Transition between conformational states of the TREK-1 K2P channel promoted by interaction with PIP 2
Transition between conformational states of the TREK-1 K2P channel promoted by interaction with PIP 2
复制标题
与 PIP 2 相互作用促进 TREK-1 K2P 通道构象状态之间的转变
DOI：
10.1101/2022.02.27.482173
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Panasawatwong A
中科院分区：
文献类型：
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作者：
Panasawatwong A
TREK家族的两孔结构域钾通道对膜脂的调节高度敏感，包括磷脂酰肌醇-4，5-二磷酸(PIP2)。先前的研究表明，PIP2增加了Trek-1通道的活性；然而，对PIP2诱导的构象转变的机制了解尚不清楚。在这里，我们使用粗粒度分子动力学和原子分子动力学模拟来模拟Trek-1的上态和下态构象上的PIP2结合位点。我们还利用平均力势和自由能微扰计算了PIP2与其他阴离子磷脂在两种构象状态下的结合自由能。我们的结果发现PIP2与涉及近端C-末端的位点的结合依赖于状态，我们表明PIP2促进了从向下状态到类似于向上状态的中间体的构象转变。这些结果与PIP2调节的功能数据一致，共同为肌醇磷脂激活Trek-1通道的结构机制提供了证据。
Members of the TREK family of two-pore domain potassium channels are highly sensitive to regulation by membrane lipids, including phosphatidylinositol-4,5-bisphosphate (PIP2). Previous studies have demonstrated that PIP2increases TREK-1 channel activity; however, the mechanistic understanding of the conformational transitions induced by PIP2remain unclear. Here, we used coarse-grained molecular dynamics and atomistic molecular dynamics simulations to model the PIP2-binding site on both the up and down state conformations of TREK-1. We also calculated the free energy of PIP2binding relative to other anionic phospholipids in both conformational states using potential of mean force and free-energy-perturbation calculations. Our results identify state-dependent binding of PIP2to sites involving the proximal C-terminus, and we show that PIP2promotes a conformational transition from a down state toward an intermediate that resembles the up state. These results are consistent with functional data for PIP2regulation, and together provide evidence for a structural mechanism of TREK-1 channel activation by phosphoinositides.