Structural basis of integrin activation by talin
Structural basis of integrin activation by talin
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DOI：
10.1016/j.cell.2006.10.048
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发表时间：
2007-01-12
期刊：
影响因子：
64.5
通讯作者：
Campbell, Iain D.
中科院分区：
文献类型：
--
作者：
Wegener, Kate L.;Partridge, Anthony W.;Campbell, Iain D.
整合素亲和力的调节（激活）对后生动物的发育和许多病理过程至关重要。talin磷酸酪氨酸结合（PTB）结构域与整合素β亚基细胞质结构域（tail）结合可引起激活，而许多其他含有PTB结构域的蛋白结合整合素而不激活它们。在这里，我们定义了talin和膜-近端整合素β 3细胞质域之间的复合物的结构，并确定了talin和激活所需的整合素尾部之间的特定接触。我们使用基于结构的诱变技术来设计talin和β 3变体，它们与野生型蛋白具有相当的亲和力相互作用，但通过与内源性talin竞争来抑制整合素的激活。这些结果揭示了talin激活整合素的独特能力的结构基础，确定了一种相互作用，可以帮助设计阻断整合素激活的治疗方法，并使具有多种整合素激活缺陷的细胞工程成为可能。
Regulation of integrin affinity (activation) is essential for metazoan development and for many pathological processes. Binding of the talin phosphotyrosine-binding (PTB) domain to integrin beta subunit cytoplasmic domains (tails) causes activation, whereas numerous other PTB-domain-containing proteins bind integrins without activating them. Here we define the structure of a complex between talin and the membrane-proximal integrin beta 3 cytoplasmic domain and identify specific contacts between talin and the integrin tail required for activation. We used structure-based mutagenesis to engineer talin and beta 3 variants that interact with comparable affinity to the wild-type proteins but inhibit integrin activation by competing with endogenous talin. These results reveal the structural basis of talin's unique ability to activate integrins, identify an interaction that could aid in the design of therapeutics to block integrin activation, and enable engineering of cells with defects in the activation of multiple classes of integrins.