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.