012961 | |||||
| Natural variant | 803 | 1 | D → G in CRC. | VAR_012962 | |||||
| Natural variant | 850 | 1 | Y → C in suspected HNPCC5 and CRC. | VAR_012963 | |||||
| Natural variant | 854 | 1 | K → M in CRC; could be a polymorphism. dbSNP rs34374438. | VAR_043961 | |||||
| Natural variant | 878 | 1 | V → A in suspected HNPCC5, colorectal/endometrial cancer and CRC. dbSNP rs2020912. | VAR_012964 | |||||
| Natural variant | 886 | 1 | I → V: dbSNP rs2020914. | VAR_014902 | |||||
| Natural variant | 901 | 1 | R → H in colorectal/endometrial cancer. | VAR_043962 | |||||
| Natural variant | 976 | 1 | R → H in CRC; sporadic. | VAR_012965 | |||||
| Natural variant | 1021 | 1 | A → D in CRC; uncertain pathogenicity. | VAR_043963 | |||||
| Natural variant | 1031 | 1 | D → V in CRC; somatic mutation. | VAR_043964 | |||||
| Natural variant | 1076 | 1 | R → C in CRC; uncertain pathogenicity. | VAR_043965 | |||||
| Natural variant | 1087 | 1 | P → T in CRC. | VAR_012966 | |||||
| Natural variant | 1095 | 1 | R → H in CRC; uncertain pathogenicity. | VAR_043966 | |||||
| Natural variant | 1100 | 1 | T → M in CRC; uncertain pathogenicity. | VAR_043967 | |||||
| Natural variant | 1158 | 1 | C → R in CRC; somatic mutation. | VAR_043968 | |||||
| Natural variant | 1163 | 1 | E → V in HNPCC5. | VAR_043969 | |||||
| Natural variant | 1193 | 1 | E → K in endometrial cancer; display marked impairment of heterodimerization with MSH2 and of in vitro mismatch repair capacity. | VAR_043970 | |||||
| Natural variant | 1213 | 1 | D → V | VAR_004491 | |||||
| Natural variant | 1219 | 1 | T → I in CRC; uncertain pathogenicity. | VAR_043971 | |||||
| Natural variant | 1232 | 1 | V → L: dbSNP rs41295276. | VAR_038039 | |||||
| Natural variant | 1234 | 1 | E → Q: dbSNP rs35717727. | VAR_038040 | |||||
| Natural variant | 1248 | 1 | H → D in CRC; uncertain pathogenicity. | VAR_043972 | |||||
| Natural variant | 1260 | 1 | V → I | VAR_004492 | |||||

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