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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

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

Gabriel Ozorowski1 / Christopher M. Ryan2 / Julian P. Whitelegge2 / 1, 3, 4, 5

1Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA

2Pasarow 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

3Center for Biomembrane Systems, University of California, Irvine, CA 92697-3900, USA

4Department of Physiology and Biophysics, University of California, Irvine, CA 92697, USA

5Department of Computer Science, University of California, Irvine, CA 92697, USA

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

Citation Information: . Volume 393, Issue 10, Pages 1151–1163, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/hsz-2012-0184, September 2012

Publication History

Published Online:


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

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