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Structure paper

TitleThe selection process of licensing a DNA mismatch for repair.
Journal, issue, pagesNat Struct Mol Biol, Vol. 28, Issue 4, Page 373-381, Year 2021
Publish dateApr 5, 2021
AuthorsRafael Fernandez-Leiro / Doreth Bhairosing-Kok / Vladislav Kunetsky / Charlie Laffeber / Herrie H Winterwerp / Flora Groothuizen / Alexander Fish / Joyce H G Lebbink / Peter Friedhoff / Titia K Sixma / Meindert H Lamers /
PubMed AbstractDNA mismatch repair detects and removes mismatches from DNA by a conserved mechanism, reducing the error rate of DNA replication by 100- to 1,000-fold. In this process, MutS homologs scan DNA, ...DNA mismatch repair detects and removes mismatches from DNA by a conserved mechanism, reducing the error rate of DNA replication by 100- to 1,000-fold. In this process, MutS homologs scan DNA, recognize mismatches and initiate repair. How the MutS homologs selectively license repair of a mismatch among millions of matched base pairs is not understood. Here we present four cryo-EM structures of Escherichia coli MutS that provide snapshots, from scanning homoduplex DNA to mismatch binding and MutL activation via an intermediate state. During scanning, the homoduplex DNA forms a steric block that prevents MutS from transitioning into the MutL-bound clamp state, which can only be overcome through kinking of the DNA at a mismatch. Structural asymmetry in all four structures indicates a division of labor between the two MutS monomers. Together, these structures reveal how a small conformational change from the homoduplex- to heteroduplex-bound MutS acts as a licensing step that triggers a dramatic conformational change that enables MutL binding and initiation of the repair cascade.
External linksNat Struct Mol Biol / PubMed:33820992
MethodsEM (single particle)
Resolution3.9 - 6.9 Å
Structure data

EMDB-11791, PDB-7ai5:
MutS in Scanning state
Method: EM (single particle) / Resolution: 4.4 Å

EMDB-11792, PDB-7ai6:
MutS in mismatch bound state
Method: EM (single particle) / Resolution: 6.9 Å

EMDB-11793, PDB-7ai7:
MutS in Intermediate state
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-11794, PDB-7aib:
MutS-MutL in clamp state
Method: EM (single particle) / Resolution: 4.7 Å

EMDB-11795, PDB-7aic:
MutS-MutL in clamp state (kinked clamp domain)
Method: EM (single particle) / Resolution: 5.0 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

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

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

Source
  • escherichia coli (E. coli)
  • synthetic construct (others)
  • escherichia coli (strain k12) (bacteria)
KeywordsDNA BINDING PROTEIN / DNA Mismatch Repair MutS

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