Scripps Florida Logo

The Cell Adhesion Laboratory

Overview

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). Focal adhesions are directed by integrin receptors, which are unique in provoking both outside-in and inside-out signaling pathways. Integrin receptor activation triggers the rapid reorganization of the actin cytoskeleton and this relies on the function of talin and vinculin, which were thought to simply act as scaffolds that bridge integrin receptors to the actin cytoskeleton. We have taken structural, biochemical, and biological approaches 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.

Vinculin Activation in Focal Adhesions

Cell Adhesion Laboratory image

(A) Vinculin is associated with the actin cytoskeleton at focal adhesions. Image shown is immunofluorescence analysis of a mouse fibroblast cell stained with Actin (red) and Vinculin (green) antibodies. Note the highly organized actin cytoskeleton of the cell, and the "focal" localization of vinculin to points of contact of the actin cytoskeleton with the extracellular matrix.

(B) Talin activates vinculin in focal adhesions by provoking helical bundle conversion. Talin's vinculin binding sites (VBS) are α-helices that bind to a helical bundle structure present in vinculin's head (Vh) domain and this severs the intramolecular interaction of Vh with vinculin's tail (Vt) domain, which normally keeps vinculin in its inactive state. This occurs through a dramatic reorganization and distortion of Vh α-helices (α1- α4), which generates an entirely new five-helical bundle structure, by a process coined helical bundle conversion. The structure of the inactive Vh-Vt complex is shown in yellow (Vh) and gray (Vt), whereas the structure of talin-activated vinculin is shown in teal (talin VBS1) and pink (Vh). Movements and helical distortions of the α-helices observed upon activation of Vh by talin VBS1 are indicated by the arrows.

___________

Overview
___________

Research
___________

Publications
___________

Lectures
___________

Thesis
___________

Laboratory Members
___________

Links
___________

Support Us
___________

Contact
___________