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Originally published In Press as doi:10.1074/jbc.M108787200 on April 10, 2002

J. Biol. Chem., Vol. 277, Issue 24, 21810-21820, June 14, 2002
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Mutations within the hMLH1 and hPMS2 Subunits of the Human MutLalpha Mismatch Repair Factor Affect Its ATPase Activity, but Not Its Ability to Interact with hMutSalpha *

Markus Räschle, Patrick Dufner, Giancarlo Marra, and Josef JiricnyDagger

From the Institute of Medical Radiobiology, August Forel-Strasse 7, Zürich 8008, Switzerland

The MutL family of mismatch repair proteins belongs to the GHKL class of ATPases, which contains also type II topoisomerases, HSP90, and histidine kinases. The nucleotide binding domains of these polypeptides are highly conserved, but this similarity has failed to help us understand the biological role of the ATPase activity of the MutL proteins in mismatch repair. hMutLalpha is a heterodimer of the human MutL homologues hMLH1 and hPMS2, and we decided to exploit its asymmetry to study this function. We now show that although the two subunits contribute differently to the ATPase activity of the heterodimer, hMutLalpha variants in which one subunit was able to bind but not hydrolyze ATP displayed similarly reduced mismatch repair activities in vitro. In contrast, variants in which either subunit was unable to bind the nucleotide were inactive. Mutation of the catalytic sites of both subunits abolished repair without altering the ability of these peptides to interact with one another. Since the binding of the nucleotide in hMutLalpha was not required for the formation of ternary complexes with the mismatch recognition factor hMutSalpha bound to a heteroduplex substrate, we propose that the ATPase activity of hMutLalpha is required downstream from this process.

* This work was supported in part by the Swiss National Science Foundation.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.

This study constitutes in part the Ph.D. projects of M. R. and P. D., carried out in collaboration with the Institute of Cell Biology of the Swiss Federal Institute of Technology in Zürich.

Dagger To whom correspondence should be addressed. Tel.: 41-1-634-8910; Fax: 41-1-634-8904; E-mail: jiricny@imr.unizh.ch.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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