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Vinculin is a 117-kDa cytoskeletal protein with 1066 amino acids. The protein contains an acidic N-terminal domain and a basic C-terminal domain separated by a proline-rich middle segment. This segment connects the five-helical bundle tail domain of vinculin to the rest of the protein. Vinculin consists of a globular head domain that contains binding sites for talin and α-actinin as well as a tyrosine phosphorylation site, while the tail region contains binding sites for F-actin, paxillin, and lipids. Vinculin is made up of anti-parallel α-helical bundles that form the five domains of the protein including the head and the tail domains. (Figure 1 from R. Borgon).

Essentially, there is an 835 amino acid N-terminal head, which is split into five 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 during protein activation 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 hydrophobic 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. The change in shape of vinculin can allow for the different domains to have other binding partners. For instance, the α-helical nature of the head domain changes depending on what the domain is bound to allowing for dynamic conformation changes within the protein. This function also extends to cancer cells, and regulating their movement and proliferation of cancer to other parts of the body.

Activation of Vinculin

Vinculin is present in equilibrium between an active and inactive state. The active state is triggered upon binding to its designated partner. These changes occur when vinculin interacts with focal adhesion points to which it is binding to. When vinculin resides in its inactive form, the protein is kept designated to the cytoplasm unlike the focal adhesion points bound from the active state. The molecule talin is thought to be the major initiator of vinculin activation due to its presence in focal complexes. The combinatorial model of vinculin states that either α-actinin or talin can activate vinculin either alone or with the assistance of PIP2 or actin. This activation takes place by separation of the head-tail connection within inactive vinculin.