Simulations of Kindlin-2 PIP binding domains reveal protonation-dependent membrane binding modes.
Simulations of Kindlin-2 PIP binding domains reveal protonation-dependent membrane binding modes.
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Kindlin-2 PIP 结合域的模拟揭示了质子化依赖性膜结合模式。
DOI：
10.1016/j.bpj.2021.11.021
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发表时间：
2021
影响因子：
3.4
通讯作者：
Nieuwkoop,AndrewJ
中科院分区：
文献类型：
--
作者：
Palmere,RobertD;Case,DavidA;Nieuwkoop,AndrewJ
Kindlin-2是Kindlin家族外周膜蛋白的一员，对整合素的激活和表皮生长因子受体的稳定起重要作用。它通过位于N-末端F0和Pleckstrin同源结构域的磷脂酰肌醇磷酸结合结构域与质膜的细胞质表面结合。这些结构域与磷脂酰肌醇4，5-二磷酸结合，更大程度上与磷脂酰肌醇3，4，5-三磷酸结合。这些磷脂酰肌醇磷酸盐与Kindlin-2的不同结合的生物学意义以及它们激活Kindlin-2的机制尚不清楚。最近，核磁共振谱鉴定了在阴离子脂类存在下，磷脂酰肌醇4，5-二磷酸和磷脂酰肌醇3，4，5-三磷酸在生理pH附近的主要质子化状态。在这里，我们对Kindlin-2的Pleckstrin同源结构域和F0结构域在含有不同质子化状态的磷脂酰肌醇4，5-二磷酸/磷脂酰肌醇3，4，5-三磷酸的膜上进行了原子模拟。这种计算方法表明，这两种磷脂酰肌醇磷酸以质子化状态依赖的方式不同地调制Kindlin-2亚域结合。我们推测，这些结合模式的变化为细胞内pH和钙离子内流提供了一种机制，以控制Kindlin-2的膜结合行为和活性。
Kindlin-2, a member of the Kindlin family of peripheral membrane proteins, is important for integrin activation and stabilization of epidermal growth factor receptor. It associates with the cytoplasmic face of the plasma membrane via dedicated phosphatidylinositol phosphate binding domains located in the N-terminal F0 and Pleckstrin Homology domains. These domains have binding affinity for phosphatidylinositol 4,5-bisphosphate and, to a greater degree, phosphatidylinositol 3,4,5-trisphosphate. The biological significance of the differential binding of these phosphatidylinositol phosphates to Kindlin-2 and the mechanism by which they activate Kindlin-2 are not well understood. Recently, ssNMR identified the predominant protonation states of phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate near physiological pH in the presence of anionic lipids. Here, we perform atomistic simulation of the bound state of the Pleckstrin Homology and F0 domains of Kindlin-2 at membranes containing phosphatidylinositol 4,5-bisphosphate/phosphatidylinositol 3,4,5-trisphosphate with differing protonation states. This computational approach demonstrates that these two phosphatidylinositol phosphates differently modulate Kindlin-2 subdomain binding in a protonation-state-dependent manner. We speculate these variations in binding mode provide a mechanism for intracellular pH and Ca2+influx to control the membrane binding behavior and activity of Kindlin-2.