Force sensing at cadherin-mediated adhesions is critical for their proper function. α-Catenin, which links cadherins to actomyosin, has a crucial role in this mechanosensing process. It has been hypothesized that force promotes vinculin binding, although this has never been demonstrated. X-ray structure further suggests that α-catenin adopts a stable auto-inhibitory conformation that makes the vinculin-binding site inaccessible. Here, by stretching single α-catenin molecules using magnetic tweezers, we show that the subdomains MI vinculin-binding domain (VBD) to MIII unfold in three characteristic steps: a reversible step at ~5 pN and two non-equilibrium steps at 10-15 pN. 5 pN unfolding forces trigger vinculin binding to the MI domain in a 1:1 ratio with nanomolar affinity, preventing MI domain refolding after force is released. Our findings demonstrate that physiologically relevant forces reversibly unfurl α-catenin, activating vinculin binding, which then stabilizes α-catenin in its open conformation, transforming force into a sustainable biochemical signal.
Background: Cadherin interactions with catenins are crucial for intercellular adhesion. Results: ␣E-catenin and vinculin cooperate to promote the time-dependent reinforcement of cadherin-mediated adhesions. Conclusion: ␣E-catenin and vinculin form a mechanoresponsive link between cadherin and the underlying actin cytoskeleton. Significance: The force-dependent modulation of ␣-catenin and vinculin recruitment contributes to the development of cadherin adhesion strength.
Combining cell biology and biomechanical analysis, we show here that the coupling between cadherin complexes and actin through tension-dependent α-catenin/vinculin association is regulating AJ stability and dynamics as well as tissue-scale mechanics.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.