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Molecular and Cellular Biology, July 2005, p. 6112-6122, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6112-6122.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Structural Dynamics of {alpha}-Actinin-Vinculin Interactions{dagger}

Philippe R. J. Bois,1 Robert A. Borgon,2,3 Clemens Vonrhein,4 and Tina Izard2*

Departments of Biochemistry,1 Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee,2 Department of Molecular Sciences, The University of Tennessee Health Science Center, Memphis, Tennessee,3 Global Phasing Limited, Sheraton House, Castle Park, Cambridge, United Kingdom4

Received 7 October 2004/ Returned for modification 28 October 2004/ Accepted 11 April 2005

{alpha}-Actinin and vinculin orchestrate reorganization of the actin cytoskeleton following the formation of adhesion junctions. {alpha}-Actinin interacts with vinculin through the binding of an {alpha}-helix ({alpha}VBS) present within the R4 spectrin repeat of its central rod domain to vinculin's N-terminal seven-helical bundle domain (Vh1). The Vh1:{alpha}VBS structure suggests that {alpha}VBS first unravels from its buried location in the triple-helical R4 repeat to allow it to bind to vinculin. {alpha}VBS binding then induces novel conformational changes in the N-terminal helical bundle of Vh1, which disrupt its intramolecular association with vinculin's tail domain and which differ from the alterations in Vh1 provoked by the binding of talin. Surprisingly, {alpha}VBS binds to Vh1 in an inverted orientation compared to the binding of talin's VBSs to vinculin. Importantly, the binding of {alpha}VBS and talin's VBSs to vinculin's Vh1 domain appear to also trigger distinct conformational changes in full-length vinculin, opening up distant regions that are buried in the inactive molecule. The data suggest a model where vinculin's Vh1 domain acts as a molecular switch that undergoes distinct structural changes provoked by talin and {alpha}-actinin binding in focal adhesions versus adherens junctions, respectively.

* Corresponding author. Mailing address: Department of Hematology-Oncology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, TN 38105. Phone: (901) 495-3996. Fax: (901) 495-4981. E-mail: tina.izard{at}stjude.org.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, July 2005, p. 6112-6122, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6112-6122.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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