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J Biol Chem. 2012 Nov 30;287(49):41232-44. doi: 10.1074/jbc.M112.402495. Epub 2012 Oct 8.

Engineered disulfide-forming amino acid substitutions interfere with a conformational change in the mismatch recognition complex Msh2-Msh6 required for mismatch repair.

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  • 1Ludwig Institute for Cancer Research, Department of Medicine, Moores-University of California San Diego Cancer Center, and Institute of Genomic Medicine, University of California School of Medicine, San Diego, La Jolla, California 92093-0669, USA.


ATP binding causes the mispair-bound Msh2-Msh6 mismatch recognition complex to slide along the DNA away from the mismatch, and ATP is required for the mispair-dependent interaction between Msh2-Msh6 and Mlh1-Pms1. It has been inferred from these observations that ATP induces conformational changes in Msh2-Msh6; however, the nature of these conformational changes and their requirement in mismatch repair are poorly understood. Here we show that ATP induces a conformational change within the C-terminal region of Msh6 that protects the trypsin cleavage site after Msh6 residue Arg(1124). An engineered disulfide bond within this region prevented the ATP-driven conformational change and resulted in an Msh2-Msh6 complex that bound mispaired bases but could not form sliding clamps or bind Mlh1-Pms1. The engineered disulfide bond also reduced mismatch repair efficiency in vivo, indicating that this ATP-driven conformational change plays a role in mismatch repair.

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