Tension Enhances the Binding Affinity of β1 Integrin by Clamping Talin Tightly: An Insight from Steered Molecular Dynamics Simulations

Integrin activation is a predominant step for cell–cell and cell–ECM interactions. Talin and Kindlin are mechanosensitive adaptor proteins that bind to the integrin cytoplasmic tail and mediate integrin activation, cytoskeleton rearrangement, and focal adhesion assembly. However, knowledge about how Talin and Kindlin synergistically assist integrin activation remains unclear. Here, we performed so-called “ramp-clamp” SMD simulations, which modeled the mechanosignaling from Kindlin, to investigate the effect of tension on the interaction of the β1 integrin cytoplasmic tail with the Talin-F3 domain. The present results showed that mild but not excessive stretching enhanced the binding of integrin with Talin. This mechanical regulation on integrin affinity to Talin referred to an event cascade, in which under stretching, the integrin cytoplasmic tail adopted allostery in response to the mechanical stimulus, remodeling of integrin in favor of Talin-association ensued, and finally, a stable, close-knit complex was formed. In the cascade, the torsion angle transition of integrin was the cue for the stable interaction of the complex under tensile force. The present work suggested a model for Talin and Kindlin to synergistically activate integrin. It should help understand integrin activation and its mechanochemical regulation mechanism, integrin-related innate cellular immune responses, cell adhesion, cell–cell interaction, and integrin-related drug development.整合素（Integrin）激活是细胞间及细胞-细胞外基质（ECM）相互作用的关键步骤。踝蛋白（Talin）与Kindlin均为机械敏感性衔接蛋白，可结合整合素胞质尾区，介导整合素激活、细胞骨架重排与黏着斑组装。然而，目前关于踝蛋白与Kindlin如何协同协助整合素激活的机制仍不明确。本研究采用“斜坡-钳位”型牵引分子动力学（SMD）模拟，构建了源自Kindlin的机械信号转导模型，以探究张力对β1整合素胞质尾区与踝蛋白-F3结构域相互作用的影响。研究结果显示，适度而非过度的牵拉可增强整合素与踝蛋白的结合。这种对整合素与踝蛋白亲和力的力学调控遵循一套事件级联反应：在牵拉作用下，整合素胞质尾区发生别构效应以响应机械刺激，随后出现有利于与踝蛋白结合的整合素构象重塑，最终形成稳定紧密的复合物。在该级联反应中，整合素的扭转角转变是张力下复合物稳定结合的触发因子。本研究提出了踝蛋白与Kindlin协同激活整合素的模型，该模型有助于理解整合素激活及其机械化学调控机制、整合素相关天然细胞免疫应答、细胞黏附、细胞间相互作用以及整合素相关药物研发。