Talin as a series of mechanochemical switches. (A) The force-induced unfolding of the 13 talin rod domains R1–R13. Six force-extension curves are shown (at a loading rate of 3.8 pN/s), and each step in the profile corresponds with a single domain unfolding independently and undergoing mechanical switching. Adapted with permission from Yao et al. (2016). (B–D) Schematic diagram representing mechanochemical switches I–IV. (B) In the absence of mechanical force, the four domains are folded, and multiple ligands can bind simultaneously. (C) Mechanical force causes one domain (in this figure, domain II) to unfold, which drives a switch in binding partners on that domain. The other three domains remain folded and bound to their ligands. (D) Higher mechanical force causes a second domain (in this figure, domain IV) to unfold, switch binding partner, and further alter the signaling complex on that talin. Talin has 13 rod domains that exhibit this switch-like behavior, so multiple permutations of switch states and MSH complexes are possible on a single talin.