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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

12 Issues per year


IMPACT FACTOR 2016: 3.273

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1437-4315
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Volume 393, Issue 10 (Oct 2012)

Issues

Withaferin A binds covalently to the N-terminal domain of annexin A2

Gabriel Ozorowski
  • Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Christopher M. Ryan
  • Pasarow Mass Spectrometry Laboratory, NPI-Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90024-1759, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Julian P. Whitelegge
  • Pasarow Mass Spectrometry Laboratory, NPI-Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA 90024-1759, USA
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/ Hartmut Luecke
  • Corresponding author
  • Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA
  • Center for Biomembrane Systems, University of California, Irvine, CA 92697-3900, USA
  • Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA
  • Department of Computer Science, University of California, Irvine, CA 92697, USA
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  • Other articles by this author:
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Published Online: 2012-09-08 | DOI: https://doi.org/10.1515/hsz-2012-0184

Abstract

Annexin A2 (AnxA2), a 38-kDa member of the Ca2+-binding annexin family, has been implicated in numerous cancer pathways. Withaferin A (WithfA), a natural plant compound, has been reported previously to bind covalently to Cys133 of the AnxA2 core domain leading to a reduction of the invasive capabilities of cancer cells by altering their cytoskeleton. We show here that AnxA2 has an inhibitory effect on actin polymerization, and a modification with WithfA significantly increases this inhibitory role of AnxA2. Using mass spectrometry and single-site mutants, we localized the WithfA-AnxA2 interaction to the N-terminal domain of AnxA2 where WithfA binds covalently to Cys9. Whereas binding to F-actin filaments has been mapped to the C terminus of AnxA2, our results suggest that the N-terminal domain modified by WithfA may also play a role in the AnxA2-actin interaction. The binding of WithfA may regulate the AnxA2-mediated actin dynamics in two distinct ways: (i) the increase of F-actin bundling activity by the Anx2/p11 heterotetramer and (ii) the decrease of actin polymerization as a result of the increased affinity of AnxA2 to the barbed end of actin microfilaments. We demonstrate the susceptibility of Cys9 of AnxA2 to chemical modifications and exclude Cys133 as a binding site for WithfA.

Keywords: actin polymerization; annexin A2, covalent modification; mass spectrometry; Robert Huber; withaferin A

About the article

Corresponding author: Hartmut Luecke, Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA


Received: 2012-04-19

Accepted: 2012-07-12

Published Online: 2012-09-08

Published in Print: 2012-10-01


Citation Information: , ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2012-0184.

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©2012 by Walter de Gruyter Berlin Boston. Copyright Clearance Center

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