Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA.
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.
Obmolova
G
G
Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ban
C
C
Hsieh
P
P
Yang
W
W
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D020137:Base Pair Mismatch; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004260:DNA Repair; D004269:DNA, Bacterial / Q000737:chemistry* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D029968:Escherichia coli Proteins; D046911:Macromolecular Substances; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D051719:MutS DNA Mismatch-Binding Protein; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes; D011485:Protein Binding; D011487:Protein Conformation; D013824:Thermus / Q000235:genetics
D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D046911:Macromolecular Substances; D009692:Nucleic Acid Heteroduplexes; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli