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J. Biol. Chem., Vol. 279, Issue 24, 24915-24918, June 11, 2004

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Identification of a Functional Switch for Actin Severing by Cytoskeletal Proteins^*

Narendra Kumar and Seema Khurana

From the Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Actin severing is vital for the organization of the actin cytoskeleton during cell motility. Severing of F-actin by the homologous proteins villin and gelsolin requires unphysiologically high calcium concentrations (20–200 µM). Here we demonstrate that high calcium releases an autoinhibited conformation in villin that is maintained by two low affinity calcium binding sites (aspartic acids 467 and 715) that interact with a cluster of basic residues in the S2 domain of villin. Mutation of either of these sites as well as tyrosine phosphorylation alters the conformation of villin resulting in a protein that can sever actin in nanomolar calcium. These results suggest that tyrosine phosphorylation rather than high calcium may be the mechanism by which villin and other related proteins sever actin in vivo.

Received for publication, March 11, 2004 , and in revised form, March 30, 2004.

^* This work was supported by grants from the American Digestive Health Foundation (Industry Research Scholar Award) and by NIDDK Grants DK-54755 and DK-65006 from the National Institutes of Health (to S. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4 and Table S1.

To whom correspondence should be addressed: University of Tennessee, Health Science Center, 894 Union Ave., Nash 402, Memphis, TN 38163. Tel.: 901-448-3410; Fax: 901-448-3505; E-mail: khurana{at}utmem.edu.

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