Vinculin activation by talin through helical bundle conversion

Tina Izard (), Gwyndaf Evans, Robert A. Borgon, Christina L. Rush, Gerard Bricogne and Philippe R. J. Bois
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Tina Izard: St Jude Children's Research Hospital
Gwyndaf Evans: Global Phasing Limited
Robert A. Borgon: St Jude Children's Research Hospital
Christina L. Rush: St Jude Children's Research Hospital
Gerard Bricogne: Global Phasing Limited
Philippe R. J. Bois: St Jude Children's Research Hospital

Nature, 2004, vol. 427, issue 6970, 171-175

Abstract: Abstract Vinculin is a conserved component and an essential regulator of both cell–cell (cadherin-mediated) and cell–matrix (integrin–talin-mediated focal adhesions) junctions, and it anchors these adhesion complexes to the actin cytoskeleton by binding to talin in integrin complexes or to α-actinin in cadherin junctions1,2,3. In its resting state, vinculin is held in a closed conformation through interactions between its head (Vh) and tail (Vt) domains4,5,6. The binding of vinculin to focal adhesions requires its association with talin. Here we report the crystal structures of human vinculin in its inactive and talin-activated states. Talin binding induces marked conformational changes in Vh, creating a novel helical bundle structure, and this alteration actively displaces Vt from Vh. These results, as well as the ability of α-actinin to also bind to Vh and displace Vt from pre-existing Vh–Vt complexes, support a model whereby Vh functions as a domain that undergoes marked structural changes that allow vinculin to direct cytoskeletal assembly in focal adhesions and adherens junctions. Notably, talin's effects on Vh structure establish helical bundle conversion as a signalling mechanism by which proteins direct cellular responses.

Date: 2004
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DOI: 10.1038/nature02281

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