Wegener Kate L, Partridge Anthony W, Han Jaewon, Pickford Andrew R, Liddington Robert C, Ginsberg Mark H, Campbell Iain D
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, England, UK.
Cell. 2007 Jan 12;128(1):171-82. doi: 10.1016/j.cell.2006.10.048.
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 beta3 cytoplasmic domain and identify specific contacts between talin and the integrin tail required for activation. We used structure-based mutagenesis to engineer talin and beta3 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.
整联蛋白亲和力（激活）的调节对于后生动物的发育和许多病理过程至关重要。踝蛋白的磷酸酪氨酸结合（PTB）结构域与整联蛋白β亚基细胞质结构域（尾部）的结合会导致激活，而许多其他含PTB结构域的蛋白质与整联蛋白结合但不会激活它们。在这里，我们确定了踝蛋白与膜近端整联蛋白β3细胞质结构域之间复合物的结构，并确定了激活所需的踝蛋白与整联蛋白尾部之间的特定接触。我们使用基于结构的诱变技术构建了与野生型蛋白具有可比亲和力但通过与内源性踝蛋白竞争来抑制整联蛋白激活的踝蛋白和β3变体。这些结果揭示了踝蛋白激活整联蛋白独特能力的结构基础，确定了一种有助于设计阻断整联蛋白激活疗法的相互作用，并能够对多种整联蛋白激活存在缺陷的细胞进行工程改造。
