"ATP increases the affinity between MutS ATPase domains. Implications for
ATP hydrolysis and conformational changes."
Lamers MH, Georgijevic D, Lebbink JH, Winterwerp HH, Agianian B, de Wind N, Sixma TK
MutS is the key protein of the Escherichia coli DNA mismatch repair
system. It recognizes mispaired and unpaired bases and has intrinsic
ATPase activity. ATP binding after mismatch recognition by MutS serves as
a switch that enables MutL binding and the subsequent initiation of
mismatch repair. However, the mechanism of this switch is poorly
understood. We have investigated the effects of ATP binding on the MutS
structure. Crystallographic studies of ATP-soaked crystals of MutS show a
trapped intermediate, with ATP in the nucleotide-binding site. Local
rearrangements of several residues around the nucleotide-binding site
suggest a movement of the two ATPase domains of the MutS dimer toward each
other. Analytical ultracentrifugation experiments confirm such a
rearrangement, showing increased affinity between the ATPase domains upon
ATP binding and decreased affinity in the presence of ADP. Mutations of
specific residues in the nucleotide-binding domain reduce the dimer
affinity of the ATPase domains. In addition, ATP-induced release of DNA is
strongly reduced in these mutants, suggesting that the two activities are
coupled. Hence, it seems plausible that modulation of the affinity between
ATPase domains is the driving force for conformational changes in the MutS
dimer. These changes are driven by distinct amino acids in the
nucleotide-binding site and form the basis for long-range interactions
between the ATPase domains and DNA-binding domains and subsequent binding
of MutL and initiation of mismatch repair.
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Last modification of this entry: Dec. 10, 2009
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