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

Publication ,  Journal Article
Sacho, EJ; Kadyrov, FA; Modrich, P; Kunkel, TA; Erie, DA
Published in: Mol Cell
January 18, 2008

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.

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Published In

Mol Cell

DOI

ISSN

1097-2765

Publication Date

January 18, 2008

Volume

29

Issue

1

Start / End Page

112 / 121

Location

United States

Related Subject Headings

  • Saccharomyces cerevisiae Proteins
  • Saccharomyces cerevisiae
  • Protein Structure, Secondary
  • Protein Conformation
  • Protein Binding
  • MutL Proteins
  • MutL Protein Homolog 1
  • Models, Molecular
  • Mismatch Repair Endonuclease PMS2
  • Microscopy, Atomic Force
 

Citation

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Sacho, E. J., Kadyrov, F. A., Modrich, P., Kunkel, T. A., & Erie, D. A. (2008). Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha. Mol Cell, 29(1), 112–121. https://doi.org/10.1016/j.molcel.2007.10.030
Sacho, Elizabeth J., Farid A. Kadyrov, Paul Modrich, Thomas A. Kunkel, and Dorothy A. Erie. “Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha.Mol Cell 29, no. 1 (January 18, 2008): 112–21. https://doi.org/10.1016/j.molcel.2007.10.030.
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.
Sacho, Elizabeth J., et al. “Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha.Mol Cell, vol. 29, no. 1, Jan. 2008, pp. 112–21. Pubmed, doi:10.1016/j.molcel.2007.10.030.
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):112–121.
Journal cover image

Published In

Mol Cell

DOI

ISSN

1097-2765

Publication Date

January 18, 2008

Volume

29

Issue

1

Start / End Page

112 / 121

Location

United States

Related Subject Headings

  • Saccharomyces cerevisiae Proteins
  • Saccharomyces cerevisiae
  • Protein Structure, Secondary
  • Protein Conformation
  • Protein Binding
  • MutL Proteins
  • MutL Protein Homolog 1
  • Models, Molecular
  • Mismatch Repair Endonuclease PMS2
  • Microscopy, Atomic Force