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In mammalian cells, vinculin is a membrane-cytoskeletal protein in focal adhesion plaques that is involved in linkage of integrin adhesion molecules to the actin cytoskeleton. Vinculin is a cytoskeletal protein associated with cell-cell and cell-matrix junctions, where it is thought to function as one of several interacting proteins involved in anchoring F-actin to the membrane.
Discovered independently by Benny Geiger and Keith Burridge, its sequence is 20%–30% similar to α-catenin, which serves a similar function.
Binding alternately to talin or α-actinin, vinculin's shape and, as a consequence, its binding properties are changed. The vinculin gene occurs as a single copy and what appears to be no close relative to take over functions in its absence. Its splice variant metavinculin (see below) also needs vinculin to heterodimerize and work in a dependent fashion.
Essentially, there is an 835 amino acid N-terminal head, which is split into four domains. This is linked to the C-terminal tail with a linker region.
The recent discovery of the 3D structure sheds light on how this protein tailors its shape to perform a variety of functions. For example, vinculin is able to control the cell's motility by simply altering its shape from active to inactive. When in its ‘inactive’ state, vinculin's conformation is characterized by the interaction between its head and tail domains. And, when transforming to the ‘active’ form, such as when talin triggers binding, the intramolecular interaction between the tail and head is severed. In other words, when talin's binding sites (VBS) of α-helices bind to a helical bundle structure in vinculin's head domain, the ‘helical bundle conversion’ is initiated, which leads to the reorganization of the α-helices (α1- α-4), resulting in an entirely new five-helical bundle structure. This function also extends to cancer cells, and regulating their movement and proliferation of cancer to other parts of the body.
In more specific terms, the amino-terminus of vinculin binds to talin, which, in turn, binds to β-integrins, and the carboxy-terminus binds to actin, phospholipids, and paxillin-forming homodimers. The binding of vinculin to talin and actin is regulated by polyphosphoinositides and inhibited by acidic phospholipids. The complex then serves to anchor actin filaments to the membrane and thus, helps to reinforce force on talin within the focal adhesions.
The loss of vinculin impacts a variety of cell functions; it disrupts the formation of the complex, and prevents cell adhesion and spreading. The absence of the protein demonstrates a decrease in spreading of cells, accompanied by reduced stress fiber formation, formation of fewer focal adhesions, and inhibition of lamellipodia extension. It was discovered that cells that are deficient in vinculin have growth cones that advance more slowly, as well as filopodia and lamellipodia that were less stable than the wild-type. Based on research, it has been postulated that the lack of vinculin may decrease cell adhesion by inhibiting focal adhesion assembly and preventing actin polymerization. On the other hand, overexpression of vinculin may restore adhesion and spreading by promoting recruitment of cytoskeletal proteins to the focal adhesion complex at the site of integrin binding. Vinculin's ability to interact with to the cytoskeleton at the focal adhesion appears to be critical for control of cytoskeletal mechanics, cell spreading, and lamellipodia formation. Thus, vinculin appears to play a key role in shape control based on its ability to modulate focal adhesion structure and function.
The length of the insert in metavinculin is 68 AA in mammals and 79 in frog. Compared metavinculin sequences from pig, man, chicken, and frog, and found the insert to be bipartite: the first part variable and the second highly conserved. Both vinculin isoforms co-localize in muscular adhesive structures, such as dense plaques in , intercalated discs in , and in . Metavinculin tail domain has a lower affinity for the head as compared with the vinculin tail. In case of metavinculin, unfurling of the C-terminal hydrophobic hairpin loop of tail domain is impaired by the negative charges of the 68-amino acid insert, thus requiring phospholipid-activated regular isoform of vinculin to fully activate the metavinculin molecule.
In cases of Small Intestinal Bacterial Overgrowth presented as IBS symptoms, anti-CdtB antibodies have been identified to affect vinculin function, which is required in gut motility.
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