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The Cell Adhesion Laboratory

Research

Cell migration and morphogenesis relies on the cell's ability to form specific contacts with its neighbors (adherens junctions) or with the extracellular matrix (focal adhesions). These contacts are directed by integrin receptors, which are unique in provoking both inside-out and outside-in signaling pathways. Integrin receptor activation triggers the rapid reorganization of the actin cytoskeleton and in focal adhesions this relies on the function of talin and vinculin, which were thought to act as scaffolds that bridge integrin receptors to the actin cytoskeleton. We have taken a structural approach to determine the roles of talin and vinculin. Surprisingly, our studies have revealed that these proteins function as direct signaling effectors that, by undergoing dramatic changes in their structures, transmit the outside-in signal.

Talin contains a globular head domain, which binds to integrin receptors, and a central rod domain that binds to other cytoskeletal proteins, in particular vinculin. Vinculin also contains a head (Vh) domain but this interacts, in an intramolecular fashion, with its tail (Vt) domain, and this interaction holds vinculin in its inactive conformation. Thus, vinculin activation involves structural changes that disrupt the Vh-Vt interaction, and the conventional model has suggested that acidic phospholipids were the "scissors" that severed this interaction by binding to Vt. Our studies solving the structures of the inactive Vh:Vt complex, and of talin's vinculin binding site (VBS) bound to the Vh domain, have now redefined how vinculin is activated in focal adhesions. Talin is now rather revealed as a direct activator of vinculin, as binding of talin's VBS to Vh disrupts the Vh-Vt interaction, by provoking dramatic alterations in the structure of the N-terminal helical bundle of Vh, by a process we have coined helical bundle conversion. Furthermore, all three of talin VBSs bind to Vh and activate vinculin in a mutually exclusive manner. These findings support a model whereby binding of one talin molecule would activate three molecules of vinculin, and this amplification explains how outside-in integrin signaling induces such rapid changes in the actin cytoskeleton.

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