Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
PLoS Comput Biol. 2013 Oct;9(10):e1003316. doi: 10.1371/journal.pcbi.1003316. Epub 2013 Oct 31.
Integrins are heterodimeric (αβ) cell surface receptors that are activated to a high affinity state by the formation of a complex involving the α/β integrin transmembrane helix dimer, the head domain of talin (a cytoplasmic protein that links integrins to actin), and the membrane. The talin head domain contains four sub-domains (F0, F1, F2 and F3) with a long cationic loop inserted in the F1 domain. Here, we model the binding and interactions of the complete talin head domain with a phospholipid bilayer, using multiscale molecular dynamics simulations. The role of the inserted F1 loop, which is missing from the crystal structure of the talin head, PDB:3IVF, is explored. The results show that the talin head domain binds to the membrane predominantly via cationic regions on the F2 and F3 subdomains and the F1 loop. Upon binding, the intact talin head adopts a novel V-shaped conformation which optimizes its interactions with the membrane. Simulations of the complex of talin with the integrin α/β TM helix dimer in a membrane, show how this complex promotes a rearrangement, and eventual dissociation of, the integrin α and β transmembrane helices. A model for the talin-mediated integrin activation is proposed which describes how the mutual interplay of interactions between transmembrane helices, the cytoplasmic talin protein, and the lipid bilayer promotes integrin inside-out activation.
整合素是异源二聚体 (αβ) 细胞表面受体，通过形成涉及 α/β 整合素跨膜螺旋二聚体、talin（将整合素连接到肌动蛋白的细胞质蛋白）的头部结构域和膜的复合物，被激活到高亲和力状态。talin 头部结构域包含四个亚结构域 (F0、F1、F2 和 F3)，带有插入 F1 结构域的长阳离子环。在这里，我们使用多尺度分子动力学模拟来模拟完整的 talin 头部与磷脂双层的结合和相互作用。探索了 talin 头部晶体结构（PDB:3IVF）中缺失的插入 F1 环的作用。结果表明，talin 头部结构域主要通过 F2 和 F3 亚结构域以及 F1 环上的阳离子区域与膜结合。结合后，完整的 talin 头部采用新颖的 V 形构象，使其与膜的相互作用最优化。在膜中模拟 talin 与整合素 α/β TM 螺旋二聚体的复合物，显示了该复合物如何促进整合素 α 和 β 跨膜螺旋的重排和最终解离。提出了一种 talin 介导的整合素激活模型，该模型描述了跨膜螺旋、细胞质 talin 蛋白和脂质双层之间的相互作用如何促进整合素的内-外激活。
