Inside-out regulation of E-cadherin conformation and adhesion

Abstract

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 by remodeling the actin cytoskeleton. Here, we show at the single molecule level, that vinculin association with the cadherin cytoplasmic region allosterically converts weak X-dimers into strong strand-swap dimers, and that this process is mediated by myosin II dependent changes in cytoskeletal tension. We also show that in epithelial cells, [~]70% of apical cadherins exist as strand-swap dimers while the remaining form X-dimers, providing two cadherin pools with different adhesive properties. Our results demonstrate, for the first time, the inside-out regulation of cadherin conformation and establish a mechanistic role for vinculin in this process. SIGNIFICANCE STATEMENTCadherin cell-cell adhesion proteins play key roles in the formation and maintenance of tissues. Their adhesion is carefully regulated to orchestrate complex movement of cells. While cadherin ectodomains bind in two conformations with different adhesive properties, the mechanisms by which cells regulate the conformation (and consequently adhesion) of individual cadherins are unknown. Here, we demonstrate that the association of intracellular vinculin to the cadherin cytoplasmic region, regulates cadherin adhesion by switching ectodomains from a weak binding to the strongly adhesive conformation. In contrast with the prevailing view which suggests that vinculin regulates adhesion solely by remodeling the cytoskeleton, we show that vinculin can directly modulate single cadherin ectodomain conformation and that this process is mediated by changes in cytoskeletal tension.