Computational and Experimental Studies of Lipid-Protein Interactions in Biomemrane Function
Computational and Experimental Studies of Lipid-Protein Interactions in Biomemrane Function
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生物膜功能中脂质-蛋白质相互作用的计算和实验研究
DOI：
10.1016/j.bpj.2015.11.1411
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发表时间：
2016
影响因子：
3.4
通讯作者：
Liang, Hongjun
中科院分区：
文献类型：
--
作者：
Musharrafieh, Rami;Chawla, Udeep;Zheng, Wan;Kaung, Liangju;Perera, Suchithranga M.D.C.;Knowles, Thomas;Huang, Annie;Pitman, Michael C.;Wang, Jun;Liang, Hongjun
整合膜蛋白占人类基因组的30%以上。大量的脂质-蛋白质相互作用有助于膜蛋白（例如 GPCR 和病毒膜离子通道）的结构和功能。我们探讨了膜的物理特性以及脂质头基上的正电荷如何调节蛋白质激活。柔性表面模型 (FSM) 描述了影响膜蛋白激活的脂质环境的物理特性 [3]。根据 FSM，膜脂质与完整膜蛋白的弹性耦合通过曲率和疏水力的平衡来定义脂质-蛋白质相互作用。使用紫外-可见光谱、FTIR 光谱 [2] 和分子动力学 (MD) 模拟，我们发现脂质双层特性（如头基和链长）通过影响构象状态来调节膜蛋白功能。使用视紫红质（一种典型的 G 蛋白偶联受体 (GPCR)）作为原型，我们使用紫外可见光谱和 MD 模拟展示了带正电荷的膜脂头基对视紫红质激活的影响。我们发现在膜脂中重组的视紫红质具有带正电荷的头基（如 DOTAP），可将平衡转变为活性 Meta-II 状态。我们提出了一种机制，其中带正电头基的膜脂与脂质-蛋白质界面上存在的 Glu134 相互作用，打破了与保守 ERY 基序中的 Arg135 的盐桥。 Glu134 和带正电的头基之间的相互作用稳定了活性 Meta-II 状态。我们的研究深入了解了膜脂-蛋白质相互作用在视紫红质激活机制中的作用，最终可以扩展到流感病毒膜离子通道和其他整合蛋白。 [1] AV Struts 等人 (2015) 方法。摩尔。生物。 1271, 133-158.[2] E. Zaitseva 等人 (2010) JACS 132, 4815-4821.[3] MF 布朗 (2012) 生物化学 51, 9782-9795。
Integral membrane proteins constitute more than 30% of the human genome. Substantial lipid-protein interactions contribute to the structure and function of membrane proteins such as GPCRs and viral membrane ion channels. We address how physical properties of the membrane as well as positive charge on the lipid head group modulate protein activation. The flexible surface model (FSM) describes physical properties of the lipid environment that effect membrane protein activation [3]. According to the FSM, elastic coupling of the membrane lipids to integral membrane proteins define lipid-protein interactions through a balance of curvature and hydrophobic forces. Using UV-visible spectroscopy, FTIR spectroscopy [2], and molecular dynamics (MD) simulations, we discovered that lipid bilayer properties like head group and chain length modulate membrane protein functioning by influencing the conformational states. Using rhodopsin, a canonical G-protein-coupled receptor (GPCR) as a prototype, we show the effect of positively charged membrane lipid head group on rhodopsin activation using UV-visible spectroscopy and MD simulations. We discovered rhodopsin reconstituted in membrane lipids with a positively charged head group like DOTAP shifts the equilibrium to active Meta-II state. We propose a mechanism where membrane lipids with positively charged head group interact with Glu134 present on lipid-protein interface breaking the salt bridge with Arg135 in the conserved ERY motif. The interaction between Glu134 and the positively charged head group stabilizes the active Meta-II state. Our study gives insight on the role of membrane lipid-protein interactions in rhodopsin activation mechanism which can ultimately be extended to influenza virus membrane ion channels and other integral proteins.[1] AV Struts et al.(2015) Meth. Mol. Biol. 1271, 133-158.[2] E. Zaitseva et al.(2010) JACS 132, 4815-4821.[3] MF Brown (2012) Biochemistry 51, 9782-9795.