Ramesh Koirala

Cadherins are essential cell-cell adhesion proteins that interact in two distinct conformations: X-dimers and strand-swap dimers. Both X-dimers and strand-swap dimers are thought to exclusively rely on symmetric sets of interactions between key amino acids on both cadherin binding partners. Here, we use single-molecule atomic force microscopy and computer simulations to show that symmetry in cadherin binding is dispensable and that cadherins can also interact in a novel conformation that asymmetrically incorporates key elements of both strand-swap dimers and X-dimers. Our results clarify the biophysical rules for cadherin binding and demonstrate that cadherins interact in a more diverse range of conformations than previously understood.

Significance: Cadherin 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 with the cadherin cytoplasmic region regulates cadherin adhesion by switching ectodomains from a weak binding to the strongly adhesive conformation. In contrast to 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 this process is mediated by changes in cytoskeletal tension.