Role of mechanical allostery in kindlin-mediated integrin activation

Kindlin proteins are central regulators of integrin-mediated cell adhesion, a process essential for various biological and pathological processes. Although structural studies have proposed that kindlins promote integrin activation and clustering via domain-swapped homodimers, this hypothesis has been challenged by the extremely slow in vitro dimerization kinetics, leaving the physiological regulatory mechanism unresolved. Here we show, via multiscale molecular simulations, that mechanical stress acts as a critical trigger for kindlin activation and homodimerization via mechanical allostery. Force accelerates the rate-limiting closed-to-open conformational transition step involved in dimerization, thereby facilitating homodimer assembly. Our simulations pinpoint specific interactions that underlie the high free-energy barrier of conformational transition, which is supported by analytical gel-filtration experiments. We further demonstrate that the relative lengths of linkers between kindlin subdomains strongly influence the propagation of mechanical allostery. Together, these results clarify how mechanical allostery enables kindlin-mediated integrin mechanoactivation and suggest potential therapeutic strategies for adhesion-related disorders. Kindlin dimerization has been proposed as a key step in integrin activation and clustering, yet its very slow in vitro kinetics challenge this role. Here, the authors show that physiological mechanical forces drive kindlin dimerization through mechanical allostery, lowering the free-energy barrier of the rate-limiting closed-to-open transition and thereby enabling rapid, force-dependent kindlin dimerization and integrin mechanoactivation.