期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 19, 期 1, 页码 72-U91出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2175
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资金
- National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK036167, ZIADK036119, ZIADK036168] Funding Source: NIH RePORTER
DNA mismatch repair corrects replication errors, thus reducing mutation rates and microsatellite instability. Genetic defects in this pathway cause Lynch syndrome and various cancers in humans. Binding of a mispaired or unpaired base by bacterial MutS and eukaryotic MutS alpha is well characterized. We report here crystal structures of human MutS beta in complex with DNA containing insertion-deletion loops (IDL) of two, three, four or six unpaired nucleotides. In contrast to eukaryotic MutS alpha and bacterial MutS, which bind the base of a mismatched nucleotide, MutS beta binds three phosphates in an IDL. DNA is severely bent at the IDL; unpaired bases are flipped out into the major groove and partially exposed to solvent. A normal downstream base pair can become unpaired; a single unpaired base can thereby be converted to an IDL of two nucleotides and recognized by MutS beta. The C-terminal dimerization domains form an integral part of the MutS structure and coordinate asymmetrical ATP hydrolysis by Msh2 and Msh3 with mismatch binding to signal for repair.
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