BPS2026 – Conformational landscape of integrin activation reveals surveillance mode without extracellular ligands or intracellular activators

Integrins play a fundamental role in cellular homeostasis by linking the extracellular matrix to the intracellular cytoskeleton through interactions with various adaptor and signaling proteins, resulting in the formation of focal adhesions (FA). Dysregulation of integrin-mediated FA assembly has been linked to numerous diseases including cancers, making integrins key targets for therapeutic intervention. Progress in integrin-targeted therapies has been hindered by a lack of structural and mechanistic understanding of integrin activation and FA formation. Using cryo-EM on native, full-length a5b1 integrin prepared without exogenous activators, we resolve multiple co-existing conformations spanning bent to extended arrangements in ligand-free conditions. The quantitative distribution of these states supports an intrinsic surveillance equilibrium, a hypothesized but previously unproven state in which integrin monitors the extracellular environment before initiating downstream outside-in signaling. Our finding provides critical insights into the activation of integrin and the formation of FA and offers new perspectives on integrin function and its potential as a therapeutic target.