Defining how multiple lipid species interact with inward rectifier potassium (Kir2) channels
Defining how multiple lipid species interact with inward rectifier potassium (Kir2) channels
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DOI：
10.1073/pnas.1918387117
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发表时间：
2020-04-07
影响因子：
11.1
通讯作者：
Sansom, Mark S. P.
中科院分区：
文献类型：
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作者：
Duncan, Anna L.;Corey, Robin A.;Sansom, Mark S. P.
蛋白质-脂质相互作用是许多完整膜蛋白功能的关键要素。这些潜在的相互作用应该与膜脂成分的复杂性和多样性一起考虑。内向整流钾通道(KIR)Kir2.2与质膜脂类有多种相互作用：磷脂酰肌醇(4，5)-二磷酸(PIP2)激活该通道；已确定第二阴离子脂质位点，增强PIP2的激活；胆固醇抑制该通道。分子动力学模拟被用来描述复杂质膜模型中Kir2.2的蛋白质-脂质相互作用的分子细节。Kir2.2已经用多种功能重要的脂类物种进行了模拟。我们的模拟表明，PIP2在晶体相互作用位置上相互作用最紧密，在这个位置上比其他脂质物种竞争更激烈。磷脂酰丝氨酸(PS)以PIP2浓度依赖的方式在先前发现的次级阴离子脂相互作用部位相互作用。这些阴离子脂类之间存在相互作用：当膜上不存在PIP2时，PS相互作用减弱，这突显了在研究蛋白质-脂类相互作用时考虑多种脂类的必要性。
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 (PIP2) activates the channel; a secondary anionic lipid site has been identified, which augments the activation by PIP2; 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 PIP2 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 PIP2 concentration-dependent manner. There is interplay between these anionic lipids: PS interactions are diminished when PIP2 is not present in the membrane, underlining the need to consider multiple lipid species when investigating protein-lipid interactions.