Structure and function of mismatch repair proteins.
DNA mismatch repair is required for maintaining genomic stability and is highly conserved from prokaryotes to eukaryotes. Errors made during DNA replication, such as deletions, insertions and mismatched basepairs, are substrates for mismatch repair. Mismatch repair is strand-specific and targets only the newly synthesized daughter strand. To initiate mismatch repair in Escherichia coli, three proteins are essential, MutS, for mismatch recognition, MutH, for introduction of a nick in the target strand, and MutL, for mediating the interactions between MutH and MutS. Homologues of MutS and MutL important for mismatch repair have been found in nearly all organisms. Mutations in MutS and MutL homologues have been linked to increased cancer susceptibility in both mice and humans. Here, we review the crystal structures of the MutH endonuclease, a conserved ATPase fragment of MutL (LN40), and complexes of LN40 with various nucleotides. Based on the crystal structure, the active site of MutH has been identified and an evolutionary relationship between MutH and type II restriction endonucleases established. Recent crystallographic and biochemical studies have revealed that MutL operates as a molecular switch with its interactions with MutH and MutS regulated by ATP binding and hydrolysis. These crystal structures also shed light on the general mechanism of mismatch repair and the roles of Mut proteins in preventing mutagenesis.
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Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. wei.yang@nih.gov
D000251:Adenosine Triphosphatases; D000255:Adenosine Triphosphate / Q000502:physiology; D000494:Allosteric Regulation; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000502:physiology; D020137:Base Pair Mismatch; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018360:Crystallography, X-Ray; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000502:physiology; D015252:Deoxyribonucleases, Type II Site-Specific / Q000737:chemistry / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000737:chemistry* / Q000502:physiology; D004926:Escherichia coli / Q000201:enzymology* / Q000235:genetics; D029968:Escherichia coli Proteins; D019143:Evolution, Molecular; D006801:Humans; D006868:Hydrolysis; D046911:Macromolecular Substances; D008274:Magnesium / Q000502:physiology; D051379:Mice; D008958:Models, Molecular; D000070956:MutL Proteins; D051719:MutS DNA Mismatch-Binding Protein; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D046911:Macromolecular Substances; C074770:MutL protein, E coli; D000255:Adenosine Triphosphate; D004706:Endodeoxyribonucleases; C059682:methyl-directed mismatch repair protein, E coli; C025630:CAGCTG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific; D000251:Adenosine Triphosphatases; D000070956:MutL Proteins; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli; D045643:DNA Repair Enzymes; D008274:Magnesium