English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair

Plotz, G., Welsch, C., Giron-Monzon, L., Friedhoff, P., Albrecht, M., Piiper, A., et al. (2006). Mutations in the MutSalpha interaction interface of MLH1 can abolish DNA mismatch repair. Nucleic Acids Research, 34, 6574-6586.

Item is

Files

show Files

Locators

show

Creators

show
hide
 Creators:
Plotz, Guido, Author
Welsch, Christoph1, Author           
Giron-Monzon, Luis, Author
Friedhoff, Peter, Author
Albrecht, Mario1, Author           
Piiper, Albrecht, Author
Biondi, Ricardo M.2, Author
Lengauer, Thomas1, Author           
Zeuzem, Stefan, Author
Raedle, Jochen, Author
Affiliations:
1Computational Biology and Applied Algorithmics, MPI for Informatics, Max Planck Society, ou_40046              
2Max Planck Society, ou_persistent13              

Content

show
hide
Free keywords: -
 Abstract: 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.

Details

show
hide
Language(s): eng - English
 Dates: 2007-02-212006
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 314628
Other: Local-ID: C125673F004B2D7B-BE71BD82A60A15E8C125723700639C8E-Albrecht2006f
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Nucleic Acids Research
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 34 Sequence Number: - Start / End Page: 6574 - 6586 Identifier: -