Abstract
Talin serves as the central mechanotransduction hub in integrin–extracellular matrix adhesion, orchestrating the assembly of focal adhesions—multi-protein complexes that link integrins to the actin cytoskeleton. While cryo-EM revealed compact, autoinhibited architectures, talin’s behavior in solution remains unknown. Here, we integrate SEC–SAXS with Monte Carlo modeling (SASSIE), using AlphaFold predictions as the initiating template to determine the conformational landscape of full-length talin in solution. We show that talin does not adopt a single compact structure but instead populates a broad, flexible conformational ensemble characterized by R3 repositioning and partial F3-R9 disengagement. Critically, this ensemble intrinsically samples activation-prone conformations without mechanical force, which establishes a dynamic conformational equilibrium that lowers the energetic barrier for integrin engagement, vinculin recruitment, and actin association. This ensemble framework unifies structural, biochemical, and mechanobiological models of talin activation and suggests that intrinsic flexibility plays a central role in adhesion initiation and force transmission.
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Acknowledgement
Z.B. discloses support for this work from the National Science Foundation (MCB-2202202). B.S., G.R. were supported by G-RISE Ph.D. traineeships from the National Institutes of Health (T32GM136499). Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health, National Institute of General Medical Sciences (P30GM133894).
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Shi, B., Reyes, G., Matsui, T. et al. Conformational flexibility of talin enables force-free sampling of activation-competent states. Commun Chem (2026). https://doi.org/10.1038/s42004-026-02067-7
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DOI: https://doi.org/10.1038/s42004-026-02067-7
