title: The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gradia
authors.forename: S
authors.initials: S
authors.lastname: Acharya
authors.forename: R
authors.initials: R
authors.lastname: Fishel
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D018983:DNA Footprinting; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D006868:Hydrolysis; D046911:Macromolecular Substances; D051718:MutS Homolog 2 Protein; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; C094443:G-T mismatch-binding protein; D020662:Guanine Nucleotide Exchange Factors; D046911:Macromolecular Substances; D011506:Proteins; D011518:Proto-Oncogene Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D020558:GTP Phosphohydrolases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein