Structural basis for vinculin activation at sites of cell adhesion

Nature. 2004 Jul 29;430(6999):583-6. doi: 10.1038/nature02610. Epub 2004 Jun 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Binding Sites
  • Calorimetry, Differential Scanning
  • Cell Adhesion
  • Chickens
  • Crystallography, X-Ray
  • Ligands
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Vinculin / chemistry*
  • Vinculin / metabolism*


  • Ligands
  • Vinculin

Associated data

  • PDB/1DOV
  • PDB/1H6G
  • PDB/1QKR
  • PDB/1ST6