Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation
Crystal structure of kindlin-2 PH domain reveals a conformational transition for its membrane anchoring and regulation of integrin activation
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DOI：
10.1007/s13238-012-2046-1
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发表时间：
2012-06-01
期刊：
影响因子：
21.1
通讯作者：
Zhang, Rongguang
中科院分区：
文献类型：
--
作者：
Liu, Yan;Zhu, Yun;Zhang, Rongguang
Kindlin-2 属于含 FERM 结构域的蛋白质亚家族，在激活整合素跨膜受体和介导细胞粘附方面发挥关键作用。与传统的 FERM 结构域相比，kindlin-2 FERM 包含插入的 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 功能。我们以 1.9 A 分辨率测定了 kindlin-2 PH 结构域的晶体结构，揭示了保守的 PH 结构域折叠，具有高电荷且开放的 PIP3 头基结合口袋。与之前报道的与 PIP3 头基结合的 kindlin-2 PH 结构域的溶液结构进行结构比较表明，在 PIP3 插入后，PIP3 结合袋入口处的高正电荷环和 PH 结构域的整个 β 桶都发生了显着的构象变化。我们认为这种“诱导契合”类型的变化对于 PIP3 将 kindlin-2 紧密结合到膜表面上至关重要，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。
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 A 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 beta 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.