Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):7803-7813. doi: 10.1073/pnas.1918387117. Epub 2020 Mar 25.
Protein-lipid interactions are a key element of the function of many integral membrane proteins. These potential interactions should be considered alongside the complexity and diversity of membrane lipid composition. Inward rectifier potassium channel (Kir) Kir2.2 has multiple interactions with plasma membrane lipids: Phosphatidylinositol (4, 5)-bisphosphate (PIP) activates the channel; a secondary anionic lipid site has been identified, which augments the activation by PIP; and cholesterol inhibits the channel. Molecular dynamics simulations are used to characterize in molecular detail the protein-lipid interactions of Kir2.2 in a model of the complex plasma membrane. Kir2.2 has been simulated with multiple, functionally important lipid species. From our simulations we show that PIP interacts most tightly at the crystallographic interaction sites, outcompeting other lipid species at this site. Phosphatidylserine (PS) interacts at the previously identified secondary anionic lipid interaction site, in a PIP concentration-dependent manner. There is interplay between these anionic lipids: PS interactions are diminished when PIP is not present in the membrane, underlining the need to consider multiple lipid species when investigating protein-lipid interactions.
蛋白质-脂质相互作用是许多整合膜蛋白功能的关键要素。这些潜在的相互作用应该与膜脂组成的复杂性和多样性一起考虑。内向整流钾通道（Kir）Kir2.2 与质膜脂质有多种相互作用：磷脂酰肌醇（4,5）-二磷酸（PIP）激活通道；已确定了一个辅助阴离子脂质结合位点，该位点增强了 PIP 的激活作用；胆固醇抑制通道。分子动力学模拟用于在复杂质膜模型中以分子细节表征 Kir2.2 的蛋白-脂质相互作用。已经用多种具有重要功能的脂质物种对 Kir2.2 进行了模拟。从我们的模拟中可以看出，PIP 在晶体学相互作用位点上的相互作用最紧密，在该位点上胜过其他脂质物种。磷脂酰丝氨酸（PS）以 PIP 浓度依赖的方式在先前确定的辅助阴离子脂质相互作用位点上相互作用。这些阴离子脂质之间存在相互作用：当膜中不存在 PIP 时，PS 相互作用会减弱，这强调了当研究蛋白-脂质相互作用时需要考虑多种脂质物种。
