Structural basis for vinculin activation at sites of cell adhesion

Constantina Bakolitsa, Daniel M. Cohen, Laurie A. Bankston, Andrey A. Bobkov, Gregory W. Cadwell, Lisa Jennings, David R. Critchley, Susan W. Craig and Robert C. Liddington ()
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Constantina Bakolitsa: The Burnham Institute
Daniel M. Cohen: Johns Hopkins University School of Medicine
Laurie A. Bankston: The Burnham Institute
Andrey A. Bobkov: The Burnham Institute
Gregory W. Cadwell: The Burnham Institute
Lisa Jennings: University of Leicester
David R. Critchley: University of Leicester
Susan W. Craig: Johns Hopkins University School of Medicine
Robert C. Liddington: The Burnham Institute

Nature, 2004, vol. 430, issue 6999, 583-586

Abstract: Abstract Vinculin is a highly conserved intracellular protein with a crucial role in the maintenance and regulation of cell adhesion and migration1,2,3. In the cytosol, vinculin adopts a default autoinhibited conformation4,5. On recruitment to cell–cell and cell–matrix adherens-type junctions, vinculin becomes activated and mediates various protein–protein interactions that regulate the links between F-actin and the cadherin and integrin families of cell-adhesion molecules. Here we describe the crystal structure of the full-length vinculin molecule (1,066 amino acids), which shows a five-domain autoinhibited conformation in which the carboxy-terminal tail domain is held pincer-like by the vinculin head, and ligand binding is regulated both sterically and allosterically. We show that conformational changes in the head, tail and proline-rich domains are linked structurally and thermodynamically, and propose a combinatorial pathway to activation that ensures that vinculin is activated only at sites of cell adhesion when two or more of its binding partners are brought into apposition.

Date: 2004
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DOI: 10.1038/nature02610

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