Structural basis for vinculin activation at sites of cell adhesion
Structural basis for vinculin activation at sites of cell adhesion
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DOI：
10.1038/nature02610
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发表时间：
2004-07-29
期刊：
影响因子：
64.8
通讯作者：
Liddington, RC
中科院分区：
文献类型：
--
作者：
Bakolitsa, C;Cohen, DM;Liddington, RC
曲马多蛋白是一种高度保守的细胞内蛋白，在维持和调节细胞粘附和迁移中起关键作用（1-3）。在胞质溶胶中，黏着斑蛋白采用默认的自抑制构象（4，5）。在募集到细胞-细胞和细胞-基质粘附分子型连接时，黏着斑蛋白被激活并介导各种蛋白质-蛋白质相互作用，调节F-肌动蛋白与细胞粘附分子的钙粘蛋白和整联蛋白家族之间的联系。在这里，我们描述了全长黏着斑蛋白分子（1，066个氨基酸）的晶体结构，它显示了五个结构域的自抑制构象，其中羧基末端的尾部结构域被黏着斑蛋白头部钳形地固定，配体结合受到空间和变构的调节。我们表明，在头部，尾部和富含脯氨酸的结构域的构象变化连接的结构和药理学，并提出了一个组合的激活途径，确保黏着斑蛋白激活只有在细胞粘附的网站时，两个或两个以上的结合伙伴被带到并置。
Vinculin is a highly conserved intracellular protein with a crucial role in the maintenance and regulation of cell adhesion and migration(1-3). In the cytosol, vinculin adopts a default autoinhibited conformation(4,5). On recruitment to cell - cell and cell - matrix adherens-type junctions, vinculin becomes activated and mediates various protein - protein interactions that regulate the links between F-actin and the cadherin and integrin families of cell-adhesion molecules. Here we describe the crystal structure of the full-length vinculin molecule ( 1,066 amino acids), which shows a five-domain autoinhibited conformation in which the carboxyterminal tail domain is held pincer-like by the vinculin head, and ligand binding is regulated both sterically and allosterically. We show that conformational changes in the head, tail and proline-rich domains are linked structurally and thermodynamically, and propose a combinatorial pathway to activation that ensures that vinculin is activated only at sites of cell adhesion when two or more of its binding partners are brought into apposition.