MutS/MutL crystal structure reveals that the MutS sliding clamp loads MutL onto DNA
- Netherlands Cancer Institute, Netherlands
- Justus-Liebig-University, Germany
- Erasmus Medical Center, Netherlands
- MRC Laboratory of Molecular Biology, United Kingdom
Abstract
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.
Article and author information
Author details
Reviewing Editor
- Leemor Joshua-Tor, Cold Spring Harbor Laboratory, United States
Version history
- Received: January 28, 2015
- Accepted: July 10, 2015
- Accepted Manuscript published: July 11, 2015 (version 1)
- Version of Record published: July 31, 2015 (version 2)
Copyright
© 2015, Groothuizen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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MutS/MutL crystal structure reveals that the MutS sliding clamp loads MutL onto DNA
eLife 4:e06744.
https://doi.org/10.7554/eLife.06744
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