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Conformational flexibility of talin enables force-free sampling of activation-competent states

Year: 2026
Type: article
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. While autoinhibited architectures of talin are known from cryo-electron microscopy, its behaviour in solution has remained underexplored. Here, the authors use size-exclusion chromatography coupled with in-line small-angle X-ray scattering, Monte Carlo modeling and AlphaFold predictions to determine the conformational landscape of full-length talin in solution, showing that this cytoplasmic adapter protein does not adopt a single compact structure but instead populates a broad, flexible conformational ensemble characterized by R3 subdomain repositioning and partial F3-R9 subdomain disengagement.
DOI: 10.1038/s42004-026-02067-7
Authors: Bright Shi, Gilbert Reyes, Tsutomu Matsui, Thomas M. Weiss, David J. E. Callaway, Zimei Bu
Language: English
Open Access status: gold
Estimated APC paid: $3,690
Funders: National Science Foundation, U.S. Department of Energy, National Institutes of Health, Office of Science, National Institute of General Medical Sciences, Basic Energy Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory
Awards: G1229526393, G1286251239, G2371548206, G262532246, G303061748, G315621713, G4202012489, G4235786860, G4581610328, G4654690619, G495301720, G498139845, G5570207115, G6550344761, Collaborative Research: Nanoscale structure and dynamics of a cell-cell adhesion complex, G7283024673, G7396808078, G7863156295, G8207748872, G8382000481, G8925327636, G-RISE: Graduate Research Initiative for Student Advancement at The City College of New York, A Synchrotron Radiation Structural Biology Resource, G911061179, G969889393
OpenAlex ID: W7161798152
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