Force-independent interactions of talin and vinculin govern integrin-mediated mechanotransduction

Abstract

Talin, vinculin and paxillin are core components of the dynamic link between integrins and actomyosin. Here we study the mechanisms that mediate their activation and association using a mitochondrial-targeting assay, structure-based mutants, and advanced microscopy. As expected, full-length vinculin and talin are auto-inhibited and do not interact with each other in this state. Contrary to previous models that propose a critical role for forces driving talin-vinculin association, our data show that force-independent relief of auto-inhibition is sufficient to mediate their tight interaction. Interestingly, paxillin can bind to both talin and vinculin when either is inactive. Further experiments demonstrate that adhesions containing paxillin and vinculin can form without talin following integrin activation. However, these are largely deficient in exerting traction forces to the matrix. Our observations lead to a model whereby paxillin contributes to talin and vinculin recruitment into nascent adhesions. Activation of the talin-vinculin axis subsequently leads to the engagement with the traction force-machinery and focal adhesion maturation.