The Human Mismatch Recognition Complex hMSH2-hMSH6 Functions as a Novel Molecular Switch

AbstractThe mechanism of DNA mismatch repair has been modeled upon biochemical studies of the E. coli DNA adenine methylation–instructed pathway where the initial recognition of mismatched nucleotides is performed by the MutS protein. MutS homologs (MSH) have been identified based on a highly conserved region containing a Walker-A adenine nucleotide binding motif. Here we show that adenine nucleotide binding and hydrolysis by the human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch. The hMSH2-hMSH6 complex is ON (binds mismatched nucleotides) in the ADP-bound form and OFF in the ATP-bound form. These results suggest a new model for the function of MutS proteins during mismatch repair in which the switch determines the timing of downstream events