Force-induced changes of α-catenin conformation stabilize vascular junctions independently of vinculin

Cadherin-mediated cell adhesion requires anchoring via the beta-catenin-alpha-catenin complex to the actin cytoskeleton, yet, alpha-catenin only binds F-actin weakly. A covalent fusion of VE-cadherin to alpha-catenin enhances actin anchorage in endothelial cells and strongly stabilizes endothelial junctions in vivo, blocking inflammatory responses. Here, we have analyzed the underlying mechanism. We found that VE-cadherin-alpha-catenin constitutively recruits the actin adaptor vinculin. However, removal of the vinculin-binding region of alpha-catenin did not impair the ability of VE-cadherin-alpha-catenin to enhance junction integrity. Searching for an alternative explanation for the junction-stabilizing mechanism, we found that an antibody-defined epitope, normally buried in a short alpha 1-helix of the actin-binding domain (ABD) of alpha-catenin, is openly displayed in junctional VE-cadherin-alpha-catenin chimera. We found that this epitope became exposed in normal alpha-catenin upon triggering thrombin-induced tension across the VE-cadherin complex. These results suggest that the VE-cadherin-alpha-catenin chimera stabilizes endothelial junctions due to conformational changes in the ABD of alpha-catenin that support constitutive strong binding to actin.

Automated summary

Cadherin-mediated cell adhesion relies on anchoring to the actin cytoskeleton via the beta-catenin-alpha-catenin complex. Fusion of VE-cadherin to alpha-catenin enhances this anchorage in endothelial cells, leading to stabilized endothelial junctions. The mechanism involves constitutive recruitment of vinculin by VE-cadherin-alpha-catenin, as well as conformational changes in the actin-binding domain of alpha-catenin.