title: Structural basis for vinculin activation at sites of cell adhesion.
abstract: 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.
authors.affiliation: Program on Cell Adhesion, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Constantina
authors.initials: C
authors.lastname: Bakolitsa
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Cohen
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Bankston
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Bobkov
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Cadwell
authors.forename: Lisa
authors.initials: L
authors.lastname: Jennings
authors.forename: David R
authors.initials: DR
authors.lastname: Critchley
authors.forename: Susan W
authors.initials: SW
authors.lastname: Craig
authors.forename: Robert C
authors.initials: RC
authors.lastname: Liddington
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D002152:Calorimetry, Differential Scanning; D002448:Cell Adhesion; D002645:Chickens; D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D016596:Vinculin / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D016596:Vinculin