Crystal structure and ATPase activity of MutL: implications for DNA repair and mutagenesis.
MutL and its homologs are essential for DNA mismatch repair. Mutations in genes encoding human homologs of MutL cause multiorgan cancer susceptibility. We have determined the crystal structure of a 40 kDa N-terminal fragment of E. coli MutL that retains all of the conserved residues in the MutL family. The structure of MutL is homologous to that of an ATPase-containing fragment of DNA gyrase. We have demonstrated that MutL binds and hydrolyzes ATP to ADP and Pi. Mutations in the MutL family that cause deficiencies in DNA mismatch repair and a predisposition to cancer mainly occur in the putative ATP-binding site. We provide evidence that the flexible, yet conserved, loops surrounding this ATP-binding site undergo conformational changes upon ATP hydrolysis thereby modulating interactions between MutL and other components of the repair machinery.
Ban
C
C
Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Yang
W
W
D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology; D018360:Crystallography, X-Ray; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004789:Enzyme Activation; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000070956:MutL Proteins; D016296:Mutagenesis; D020653:Peptide Elongation Factor G; D010445:Peptide Elongation Factors / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D011487:Protein Conformation
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D018841:HSP90 Heat-Shock Proteins; C074770:MutL protein, E coli; D020653:Peptide Elongation Factor G; D010445:Peptide Elongation Factors; D010446:Peptide Fragments; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D004706:Endodeoxyribonucleases; C059682:methyl-directed mismatch repair protein, E coli; D000251:Adenosine Triphosphatases; D000070956:MutL Proteins; D004250:DNA Topoisomerases, Type II; D045643:DNA Repair Enzymes