The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch

Cell. 1997 Dec 26;91(7):995-1005. doi: 10.1016/s0092-8674(00)80490-0.


The 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • DNA Footprinting
  • DNA Repair*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Eukaryotic Initiation Factor-2 / metabolism
  • GTP Phosphohydrolases / metabolism
  • Guanine Nucleotide Exchange Factors
  • Humans
  • Hydrolysis
  • Macromolecular Substances
  • MutS Homolog 2 Protein
  • Proteins / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*


  • DNA-Binding Proteins
  • Eukaryotic Initiation Factor-2
  • G-T mismatch-binding protein
  • Guanine Nucleotide Exchange Factors
  • Macromolecular Substances
  • Proteins
  • Proto-Oncogene Proteins
  • Adenosine Diphosphate
  • Adenosine Triphosphate
  • GTP Phosphohydrolases
  • MSH2 protein, human
  • MutS Homolog 2 Protein