Hypothetical mechanoregulation of the cadherin dimerization state. (A) Cadherin dimer in solution cannot be regulated by traction forces and freely shuttles between X and strand-swap modes. Once in X mode, the dimer becomes unstable and may dissociate. Such uncontrolled strand swap–to–X dimer transitions must significantly decrease cadherin dimerization affinity in most in vitro binding assays. (B) The same cadherin dimer, engaged in cell–cell adhesion, cannot freely shuttle between two binding modes. If the junction is stretched by contracting forces, cadherin in the dimer interacts exclusively through strand swapping because their X dimer interfaces (positions of both interfaces are indicated) are far away from one another. In contrast, closing the intercellular gap (for instance, by actin polymerization) compresses the dimer. In such a compressed form, X dimer interfaces are perfectly aligned, facilitating the strand swap–to–X dimer transition, thereby strongly increasing the probability of dimer dissociation.