Talin激活机制及其力学调控

项目名称： Talin激活机制及其力学调控

项目编号： No.11302240

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 张勇

作者单位： 中国科学院生物物理研究所

项目金额： 28万元

中文摘要： 踝蛋白(talin)参与诸多整合素相关的细胞粘附行为，可将细胞外基质和细胞内骨架肌动蛋白通过整合素串联起来，是细胞间力信号传导通路中的重要一环。在非活化状态下，talin的F3域和ROD域相互作用，构成自抑制结构，其活化后可发挥功能，但无控制的活化又会导致整合素功能紊乱，引起诸多疾病，因此talin的激活机理受到广泛关注，但至今没有形成完整结论。本项目将通过单分子力学实验研究talin的F2F3域与ROD域的相互作用，F2F3域与不同组分磷脂膜的作用，以及F2F3域在受到ROD域竞争作用时与不同组分磷脂膜的相互作用，并使用分子动力学方法模拟相应过程，得到对应的力谱和原子级别的信息。综合力谱实验与理论模拟的结果，确定talin活化过程中的关键残基，明确磷脂膜与机械力在此过程中的作用，总结出talin的激活及力学调控机制。本研究将有助于完善细胞间力信号传导机理，为治疗相关疾病提供理论依据。

中文关键词： 细胞粘附；力学调控；蛋白-质膜相互作用；单分子力谱；分子动力学模拟

英文摘要： Talin is a high molecular weight and highly abundant cytosolic protein, which regulates a wide variety of integrin-mediated cell adhesion processes, such as cellular spreading, migration, proliferation and the cellular deformation-related processes. Talin has been known to not only be a mechanical linker between cell-extracellular matrix and the actin cytoskeleton, but active integrin inside-out mechanical signaling, thereby form the bidirectional mechanical signaling pathway. Talin adopts an auto-inhibited conformation in its inactive state, where the autoinhibited interaction between F3 domain and ROD domain shields the F3 domain of talin and prevents it interacting with integrin. Uncontrolled talin activity could result in dysfunction of integrin, and lead to many cell function disorders. Therefore, activation mechanism of talin is investigated widely in recent decades, but is not compelete and convinced untill today. In this study, we will make use of the self-made Atomic Force Microscope to perform the single molecule force experiments to investigate the interactions between F3 and ROD domain by measuring their interaction, employ the molecular dynamics method to carry out the all-atomic simulation to study the corresponding disassociation process of F3 and ROD domain of talin. The interaction between F2F3

英文关键词： cell adhesion；force regulation；protein-membrane interaction；single molecule force spectroscopy；molecular dynamics simulations