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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Bright Shi,
  • Gilbert Reyes,
  • Tsutomu Matsui,
  • Thomas M. Weiss,
  • David J. E. Callaway,
  • Zimei Bu

摘要

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.