Molecular Dynamics Study of Vinculin Activation due to Talin Binding

Seung Lee, Massachusetts Institute of Technology

Photo of Seung Lee

Vinculin is a very interesting focal adhesion protein that functions as a cross-link between the integrin and the cytoskeleton network. It is known to be able to bind to at least eight different focal adhesion proteins, and from this observation, it has been postulated that vinculin might be involved in recruitment of other focal adhesion proteins to the focal adhesion site. In its inactive state, vinculin head (Vh) domain intramolecularly binds to vinculin tail (Vt) domain, hiding many of its cryptic binding sites from most of its partner proteins. Upon binding to an activator protein, phosphatidylinositol 4,5-bisphosphate, the vinculin can be activated by dissociating Vt from Vh revealing the cryptic binding sites to other proteins. Recently, it has been shown that talin also can activate vinculin, and both Vh/Vt complex and Vh/talin complex are crystallized (Izard, 2004). Izard et al. observed the Vt/Vh complex dissociating upon introduction of talin to the Vh/Vt solution, the product being Vh/talin complex and Vt. The crystal structures of the complexes show large conformational difference of Vh when it is bound to Vt and to talin, suggesting the high-affinity talin is pulling Vh away from Vt to cause the dissociation. Our plan of study is to introduce talin to its binding site on Vh as Vh is complexed to Vt within the numerical model. When the dissociation of Vh/Vt is accomplished, based on that validation, the precise mechanism of vinculin activation due to talin binding will be determined from the numerical result by looking at the mechanical interacttion, electrostatic interaction, and free energy evaluation.

Abstract Author(s): Seung E. Lee, Mohammad R. Kaazempur-Mofrad, Roger D. Kamm