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 cytoskeletonand coordinates signaling at integrin adhesion complexes. A second integrin-bindingsite (IBS2) has been proposed within the R11–R12 region of the talin rod, althoughthe molecular basis of this interaction has remained unclear. Here, we show that talinR11 contains a cryptic aggregation-prone region (APR) embedded within Helix50.Mechanical unfolding of R11 exposes this motif, enabling high-affinity talin–talininteractions and force-dependent self-association. The isolated APR forms amyloid-likefibers in vitro, and APR-disrupting gatekeeper mutations suppress fiber formation,talin self-association, and cellular recruitment. We therefore designate this motifAggregation-Prone Region 1 (APR1). Mitochondrial-targeting experiments demon-strate that APR1-dependent recruitment occurs in cells independently of focal adhesionsand integrins. APR1 overlaps the vinculin-binding site in Helix50, and vinculin dis-rupts preexisting talin assemblies, revealing a mechano-chaperone function for vinculin.Disruption of APR1-mediated self-association does not impair adhesion formation butinstead generates larger, more talin-rich adhesions with altered assembly dynamics andsignaling properties, indicating a role for APR1 in regulating adhesion remodeling.Together, these findings identify force-dependent talin self-association as a mechanism inmechanotransduction and suggest that the region previously designated IBS2 functionsprimarily as an aggregation-prone regulatory element.