Beyond structure: Mechanism and dynamics of intercellular adhesion

This review summarizes findings from multiple complementary quantitative investigations of adhesion by classical cadherins. The systems investigated range from single molecules to cells, and the approaches used quantify the kinetics, energetics and mechanical strengths of cadherin bonds. The cumulative results demonstrate that cadherins adhere via a multistage binding mechanism that involves multiple extracellular domains. In kinetic measurements of cell adhesion, cell pairs first form a low-probability-binding state with fast kinetics. This is followed by a lag and a slow transition to a second, high-probability, binding state. This two-stage process is independent of the cytoplasmic domain. Studies with domain-deletion mutants demonstrate that the N-terminal domains are required for the first, fast, weak binding. However, the full-ectodomain and EC3 (extracellular repeat 3), in particular, are required to form the second, high-probability, binding state, which is characterized by slow dissociation kinetics and much stronger adhesive bonds. Together, these different studies reveal a more complex multistage binding mechanism than was predicted by structural models.