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 susc eptibility. We have determined the crystal structure of a 40 kDa N-ter minal fragment of E. coli MutL that retains all of the conserved resid ues in the MutL family. The structure of MutL is homologous to that of an ATPase-containing fragment of DNA gyrase. We have demonstrated tha t MutL binds and hydrolyzes ATP to ADP and Pi. Mutations in the MutL f amily that cause deficiencies in DNA mismatch repair and a predisposit ion to cancer mainly occur in the putative ATP-binding site. We provid e evidence that the flexible, yet conserved, loops surrounding this AT P-binding site undergo conformational changes upon ATP hydrolysis ther eby modulating interactions between MutL and other components of the r epair machinery.