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 by remodeling the actin cytoskeleton. Here, we show at the singlemolecule 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, similar to 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 the inside-out regulation of cadherin conformation and establish a mechanistic role for vinculin in this process.

Automated summary

Cadherin cell-cell adhesion proteins are crucial for tissue morphogenesis and wound healing. Research has shown that vinculin can convert weak X-dimers of cadherin into strong strand-swap dimers, thereby regulating cell-cell adhesion. This process is mediated by myosin II-dependent changes in cytoskeletal tension, providing insight into the mechanisms of cadherin conformational regulation.