Protein Structural Changes Modulate Cell Adhesion

Researchers have used x-ray crystallography techniques to elucidate structural changes that occur when the membrane protein vinculin binds to other proteins such as talin and actin.

Vinculin is a 117 kDa protein localized to focal adhesions. The globular head region of vinculin (Vh) contains the binding sites for talin and alpha-actinin, whereas its rod-like tail domain (Vt) contains the binding sites for F-actin and paxillin. The crystal structure of Vt features a bundle of five amphipathic helices and a C-terminal arm, which emerges as a hydrophobic hairpin surrounded by a collar of basic residues. Vinculin is a conserved component and an essential regulator of both 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 alpha-actinin in cadherin junctions.

Talin is a 270 kDa actin-binding protein that localizes to focal adhesions. Two talin molecules form a homodimer with an antiparallel orientation. Proteolysis with thrombin divides talin into an N-terminal head domain and a C-terminal rod domain. The C-terminal rod domain binds to the focal adhesion protein F-actin and to vinculin.

Investigators at St. Jude Children's Research Hospital (Memphis, TN, USA) wrote in the January 8, 2004, issue of Nature that talin binding induced marked conformational changes in Vh, creating a novel helical bundle structure, and this alteration actively displaced Vt from Vh. These results, as well as the ability of alpha-actinin to also bind to Vh and displace Vt from pre-existing Vh-Vt complexes, supported a model whereby Vh functioned as a domain that underwent marked structural changes that allowed vinculin to direct cytoskeletal assembly in focal adhesions and adherens junctions.

"Vinculin is a critical protein that performs different roles in the body,” explained senior author Dr. Philippe R.J. Bois, professor of genetics at St. Jude Children's Research Hospital. "It is a master conductor of much of the cell's life, changing its shape to conduct the cell's business according to the cell's immediate needs.”




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