8AG6

human MutSalpha (MSH2/MSH6) binding to DNA with a GT mismatch

Summary for 8AG6

• Entry DOI: 10.2210/pdb8ag6/pdb
• EMDB information: 15417 15518 15519
• Descriptor: DNA mismatch repair protein Msh2, DNA mismatch repair protein Msh6, DNA (50-MER), ... (6 entities in total)
• Functional Keywords: dna mismatch repair, mmr, mutsa, lynch syndrome, dna binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 294902.44

Authors

Bruekner, S.R.,Sixma, T.K. (deposition date: 2022-07-19, release date: 2023-01-25, Last modification date: 2024-07-24)

Primary citation

Bruekner, S.R.,Pieters, W.,Fish, A.,Liaci, A.M.,Scheffers, S.,Rayner, E.,Kaldenbach, D.,Drost, L.,Dekker, M.,van Hees-Stuivenberg, S.,Delzenne-Goette, E.,de Konink, C.,Houlleberghs, H.,Dubbink, H.J.,AlSaegh, A.,de Wind, N.,Forster, F.,Te Riele, H.,Sixma, T.K.
Unexpected moves: a conformational change in MutS alpha enables high-affinity DNA mismatch binding.
Nucleic Acids Res., 51:1173-1188, 2023

PubMed Abstract: The DNA mismatch repair protein MutSα recognizes wrongly incorporated DNA bases and initiates their correction during DNA replication. Dysfunctions in mismatch repair lead to a predisposition to cancer. Here, we study the homozygous mutation V63E in MSH2 that was found in the germline of a patient with suspected constitutional mismatch repair deficiency syndrome who developed colorectal cancer before the age of 30. Characterization of the mutant in mouse models, as well as slippage and repair assays, shows a mildly pathogenic phenotype. Using cryogenic electron microscopy and surface plasmon resonance, we explored the mechanistic effect of this mutation on MutSα function. We discovered that V63E disrupts a previously unappreciated interface between the mismatch binding domains (MBDs) of MSH2 and MSH6 and leads to reduced DNA binding. Our research identifies this interface as a 'safety lock' that ensures high-affinity DNA binding to increase replication fidelity. Our mechanistic model explains the hypomorphic phenotype of the V63E patient mutation and other variants in the MBD interface.

PubMed: 36715327
DOI: 10.1093/nar/gkad015

Experimental method

ELECTRON MICROSCOPY (2.8 Å)