Vinculin activation by talin through helical bundle conversion
Vinculin activation by talin through helical bundle conversion
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DOI：
10.1038/nature02281
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发表时间：
2004-01-08
期刊：
影响因子：
64.8
通讯作者：
Bois, PRJ
中科院分区：
文献类型：
--
作者：
Izard, T;Evans, G;Bois, PRJ
纽蛋白是细胞-细胞(钙粘素介导的)和细胞-基质(整合素-Talin介导的焦点粘连)连接的保守成分和重要调节因子，它通过与整合素复合体中的talin或钙粘附素连接中的α-Actinin结合，将这些黏附复合体锚定在肌动蛋白细胞骨架上(1-3)。在静止状态下，纽蛋白通过其头部(Vh)和尾部(Vt)结构域(4-6)的相互作用以封闭的构象保持。纽蛋白与局灶性粘连的结合需要与Talin结合。在这里，我们报告了人纽蛋白在其非活性状态和Talin激活状态下的晶体结构。Talin结合导致VH发生显著的构象变化，形成一种新的螺旋束结构，这种变化主动地取代了VH的Vt。这些结果，以及α-肌动蛋白与VH结合并取代VH Vt复合体的能力，支持了VH作为一个结构域发生显著结构变化的模型，该结构域允许vinculin在局部粘连和粘连连接中直接组装细胞骨架。值得注意的是，Talin对VH结构的影响建立了螺旋束转换作为蛋白质引导细胞反应的信号机制。
Vinculin is a conserved component and an essential regulator of both cell-cell (cadherin-mediated) and cell-matrix (integrin talin- mediated focal adhesions) junctions, and it anchors these adhesion complexes to the actin cytoskeleton by binding to talin in integrin complexes or to alpha-actinin in cadherin junctions(1-3). In its resting state, vinculin is held in a closed conformation through interactions between its head (Vh) and tail (Vt) domains(4-6). The binding of vinculin to focal adhesions requires its association with talin. Here we report the crystal structures of human vinculin in its inactive and talin- activated states. Talin binding induces marked conformational changes in Vh, creating a novel helical bundle structure, and this alteration actively displaces Vt from Vh. These results, as well as the ability of alpha-actinin to also bind to Vh and displace Vt from pre-existing Vh Vt complexes, support a model whereby Vh functions as a domain that undergoes marked structural changes that allow vinculin to direct cytoskeletal assembly in focal adhesions and adherens junctions. Notably, talin's effects on Vh structure establish helical bundle conversion as a signalling mechanism by which proteins direct cellular responses.