Focal Adhesion Mechanotransduction: Molecular Events Leading to Vinculin Activation

Focal adhesions are formed as a molecular glue linking cytoskeletal actin filaments to the extracellular matrix (ECM). They are formed at the site of mechanical stimulation (1) and involve and initial recruitment of talin and vinculin to ECM bound integrin molecules at the site of external stimulation. Talin recruitment and its force-induced activation and subsequent interaction with vinculin have been extensively studied (2–4). Vinculin is natively in an auto-inhibited conformation and its activation involves removal of a steric hindrance preventing binding of Vt with actin (5) (Figure 1). Several hypotheses have been put forth regarding vinculin activation and its subsequent interaction with actin: 1) vinculin activation requires only interaction with talin at domain 1 (D1) (6), 2) a simultaneous interaction with both actin and talin is necessary to achieve vinculin activation (7), 3) once activated vinculin interacts with actin via an electrostatic interaction between Vt and two regions on F-actin (5). Each of these hypotheses is evaluated through molecular dynamics simulation and analysis.