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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-31260

Räschle, M; Dufner, P; Marra, G; Jiricny, J (2002). 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. Journal of Biological Chemistry, 277(24):21810-21820.

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Abstract

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.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
DDC:570 Life sciences; biology
Language:English
Date:2002
Deposited On:09 Jul 2010 10:36
Last Modified:07 Jul 2014 12:07
Publisher:American Society for Biochemistry and Molecular Biology
ISSN:0021-9258
Additional Information:This research was originally published in: Räschle, M; Dufner, P; Marra, G; Jiricny, J (2002). 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. Journal of Biological Chemistry, 277(24):21810-21820. © the American Society for Biochemistry and Molecular Biology.
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1074/jbc.M108787200
PubMed ID:11948175
Citations:Web of Science®. Times Cited: 66
Google Scholar™
Scopus®. Citation Count: 70

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