"Mechanism of MutS searching for DNA mismatches and signaling repair."
Tessmer I, Yang Y, Zhai J, Du C, Hsieh P, Hingorani MM, Erie DA
DNA mismatch repair is initiated by the recognition of mismatches by MutS
proteins. The mechanism by which MutS searches for and recognizes
mismatches and subsequently signals repair remains poorly understood. We
used single-molecule analyses of atomic force microscopy images of
MutS-DNA complexes, coupled with biochemical assays, to determine the
distributions of conformational states, the DNA binding affinities, and
the ATPase activities of wild type and two mutants of MutS, with alanine
substitutions in the conserved Phe-Xaa-Glu mismatch recognition motif. We
find that on homoduplex DNA, the conserved Glu, but not the Phe,
facilitates MutS-induced DNA bending, whereas at mismatches, both Phe and
Glu promote the formation of an unbent conformation. The data reveal an
unusual role for the Phe residue in that it promotes the unbending, not
bending, of DNA at mismatch sites. In addition, formation of the specific
unbent MutS-DNA conformation at mismatches appears to be required for the
inhibition of ATP hydrolysis by MutS that signals initiation of repair.
These results provide a structural explanation for the mechanism by which
MutS searches for and recognizes mismatches and for the observed
phenotypes of mutants with substitutions in the Phe-Xaa-Glu motif.
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Last modification of this entry: Dec. 10, 2009
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