National Laboratory of Biophysics, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Protein Cell. 2012 Jun;3(6):434-40. doi: 10.1007/s13238-012-2046-1. Epub 2012 May 31.
Kindlin-2 belongs to a subfamily of FERM domain containing proteins, which plays key roles in activating integrin transmembrane receptors and mediating cell adhesion. Compared to conventional FERM domains, kindlin-2 FERM contains an inserted pleckstrin homology (PH) domain that specifically binds to phosphatidylinositol (3,4,5) trisphosphate (PIP3) and regulates the kindlin-2 function. We have determined the crystal structure of kindlin-2 PH domain at 1.9 Å resolution, which reveals a conserved PH domain fold with a highly charged and open binding pocket for PIP3 head group. Structural comparison with a previously reported solution structure of kindlin-2 PH domain bound to PIP3 head group reveals that upon PIP3 insertion, there is a significant conformational change of both the highly positively charged loop at the entry of the PIP3 binding pocket and the entire β barrel of the PH domain. We propose that such "induced-fit" type change is crucial for the tight binding of PIP3 to anchor kindlin-2 onto the membrane surface, thereby promoting its binding to integrins. Our results provide important structural insight into kindlin-2-mediated membrane anchoring and integrin activation.
Kindlin-2 属于 FERM 结构域蛋白的一个亚家族，在激活整合素跨膜受体和介导细胞黏附中发挥关键作用。与传统的 FERM 结构域相比，Kindlin-2 的 FERM 结构域含有一个插入的 pleckstrin 同源（PH）结构域，该结构域特异性结合磷脂酰肌醇（3,4,5）三磷酸（PIP3）并调节 Kindlin-2 的功能。我们已经确定了 Kindlin-2 PH 结构域的晶体结构，分辨率为 1.9Å，揭示了一个保守的 PH 结构域折叠，具有带高电荷的开放 PIP3 头部结合口袋。与之前报道的与 PIP3 头部结合的 Kindlin-2 PH 结构域的溶液结构的结构比较表明，在 PIP3 插入后，高度带正电荷的 PIP3 结合口袋入口处的环和 PH 结构域的整个β桶都发生了显著的构象变化。我们提出，这种“诱导契合”类型的变化对于 PIP3 与锚定 Kindlin-2 到膜表面的紧密结合至关重要，从而促进其与整合素的结合。我们的结果为 Kindlin-2 介导的膜锚定和整合素激活提供了重要的结构见解。
