Allosteric regulation of G protein-coupled receptor activity by phospholipids.
Allosteric regulation of G protein-coupled receptor activity by phospholipids.
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DOI：
10.1038/nchembio.1960
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发表时间：
2016-01
影响因子：
14.8
通讯作者：
Govaerts C
中科院分区：
文献类型：
--
作者：
Dawaliby R;Trubbia C;Delporte C;Masureel M;Van Antwerpen P;Kobilka BK;Govaerts C
脂质正在成为膜蛋白结构和活性的关键调节剂。这种效应可以归因于双层性质（厚度、曲率和表面张力）的改变或特定脂质与蛋白质表面的结合。对于G蛋白偶联受体（GPCR），磷脂对受体结构和活性的影响仍然知之甚少。在此，我们在高密度脂质颗粒中重构纯化的β2-肾上腺素能受体，以系统地表征生物学相关磷脂对受体活性的影响。我们观察到，脂质头基类型影响配体结合（激动剂和拮抗剂）和受体活化。具体而言，磷脂酰甘油明显有利于激动剂结合并促进受体活化，而磷脂酰乙醇胺有利于拮抗剂结合并稳定受体的非活性状态。然后，我们表明，这些效果可以概括与洗涤剂溶解的脂质，表明功能调制发生在没有双层。我们的数据表明，磷脂作为GPCR活性的直接变构调节剂。
Lipids are emerging as key regulators of membrane protein structure and activity. Such effects can either be attributed to modification in bilayer properties (thickness, curvature and surface tension) or to binding of specific lipids to the protein surface. For G Protein-Coupled Receptors (GPCRs), the effect of phospholipids on receptor structure and activity remains poorly understood. Here we reconstituted purified β2-adrenergic receptor in High-Density-Lipoparticles to systematically characterize the effect of biologically relevant phospholipids on receptor activity. We observe that the lipid head-group type affects ligand binding (agonist and antagonist) and receptor activation. Specifically, phosphatidylgycerol markedly favors agonist binding and facilitates receptor activation while phosphatidylethanolamine favors antagonist binding and stabilizes the inactive state of the receptor. We then show that these effects can be recapitulated with detergent-solubilized lipids, demonstrating that the functional modulation occurs in the absence of a bilayer. Our data suggest that phospholipids act as direct allosteric modulators of GPCR activity.