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Related Experiment Videos

Solution structure of human cofilin: actin binding, pH sensitivity, and relationship to actin-depolymerizing factor.

Brian J Pope1, Karen M Zierler-Gould, Ronald Kühne

  • 1Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom.

The Journal of Biological Chemistry
|November 25, 2003
PubMed
Summary
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Human actin-depolymerizing factor (ADF) and cofilin are pH-sensitive proteins. Structural differences, particularly at the F-actin-binding site, explain ADF

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Background:

  • Human actin-depolymerizing factor (ADF) and cofilin are essential actin-binding proteins.
  • Both proteins exhibit pH sensitivity and depolymerize actin filaments.
  • Despite high sequence identity (72%), ADF shows significantly higher depolymerizing activity than cofilin at pH 8.

Purpose of the Study:

  • To elucidate the structural basis for the differential biochemical activities of human ADF and cofilin.
  • To understand the molecular mechanisms underlying the pH sensitivity of these actin-depolymerizing proteins.

Main Methods:

  • Nuclear magnetic resonance (NMR) spectroscopy was used to determine the structure of human cofilin.
  • Comparative structural analysis of human cofilin and ADF.

Related Experiment Videos

  • Site-directed mutagenesis (S3D, K96Q) and chemical shift perturbation studies to map actin-binding sites and pH-sensitive residues.

    • Main Results:

    • Key sequence differences between ADF and cofilin correlate with unique structural features in the F-actin-binding site.
    • Cofilin possesses a C-terminal beta-strand absent in ADF, altering the environment of Lys96, crucial for F-actin binding.
    • A conserved salt bridge (His133-Asp98/Glu98) likely mediates pH sensitivity.
    • Residues 133-138 in beta5 are implicated in G-actin binding, F-actin binding, and pH sensitivity, acting as a bridge between these sites.

    Conclusions:

    • Structural variations, particularly in the F-actin-binding region and involving specific residues like Lys96, explain the distinct activities of ADF and cofilin.
    • The conserved salt bridge involving His133 and Asp98/Glu98 is critical for the pH-dependent function of both proteins.
    • Strand beta5 plays a pivotal role in integrating actin binding and pH responsiveness in ADF/cofilin.