Molecular Target Synopsis
Overview
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MSH6 (P52701) - Overview - Molecular Target Synopsis

Protein


MSH6, DNA mismatch repair protein Msh6
UniProt P52701

Also Known as MSH6_HUMAN, MSH6, GTBP

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. Component of the DNA mismatch repair (MMR) complex composed at least of MSH2, MSH3, MSH6, PMS1 and MLH1 (PubMed:26300262). Heterodimer consisting of MSH2-MSH6 (MutS alpha) (PubMed:8942985, PubMed:7604264). Forms a ternary complex with MutL alpha (MLH1-PMS1). Interacts with MCM9 (PubMed:26300262). 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 (PubMed:10783165). This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains (PubMed:10783165).

6OQM
CRYSTAL STRUCTURE OF THE MSH6 PWWP DOMAIN
RCSB/PDB
Inspect Structure
See all 3D Structures for MSH6

Isoforms / Transcripts (Protein Coding)


Sub-cellular localization


UniProt: MSH6 is active in the following subcellular-locations: chromosome, nucleus.
GO terms: MSH6 is active in the following subcellular-locations: cytosol, Golgi apparatus, intracellular membrane-bounded organelle, mismatch repair complex, MutSalpha complex, nuclear chromatin, nucleoplasm, nucleus.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project MSH6 has gain in 2 cell-lines, loss in 2 cell-lines and no signal in 1001 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: A549, K_562, SN12C

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: SU-DHL-5, WSU-FSCCL, TK

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: NHLF, HeLa-S3, MCF-7

(see details)

3D Structures


For MSH6 there are:
7 structures (7 chains) solved
3 are solved in complex with at least one small molecule ligand



(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


MSH6 has been screened with compounds ( bioactivities). (see details)