脂质作用位点塑造五聚体配体门控离子通道的激动剂反应。
A lipid site shapes the agonist response of a pentameric ligand-gated ion channel.
机构信息
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Laboratory for the Structure and Function of Biological Membranes, Center for Structural Biology and Bioinformatics, Université libre de Bruxelles, Brussels, Belgium.
出版信息
Nat Chem Biol. 2019 Dec;15(12):1156-1164. doi: 10.1038/s41589-019-0369-4. Epub 2019 Oct 7.
Phospholipids are key components of cellular membranes and are emerging as important functional regulators of different membrane proteins, including pentameric ligand-gated ion channels (pLGICs). Here, we take advantage of the prokaryote channel ELIC (Erwinia ligand-gated ion channel) as a model to understand the determinants of phospholipid interactions in this family of receptors. A high-resolution structure of ELIC in a lipid-bound state reveals a phospholipid site at the lower half of pore-forming transmembrane helices M1 and M4 and at a nearby site for neurosteroids, cholesterol or general anesthetics. This site is shaped by an M4-helix kink and a Trp-Arg-Pro triad that is highly conserved in eukaryote GABA and glycine receptors. A combined approach reveals that M4 is intrinsically flexible and that M4 deletions or disruptions of the lipid-binding site accelerate desensitization in ELIC, suggesting that lipid interactions shape the agonist response. Our data offer a structural context for understanding lipid modulation in pLGICs.
磷脂是细胞膜的关键组成部分，并且正在成为不同膜蛋白（包括五聚体配体门控离子通道（pLGIC））的重要功能调节剂。在这里，我们利用原核通道 ELIC（Erwinia 配体门控离子通道）作为模型来了解该受体家族中磷脂相互作用的决定因素。在脂结合状态下的 ELIC 的高分辨率结构揭示了位于形成跨膜螺旋 M1 和 M4 的下半部分的磷脂结合位点，以及位于附近的神经甾体、胆固醇或全身麻醉剂的结合位点。该位点由 M4 螺旋扭曲和高度保守的三肽 Trp-Arg-Pro 形成，在真核 GABA 和甘氨酸受体中也是如此。综合方法表明 M4 本质上是灵活的，并且 M4 缺失或破坏脂质结合位点会加速 ELIC 的脱敏，这表明脂质相互作用塑造了激动剂反应。我们的数据为理解 pLGIC 中的脂质调节提供了结构背景。
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