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Originally published In Press as doi:10.1074/jbc.C100450200 on October 18, 2001

J. Biol. Chem., Vol. 276, Issue 49, 46225-46229, December 7, 2001
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Asymmetric Recognition of DNA Local Distortion
STRUCTURE-BASED FUNCTIONAL STUDIES OF EUKARYOTIC Msh2-Msh6*

Karin DrotschmannDagger , Wei Yang§, Floyd E. Brownewell||, Eric T. Kool||, and Thomas A. KunkelDagger ||**

From the Dagger  Laboratory of Molecular Genetics and  Laboratory of Structural Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, the § Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, and the || Department of Chemistry, Stanford University, Stanford, California 94305

Crystal structures of bacterial MutS homodimers bound to mismatched DNA reveal asymmetric interactions of the two subunits with DNA. A phenylalanine and glutamate of one subunit make mismatched base-specific interactions, and residues of both subunits contact the DNA backbone surrounding the mismatched base, but asymmetrically. A number of amino acids in MutS that contact the DNA are conserved in the eukaryotic Msh2-Msh6 heterodimer. We report here that yeast strains with amino acids substituted for residues inferred to interact with the DNA backbone or mismatched base have elevated spontaneous mutation rates consistent with defective mismatch repair. Purified Msh2-Msh6 with substitutions in the conserved Phe337 and Glu339 in Msh6 thought to stack or hydrogen bond, respectively, with the mismatched base do have reduced DNA binding affinity but normal ATPase activity. Moreover, wild-type Msh2-Msh6 binds with lower affinity to mismatches with thymine replaced by difluorotoluene, which lacks the ability to hydrogen bond. The results suggest that yeast Msh2-Msh6 interacts asymmetrically with the DNA through base-specific stacking and hydrogen bonding interactions and backbone contacts. The importance of these contacts decreases with increasing distance from the mismatch, implying that interactions at and near the mismatch are important for binding in a kinked DNA conformation.

* This work was supported in part by National Institutes of Health Grant GM52956 (to E. T. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Laboratory of Structural Biology, NIEHS, NIH, 111 T. W. Alexander Dr., P. O. Box 12233, Research Triangle Park, NC 27709. Tel.: 919-541-2644; Fax: 919-541-7613; E-mail: kunkel@niehs.nih.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.