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J. Biol. Chem., Vol. 281, Issue 39, 29148-29154, September 29, 2006

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Insights into Allosteric Control of Vinculin Function from Its Large Scale Conformational Dynamics^*

Yiwen Chen and Nikolay V. Dokholyan¹

From the Department of Physics and Astronomy and the Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599

Vinculin is an important constituent of both cell-cell and cell-matrix junctions, where it plays crucial roles in the regulation of cell adhesion and migration. When activated, it mediates the linkage between cadherins (cell-cell) or integrins (cell-matrix) and the actin cytoskeleton through interactions with various proteins. The activation of vinculin requires structural conversions from an autoinhibited conformation to the "open" conformations in which the occluded binding sites of its different ligands become exposed, while the structural dynamics underlying the vinculin activation remains largely unknown. Here we report the first computational study of large scale conformational dynamics of full-length vinculin. We find that the "holding" and "releasing" motions between vinculin tail and pincer-like structure formed by first three domains of vinculin are the dominant motions near the native state of vinculin, indicating that an inherent flexibility of vinculin has a large influence on its allostery. We also find a cooperative dissociation between the head and tail domains of vinculin with increasing temperature in both thermodynamic and kinetic simulations, implying that vinculin may function as an allosteric switch in response to external signals. We show that the kinetics of vinculin unfolding exhibits specific sequential patterns, suggesting that a sophisticated interplay between domains may synergistically contribute to vinculin activation. We further find that the interaction between vinculin-binding site peptide from talin and vinculin significantly destabilizes the intramolecular head-tail interactions, suggesting a direct role of talin binding in vinculin activation.

Received for publication, June 8, 2006

^* This work was supported in part by Muscular Dystrophy Association Grant MDA3720, American Heart Association Grant 0665361U, and North Carolina Biotechnology Center Grant 2006-MRG-1107 (to N. V. D.). 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.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-843-2513; Fax: 919-966-2852; E-mail: dokh{at}med.unc.edu.

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