Kiema Tiila, Lad Yatish, Jiang Pengju, Oxley Camilla L, Baldassarre Massimiliano, Wegener Kate L, Campbell Iain D, Ylänne Jari, Calderwood David A
Biocenter Oulu, Department of Biochemistry, University of Oulu, FIN-90014 Oulu, Finland.
Mol Cell. 2006 Feb 3;21(3):337-47. doi: 10.1016/j.molcel.2006.01.011.
The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin beta cytoplasmic tail forms an extended beta strand that interacts with beta strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.
黏附受体跨细胞膜传递生化信号和机械力的能力取决于其与肌动蛋白细胞骨架的相互作用。细丝蛋白是一种大型的肌动蛋白交联蛋白，可将多种跨膜蛋白和信号蛋白连接到细胞骨架。在此，我们描述了细丝蛋白A与整合素黏附受体之间界面的高分辨率结构。结合时，整合素β胞质尾形成一条延伸的β链，与细丝蛋白免疫球蛋白样结构域（IgFLN）21的β链C和D相互作用。该界面在许多整合素中都很常见，我们认为它是其他IgFLN结构域相互作用的原型。值得注意的是，结构上确定的细丝蛋白结合位点与整合素调节蛋白踝蛋白的结合位点重叠，并且这些蛋白竞争与整合素尾的结合，从而使整合素-细丝蛋白相互作用影响踝蛋白依赖性整合素激活。模拟磷酸苏氨酸的突变抑制细丝蛋白而非踝蛋白的结合，这表明激酶可能调节这种竞争并提供控制整合素功能的额外手段。
