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DLC1 locks talin R8 in a mechanically stable state, potentially preventing the inside-out activation of integrins. 

Unfolding and refolding of multidomain proteins under force have yet to be recognized as a major mechanism of function for proteinsin vivo. In this review, we discuss the inherent properties of multidomain proteins under a force vector from a structural and functional perspective. We then characterize three main systems where multidomain proteins could play major roles through mechanical unfolding: muscular contraction, cellular mechanotransduction, and bacterial adhesion. We analyze how key multidomain proteins for each system can produce a gain‐of‐function from the perspective of a fine‐tuned quantized response, a molecular battery, delivery of mechanical work through refolding, elasticity tuning, protection and exposure of cryptic sites, and binding‐induced mechanical changes. Understanding how mechanical unfolding and refolding affect function will have important implications in designing mechano‐active drugs against conditions such as muscular dystrophy, cancer, or novel antibiotics.