Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha.
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Sacho EJ, Kadyrov FA, Modrich P, Kunkel TA, Erie DA
Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha.
Mol Cell. 2008 Jan 18;29(1):112-21. doi: 10.1016/j.molcel.2007.10.030.
- PubMed ID
- 18206974 [ View in PubMed]
- Abstract
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.