Inside-out regulation of E-cadherin conformation and adhesion

Cadherin cell-cell adhesion proteins play key roles in tissue morphogenesis and wound healing. Cadherin ectodomains bind in two conformations, X-dimers and strand-swap dimers, with different adhesive properties. However, the mechanisms by which cells regulate ectodomain conformation are unknown. Cadherin intracellular regions associate with several actin-binding proteins including vinculin, which are believed to tune cell-cell adhesion, solely by remodeling the actin cytoskeleton. Here, we demonstrate that vinculin association with the cadherin cytoplasmic region, also allosterically regulates ectodomain structure and adhesion, by converting weaker X-dimers into stronger strand-swap dimers. We also show that in epithelial cells, only half of apical cadherins are linked to the cytoskeleton. Furthermore, only 70% of apical cadherins form strand-swap dimers while the remaining form X-dimers, which provides cells with two cadherin pools with different adhesive properties. Our results showing allosteric modulation of adhesion at the single-molecule level are the first demonstration of inside-out regulation of cadherin conformation.