Talin-based molecular clutch mediates mechanotransmission. (A) Domain organization of talin. The N-terminal talin head domain (THD) is an atypical FERM domain composed of F0, F1, F2, and F3 subdomains containing an integrin tail–binding site (IBS1). THD is linked to the talin rod domain via a flexible linker of ∼80 amino acids. The talin rod domain contains 13 helix bundles (R1–R13) and a dimerization domain (DD) and a second, underinvestigated integrin tail-binding site (IBS2). The IBS1, IBS2, three actin-binding sites (ABS1–3), two critical vinculin-binding sites (VBSs) in the R3 and R8 domains, and binding sites for RIAM, Kank2, and DLC1 are shown. The remaining VBSs are not depicted. (B) Model depicting the mechanical response of the molecular clutch and integrin–ligand bonds on the soft or rigid ECM in the presence or absence of Kank2. On soft substrates, the slow loading rates fail to induce talin unfolding and vinculin recruitment before the slip bond between integrin and the ligand ruptures under low force. In contrast, on rigid substrate, high loading rates induce vinculin-dependent clutch reinforcement, catch bond formation, and high force transmission. Kank2 interferes with F-actin binding to the talin ABS2, leading to reduced force transmission across talin as well as a diminished activation of VBSs. Consequently, Kank2 abrogates the clutch reinforcement and induces frequent ruptures of the slip bond between integrin and ligand even on rigid substrates.