Abstract
DNA mismatch repair is critical for increasing replication fidelity in organisms ranging from bacteria to humans. MutS protein, a member of the ABC ATPase superfamily, recognizes mispaired and unpaired bases in duplex DNA and initiates mismatch repair. Mutations in human MutS genes cause a predisposition to hereditary nonpolyposis colorectal cancer as well as sporadic tumours. Here we report the crystal structures of a MutS protein and a complex of MutS with a heteroduplex DNA containing an unpaired base. The structures reveal the general architecture of members of the MutS family, an induced-fit mechanism of recognition between four domains of a MutS dimer and a heteroduplex kinked at the mismatch, a composite ATPase active site composed of residues from both MutS subunits, and a transmitter region connecting the mismatch-binding and ATPase domains. The crystal structures also provide a molecular framework for understanding hereditary nonpolyposis colorectal cancer mutations and for postulating testable roles of MutS.
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Acknowledgements
We thank I. Biswas for TAQ MutS expression vectors; Z. Dauter and C. Ogata for synchrotron beamline support; G. Poy for oligonucleotide synthesis; Q. Zhao for assistance in data collection; E. Alani, D. Camerini-Otero, R. Craigie, M. Gellert, M. Junop, T. Kunkel, D. Leahy, K. Mizuuchi, H. Nash and M. Radman for discussions and comments on the manuscript.
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Obmolova, G., Ban, C., Hsieh, P. et al. Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA. Nature 407, 703–710 (2000). https://doi.org/10.1038/35037509
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DOI: https://doi.org/10.1038/35037509
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