Role of vinculin in the structural dynamics of cadherin-catenin complexes and its implications for F-actin binding.

Abstract

Adherens junctions (AJs) are essential for maintaining tissue integrity and regulating intercellular signaling and tumor progression. At the core of AJs is the cadherin-catenin (ABE) complex, which links to the cytoskeletal actin filament (F-actin). Vinculin, a cytoskeletal protein, is recruited to AJs under recurrently high tensions to modulate cell adhesion. However, the molecular mechanisms underlying vinculin recruitment and activation remain elusive due to the highly dynamic and heterogeneous nature of the cadherin-catenin-vinculin (VABE) complex. In this study, we performed molecular dynamics (MD) simulations to probe the structure, dynamics, and domain interactions within the VABE complex. Our simulations reveal that vinculin binding enhances the conformational flexibility of α-catenin and expands the configurational space sampled by its actin-binding domain (ABD). This is consistent with an increase in configurational entropy upon complex assembly, suggesting that an entropic trap mechanism-previously proposed for ABE-may also underlie force-sensitive binding in the VABE complex. Furthermore, we provide detailed structural insights into α-catenin/vinculin and α-catenin/β-catenin interactions, elucidating how vinculin recruitment impacts the dynamics of the ABE complex. Interestingly, while vinculin binding increases overall structural fluctuations, ABD exposure remains comparable to that of the ABE complex alone. This is likely due to ABD's interaction with the M1 subdomain, which emerges from α-catenin unfolding upon vinculin binding. Together, these findings deepen our understanding of vinculin-mediated mechanotransduction at AJs and its role in modulating cytoskeletal dynamics.