MutS/MutL crystal structure reveals that the MutS sliding clamp loads MutL onto DNA

To avoid mutations in the genome, DNA replication is generally followed by DNA mismatch repair (MMR). MMR starts when a MutS homolog recognizes a mismatch and undergoes an ATP-dependent transformation to an elusive sliding clamp state. How this transient state promotes MutL homolog recruitment and a...

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Bibliographic Details
Published in:eLife 2015-07, Vol.4, p.e06744-e06744
Main Authors: Groothuizen, Flora S, Winkler, Ines, Cristóvão, Michele, Fish, Alexander, Winterwerp, Herrie H K, Reumer, Annet, Marx, Andreas D, Hermans, Nicolaas, Nicholls, Robert A, Murshudov, Garib N, Lebbink, Joyce H G, Friedhoff, Peter, Sixma, Titia K
Format: Article
Language:English
Subjects:
Adenosine Triphosphatases - chemistry
Adenosine Triphosphatases - metabolism
Bans
Biochemistry
Biophysics and Structural Biology
Cancer
Cell division
Chromatography
Colorectal cancer
Conformation
Crystal structure
Crystallography, X-Ray
Deoxyribonucleic acid
DNA
DNA - metabolism
DNA biosynthesis
DNA mismatch repair
DNA repair
Escherichia coli Proteins - chemistry
Escherichia coli Proteins - metabolism
Genes and Chromosomes
Genetic disorders
Genetic transformation
Genomes
Glycerol
human
Laboratories
Lynch syndrome
Mismatch repair
Models, Molecular
MutL Proteins
MutS DNA Mismatch-Binding Protein - chemistry
MutS DNA Mismatch-Binding Protein - metabolism
Protein Binding
Protein Conformation
Proteins
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Summary:To avoid mutations in the genome, DNA replication is generally followed by DNA mismatch repair (MMR). MMR starts when a MutS homolog recognizes a mismatch and undergoes an ATP-dependent transformation to an elusive sliding clamp state. How this transient state promotes MutL homolog recruitment and activation of repair is unclear. Here we present a crystal structure of the MutS/MutL complex using a site-specifically crosslinked complex and examine how large conformational changes lead to activation of MutL. The structure captures MutS in the sliding clamp conformation, where tilting of the MutS subunits across each other pushes DNA into a new channel, and reorientation of the connector domain creates an interface for MutL with both MutS subunits. Our work explains how the sliding clamp promotes loading of MutL onto DNA, to activate downstream effectors. We thus elucidate a crucial mechanism that ensures that MMR is initiated only after detection of a DNA mismatch.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.06744