Vinculin is important in the maintenance and regulation of cell adhesion and migration, and it adopts an autoinhibited conformation in the cytosol. It becomes activated on recruitment to cell–cell and cell–matrix adherens-type junctions, where it mediates protein–protein interactions that control the links between filamentous (F)-actin and cell-adhesion molecules. So, how is vinculin activation controlled? A 3.1-Å crystal structure of vinculin, which is described by Liddington and colleagues in Nature, now reveals clues.
Vinculin contains five domains: D1–D3 form the head, D4 seems to form the neck, and there is a fifth tail domain. The structure reveals the autoinhibited conformation — D1 and D3 form a pair of pincers that hold the tail domain in the autoinhibitory position. By combining their structural data with other data on, for example, the location of protein-binding sites on vinculin and the affinities of vinculin domains for their binding partners, the authors were able to propose a pathway for vinculin activation. Ligand binding to vinculin is regulated sterically and allosterically, and they propose that vinculin activation occurs through a combinatorial pathway, which ensures that activation occurs only at cell-adhesion sites in the presence of two or more binding partners. As the binding sites for phosphatidylinositol-4,5-bisphosphate and F-actin on vinculin are not fully occluded in the autoinhibited structure, these ligands might initiate two alternative pathways to activation. REFERENCES Bakolitsa, C. et al. Structural basis for vinculin activation at sites of cell adhesion. Nature 13 June 2004 (doi:10.1038/nature02610)
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