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TitleUnexpected moves: a conformational change in MutSα enables high-affinity DNA mismatch binding.
Journal, issue, pagesNucleic Acids Res, Vol. 51, Issue 3, Page 1173-1188, Year 2023
Publish dateFeb 22, 2023
AuthorsSusanne R Bruekner / Wietske Pieters / Alexander Fish / A Manuel Liaci / Serge Scheffers / Emily Rayner / Daphne Kaldenbach / Lisa Drost / Marleen Dekker / Sandrine van Hees-Stuivenberg / Elly Delzenne-Goette / Charlotte de Konink / Hellen Houlleberghs / Hendrikus Jan Dubbink / Abeer AlSaegh / Niels de Wind / Friedrich Förster / Hein Te Riele / Titia K Sixma /
PubMed AbstractThe 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 ...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.
External linksNucleic Acids Res / PubMed:36715327 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 4.1 Å
Structure data

15417

8ag6

EMDB-15417, PDB-8ag6:
human MutSalpha (MSH2/MSH6) binding to DNA with a GT mismatch
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-15519: human MutSalpha (MSH2/MSH6) on DNA containing a GT mismatch in the presence of ADP
Method: EM (single particle) / Resolution: 4.1 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsDNA BINDING PROTEIN / DNA mismatch repair / MMR / MutSa / Lynch Syndrome

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