The coordinated functions of the E. coli MutS and MutL proteins in mismatch repair.
The Escherichia coli MutS and MutL proteins have been conserved throughout evolution, although their combined functions in mismatch repair (MMR) are poorly understood. We have used biochemical and genetic studies to ascertain a physiologically relevant mechanism for MMR. The MutS protein functions as a regional lesion sensor. ADP-bound MutS specifically recognizes a mismatch. Repetitive rounds of mismatch-provoked ADP-->ATP exchange results in the loading of multiple MutS hydrolysis-independent sliding clamps onto the adjoining duplex DNA. MutL can only associate with ATP-bound MutS sliding clamps. Interaction of the MutS-MutL sliding clamp complex with MutH triggers ATP binding by MutL that enhances the endonuclease activity of MutH. Additionally, MutL promotes ATP binding-independent turnover of idle MutS sliding clamps. These results support a model of MMR that relies on two dynamic and redundant ATP-regulated molecular switches.
Acharya
Samir
S
Genetics and Molecular Biology Program, Kimmel Cancer Center - BLSB 933, 233 S. 10th Street, Philadelphia, PA 19107, USA. s_acharya@lac.jci.tju.edu
Foster
Patricia L
PL
Brooks
Peter
P
Fishel
Richard
R
D000244:Adenosine Diphosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000255:Adenosine Triphosphate / Q000378:metabolism; D001426:Bacterial Proteins; D020137:Base Pair Mismatch / Q000235:genetics*; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D008958:Models, Molecular; D000070956:MutL Proteins; D051719:MutS DNA Mismatch-Binding Protein; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics
D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; C074770:MutL protein, E coli; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D000070956:MutL Proteins; D051719:MutS DNA Mismatch-Binding Protein; C497175:MutS protein, E coli