Structural basis for vinculin activation at sites of cell adhesion

• Published in: Nature Vol. 430; no. 6999; pp. 583 - 586
• Main Authors: Liddington, Robert C, Bakolitsa, Constantina, Cohen, Daniel M, Bankston, Laurie A, Bobkov, Andrey A, Cadwell, Gregory W, Jennings, Lisa, Critchley, David R, Craig, Susan W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 29.07.2004; Nature Publishing Group
• Subjects: Adhesion; Allosteric Regulation; Amino acids; Animals; Binding Sites; Biochemistry; Biological and medical sciences; Calorimetry, Differential Scanning; Cell Adhesion; Cell interactions, adhesion; Cells; Chickens; Crystalline structure; Crystallography, X-Ray; Fundamental and applied biological sciences. Psychology; Ligands; Models, Molecular; Molecular and cellular biology; Molecular biophysics; Protein Binding; Protein Structure, Tertiary; Proteins; Structure in molecular biology; Structure-Activity Relationship; Thermodynamics; Vinculin - chemistry; Vinculin - metabolism; Cell cell interaction; Activation; Adhesion; Crystalline structure
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature02610

Vinculin is a highly conserved intracellular protein with a crucial role in the maintenance and regulation of cell adhesion and migration. In the cytosol, vinculin adopts a default autoinhibited conformation. 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.