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J. Biol. Chem., Vol. 282, Issue 22, 16345-16354, June 1, 2007

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Escherichia coli MutS Tetramerization Domain Structure Reveals That Stable Dimers but Not Tetramers Are Essential for DNA Mismatch Repair in Vivo^*

From the Ludwig Institute for Cancer Research, Departments of Medicine and Cellular and Molecular Medicine and Cancer Center, University of California, San Diego School of Medicine, La Jolla, California 92093-0669

The Escherichia coli mispair-binding protein MutS forms dimers and tetramers in vitro, although the functional form in vivo is under debate. Here we demonstrate that the MutS tetramer is extended in solution using small angle x-ray scattering and the crystal structure of the C-terminal 34 amino acids of MutS containing the tetramer-forming domain fused to maltose-binding protein (MBP). Wild-type C-terminal MBP fusions formed tetramers and could bind MutS and MutS-MutL-DNA complexes. In contrast, D835R and R840E mutations predicted to disrupt tetrameric interactions only allowed dimerization of MBP. A chromosomal MutS truncation mutation eliminating the dimerization/tetramerization domain eliminated mismatch repair, whereas the tetramer-disrupting MutS D835R and R840E mutations only modestly affected MutS function. These results demonstrate that dimerization but not tetramerization of the MutS C terminus is essential for mismatch repair.

Received for publication, January 30, 2007 , and in revised form, March 29, 2007.

The atomic coordinates and structure factors (code 2ok2) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Grants GM50006 and CA92584. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ There are co-first authors.

² Supported as a Robert Black fellow of the Damon Runyon Cancer Research Foundation.

³ To whom correspondence should be addressed: Ludwig Institute for Cancer Research, Depts. of Medicine and Cellular and Molecular Medicine and Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Dr., La Jolla, CA 92093-0669. Tel.: 858-552-4920 (ext. 7804); Fax: 858-534-7750; E-mail: rkolodner{at}ucsd.edu.

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				R. D. Kolodner, M. L. Mendillo, and C. D. Putnam Coupling distant sites in DNA during DNA mismatch repair PNAS, August 7, 2007; 104(32): 12953 - 12954. [Full Text] [PDF]