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J. Biol. Chem., Vol. 281, Issue 11, 7228-7236, March 17, 2006

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The Vinculin Binding Sites of Talin and -Actinin Are Sufficient to Activate Vinculin^*

Philippe R. J. Bois, Brendan P. O'Hara, Daniel Nietlispach^¶, John Kirkpatrick^¶, and Tina Izard¹

From the Departments of Biochemistry and Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, 38105 and the ^¶Department of Biochemistry, University of Cambridge, CB2 1GA Cambridge, United Kingdom

Vinculin regulates both cell-cell and cell-matrix junctions and anchors adhesion complexes to the actin cytoskeleton through its interactions with the vinculin binding sites of -actinin or talin. Activation of vinculin requires a severing of the intramolecular interactions between its N- and C-terminal domains, which is necessary for vinculin to bind to F-actin; yet how this occurs in cells is not resolved. We tested the hypothesis that talin and -actinin activate vinculin through their vinculin binding sites. Indeed, we show that these vinculin binding sites have a high affinity for full-length vinculin, are sufficient to sever the head-tail interactions of vinculin, and they induce conformational changes that allow vinculin to bind to F-actin. Finally, microinjection of these vinculin binding sites specifically targets vinculin in cells, disrupting its interactions with talin and -actinin and disassembling focal adhesions. In their native (inactive) states the vinculin binding sites of talin and -actinin are buried within helical bundles present in their central rod domains. Collectively, these results support a model where the engagement of adhesion receptors first activates talin or -actinin, by provoking structural changes that allow their vinculin binding sites to swing out, which are then sufficient to bind to and activate vinculin.

Received for publication, September 21, 2005 , and in revised form, November 16, 2005.

^* This work was supported by the National Institutes of Health Grant GM071596, the Cancer Center Support (CORE) Grant CA21765, and by the American Lebanese Syrian Associated Charities (ALSAC). 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 text and movies.

¹ To whom correspondence should be addressed: Cell Adhesion Laboratory, Dept. of Hematology-Oncology, St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN, 38105. Tel.: 901-495-3996; Fax: 901-495-4981; E-mail: tina.izard{at}stjude.org.

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