An aggregation-prone region in talin controls talin self-interactions and regulates integrin adhesion complex dynamics

Talin is a mechanosensitive scaffold that couples integrins to the actin cytoskeleton and coordinates signaling at integrin adhesion complexes. A second integrin-binding site (IBS2) has been proposed within the R11–R12 region of the talin rod, although the molecular basis of this interaction has remained unclear. Here, we show that talin R11 contains a cryptic aggregation-prone region (APR) embedded within Helix50. Mechanical unfolding of R11 exposes this motif, enabling high-affinity talin–talin interactions and force-dependent self-association. The isolated APR forms amyloid-like fibers in vitro, and APR-disrupting gatekeeper mutations suppress fiber formation, talin self-association, and cellular recruitment. We therefore designate this motif Aggregation-Prone Region 1 (APR1). Mitochondrial-targeting experiments demonstrate that APR1-dependent recruitment occurs in cells independently of focal adhesions and integrins. APR1 overlaps the vinculin-binding site in Helix50, and vinculin disrupts preexisting talin assemblies, revealing a mechano-chaperone function for vinculin. Disruption of APR1-mediated self-association does not impair adhesion formation but instead generates larger, more talin-rich adhesions with altered assembly dynamics and signaling properties, indicating a role for APR1 in regulating adhesion remodeling. Together, these findings identify force-dependent talin self-association as a mechanism in mechanotransduction and suggest that the region previously designated IBS2 functions primarily as an aggregation-prone regulatory element.