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Transition between conformational states of the TREK-1 K2P channel promoted by interaction with PIP2
Biophysical Journal ( IF 3.2 ) Pub Date : 2022-05-19 , DOI: 10.1016/j.bpj.2022.05.019
Adisorn Panasawatwong 1 , Tanadet Pipatpolkai 2 , Stephen J Tucker 3
Affiliation  

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 PIP2 increases TREK-1 channel activity; however, the mechanistic understanding of the conformational transitions induced by PIP2 remain 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 PIP2 binding 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 PIP2 to sites involving the proximal C-terminus, and we show that PIP2 promotes a conformational transition from a down state toward an intermediate that resembles the up state. These results are consistent with functional data for PIP2 regulation, and together provide evidence for a structural mechanism of TREK-1 channel activation by phosphoinositides.



中文翻译:

与 PIP2 相互作用促进 TREK-1 K2P 通道构象状态之间的转变

双孔结构域钾通道 TREK 家族的成员对膜脂的调节高度敏感,包括磷脂酰肌醇-4,5-二磷酸 (PIP 2 )。先前的研究表明,PIP 2会增加 TREK-1 通道的活性;然而,对 PIP 2诱导的构象转变的机制理解仍不清楚。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 上态和下态构象上的PIP 2结合位点。我们还计算了 PIP 2的自由能使用平均力势和自由能微扰计算,在两种构象状态下相对于其他阴离子磷脂进行结合。我们的结果确定了 PIP 2与涉及近端 C 末端的位点的状态依赖性结合,并且我们表明 PIP 2促进从向下状态到类似于向上状态的中间状态的构象转变。这些结果与 PIP 2调节的功能数据一致,并共同为磷酸肌醇激活 TREK-1 通道的结构机制提供了证据。

更新日期:2022-05-19
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