Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha.

Published

Journal Article

MutL alpha, the heterodimeric eukaryotic MutL homolog, is required for DNA mismatch repair (MMR) in vivo. It has been suggested that conformational changes, modulated by adenine nucleotides, mediate the interactions of MutL alpha with other proteins in the MMR pathway, coordinating the recognition of DNA mismatches by MutS alpha and the activation of MutL alpha with the downstream events that lead to repair. Thus far, the only evidence for these conformational changes has come from X-ray crystallography of isolated domains, indirect biochemical analyses, and comparison to other members of the GHL ATPase family to which MutL alpha belongs. Using atomic force microscopy (AFM), coupled with biochemical techniques, we demonstrate that adenine nucleotides induce large asymmetric conformational changes in full-length yeast and human MutL alpha and that these changes are associated with significant increases in secondary structure. These data reveal an ATPase cycle in which sequential nucleotide binding, hydrolysis, and release modulate the conformational states of MutL alpha.

Full Text

Duke Authors

Cited Authors

  • Sacho, EJ; Kadyrov, FA; Modrich, P; Kunkel, TA; Erie, DA

Published Date

  • January 18, 2008

Published In

Volume / Issue

  • 29 / 1

Start / End Page

  • 112 - 121

PubMed ID

  • 18206974

Pubmed Central ID

  • 18206974

International Standard Serial Number (ISSN)

  • 1097-2765

Digital Object Identifier (DOI)

  • 10.1016/j.molcel.2007.10.030

Language

  • eng

Conference Location

  • United States