1. Program on Cell Adhesion, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
2. Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
3. Department of Biochemistry, University of Leicester, Leicester LE1 7RH, UK

Correspondence to: Robert C. Liddington¹ Email: rlidding@burnham.org
The atomic coordinates have been deposited in the PDB under accession codes 1ST6 (coordinates) and r1ST6sf (structure factors).

Abstract

Vinculin is a highly conserved intracellular protein with a crucial role in the maintenance and regulation of cell adhesion and migration^{1, 2, 3}. In the cytosol, vinculin adopts a default autoinhibited conformation^{4, 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.

1. Program on Cell Adhesion, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
2. Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
3. Department of Biochemistry, University of Leicester, Leicester LE1 7RH, UK

Correspondence to: Robert C. Liddington¹ Email: rlidding@burnham.org
The atomic coordinates have been deposited in the PDB under accession codes 1ST6 (coordinates) and r1ST6sf (structure factors).

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.