Nucleic Acids Research Advance Access originally published online on November 28, 2006
Nucleic Acids Research 2006 34(22):6574-6586; doi:10.1093/nar/gkl944
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Nucleic Acids Research, 2006, Vol. 34, No. 22 6574-6586
© 2006 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Mutations in the MutS
interaction interface of MLH1 can abolish DNA mismatch repair
1 Klinik für Innere Medizin II, Gebäude 41 Kirrberger Straße, Universität des Saarlandes, D-66421 Homburg/Saar, Germany 2 Max Planck Institut für Informatik, Stuhlsatzenhausweg 85 D-66123 Saarbrücken, Germany 3 Institut für Biochemie (FB 08), Justus-Liebig-Universität Giessen D-35392 Giessen, Germany
*To whom correspondence should be addressed. Tel: +49 6841 16 23253; Fax: +49 6841 16 23570; Email: guido.plotz{at}uniklinik-saarland.de
Received June 29, 2006. Revised October 10, 2006. Accepted October 20, 2006.
MutL
, a heterodimer of MLH1 and PMS2, plays a central role in human DNA mismatch repair. It interacts ATP-dependently with the mismatch detector MutS and assembles and controls further repair enzymes. We tested if the interaction of MutL with DNA-bound MutS is impaired by cancer-associated mutations in MLH1, and identified one mutation (Ala128Pro) which abolished interaction as well as mismatch repair activity. Further examinations revealed three more residues whose mutation interfered with interaction. Homology modelling of MLH1 showed that all residues clustered in a small accessible surface patch, suggesting that the major interaction interface of MutL for MutS is located on the edge of an extensive ß-sheet that backs the MLH1 ATP binding pocket. Bioinformatic analysis confirmed that this patch corresponds to a conserved potential protein–protein interaction interface which is present in both human MLH1 and its E.coli homologue MutL. MutL could be site-specifically crosslinked to MutS from this patch, confirming that the bacterial MutL–MutS complex is established by the corresponding interface in MutL. This is the first study that identifies the conserved major MutL–MutS interaction interface in MLH1 and demonstrates that mutations in this interface can affect interaction and mismatch repair, and thereby can also contribute to cancer development.
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