Full-Length P2X7 Structures Reveal How Palmitoylation Prevents Channel Desensitization
Full-Length P2X7 Structures Reveal How Palmitoylation Prevents Channel Desensitization
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DOI：
10.1016/j.cell.2019.09.017
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发表时间：
2019-10-17
期刊：
影响因子：
64.5
通讯作者：
Mansoor, Steven E.
中科院分区：
文献类型：
--
作者：
McCarthy, Alanna E.;Yoshioka, Craig;Mansoor, Steven E.
P2X受体是由细胞外ATP激活的三聚体非选择性阳离子通道。P2X(7)受体亚型是一个药理靶点，因为它参与了细胞凋亡、炎症和肿瘤进展途径。它是结构上和功能上最不同的P2X亚型，包含一个独特的细胞质结构域，对受体启动凋亡和不脱敏至关重要。然而，缺乏关于细胞质结构域的结构信息阻碍了对这些过程背后的分子机制的理解。我们报道了全长大鼠P2X(7)受体在载脂蛋白和三磷酸腺苷结合状态下的冷冻电子显微镜结构。这些结构揭示了细胞质元件C-CyS锚是如何通过将孔衬螺旋锚定在带有棕榈酰基的膜上来防止脱敏的。它们显示了第二个具有独特折叠的细胞质元件--细胞质压舱物，它出人意料地包含一个锌离子复合体和一个鸟苷核苷酸结合部位。我们的结构提供了对P2X受体细胞质区域的结构和功能的首次洞察。
P2X receptors are trimeric, non-selective cation channels activated by extracellular ATP. The P2X(7) receptor subtype is a pharmacological target because of involvement in apoptotic, inflammatory, and tumor progression pathways. It is the most structurally and functionally distinct P2X subtype, containing a unique cytoplasmic domain critical for the receptor to initiate apoptosis and not undergo desensitization. However, lack of structural information about the cytoplasmic domain has hindered understanding of the molecular mechanisms underlying these processes. We report cryoelectron microscopy structures of full-length rat P2X(7) receptor in apo and ATP-bound states. These structures reveal how one cytoplasmic element, the C-cys anchor, prevents desensitization by anchoring the pore-lining helix to the membrane with palmitoyl groups. They show a second cytoplasmic element with a unique fold, the cytoplasmic ballast, which unexpectedly contains a zinc ion complex and a guanosine nucleotide binding site. Our structures provide first insights into the architecture and function of a P2X receptor cytoplasmic domain.