Journal
EMBO JOURNAL
Volume 31, Issue 11, Pages 2528-2540Publisher
WILEY
DOI: 10.1038/emboj.2012.95
Keywords
DNA mismatch repair; MMR; MutS; protein conformational change; sliding clamp
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Funding
- American Cancer Society [RSG-10-048]
- NSF [MCB 1022203]
- NIH [GM08294, GM079480, F31 GM087096]
- Division Of Integrative Organismal Systems
- Direct For Biological Sciences [1022203] Funding Source: National Science Foundation
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MutS protein recognizes mispaired bases in DNA and targets them for mismatch repair. Little is known about the transient conformations of MutS as it signals initiation of repair. We have used single-molecule fluorescence resonance energy transfer (FRET) measurements to report the conformational dynamics of MutS during this process. We find that the DNA-binding domains of MutS dynamically interconvert among multiple conformations when the protein is free and while it scans homoduplex DNA. Mismatch recognition restricts MutS conformation to a single state. Steady-state measurements in the presence of nucleotides suggest that both ATP and ADP must be bound to MutS during its conversion to a sliding clamp form that signals repair. The transition from mismatch recognition to the sliding clamp occurs via two sequential conformational changes. These intermediate conformations of the MutS: DNA complex persist for seconds, providing ample opportunity for interaction with downstream proteins required for repair. The EMBO Journal (2012) 31, 2528-2540. doi: 10.1038/emboj.2012.95; Published online 13 April 2012
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