Anthis Nicholas J, Wegener Kate L, Ye Feng, Kim Chungho, Goult Benjamin T, Lowe Edward D, Vakonakis Ioannis, Bate Neil, Critchley David R, Ginsberg Mark H, Campbell Iain D
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
EMBO J. 2009 Nov 18;28(22):3623-32. doi: 10.1038/emboj.2009.287. Epub 2009 Oct 1.
Fundamental to cell adhesion and migration, integrins are large heterodimeric membrane proteins that uniquely mediate inside-out signal transduction, whereby adhesion to the extracellular matrix is activated from within the cell by direct binding of talin to the cytoplasmic tail of the beta integrin subunit. Here, we report the first structure of talin bound to an authentic full-length beta integrin tail. Using biophysical and whole cell measurements, we show that a specific ionic interaction between the talin F3 domain and the membrane-proximal helix of the beta tail disrupts an integrin alpha/beta salt bridge that helps maintain the integrin inactive state. Second, we identify a positively charged surface on the talin F2 domain that precisely orients talin to disrupt the heterodimeric integrin transmembrane (TM) complex. These results show key structural features that explain the ability of talin to mediate inside-out TM signalling.
整合素是细胞黏附和迁移的基础，是大型异二聚体膜蛋白，它独特地介导由内向外的信号转导，即通过踝蛋白直接结合到β整合素亚基的细胞质尾部，从细胞内部激活与细胞外基质的黏附。在这里，我们报道了踝蛋白与真实全长β整合素尾部结合的首个结构。通过生物物理和全细胞测量，我们表明踝蛋白F3结构域与β尾部膜近端螺旋之间的特定离子相互作用破坏了有助于维持整合素非活性状态的整合素α/β盐桥。其次，我们在踝蛋白F2结构域上鉴定出一个带正电荷的表面，该表面精确地定位踝蛋白以破坏异二聚体整合素跨膜（TM）复合物。这些结果显示了解释踝蛋白介导由内向外TM信号传导能力的关键结构特征。
