Regulating G protein-coupled receptors by topological inversion
Regulating G protein-coupled receptors by topological inversion
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DOI：
10.7554/elife.40234
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发表时间：
2019-03-05
期刊：
影响因子：
7.7
通讯作者：
Ye, Jin
中科院分区：
文献类型：
--
作者：
Denard, Bray;Han, Sungwon;Ye, Jin
G蛋白偶联受体（GPCR）是一个含有7个跨膜螺旋的蛋白质家族，蛋白质的N-和C-末端分别位于细胞外空间和胞质溶胶。在这里，我们报告说，神经酰胺或相关的鞘脂可能会反转拓扑结构的许多GPCR，包含一个GXXXN基序在其第一个跨膜螺旋。这种拓扑调控的功能意义由CCR 5趋化因子受体说明。在不存在脂多糖（LPS）的情况下，CCR 5采用与GPCR一致的拓扑结构，允许小鼠腹腔巨噬细胞向其配体CCL 5迁移。LPS刺激导致二氢神经酰胺的产生增加，其反转CCR 5的拓扑结构，防止巨噬细胞向CCL 5迁移。这些结果表明，GPCR可能并不总是采用相同的拓扑结构，可以通过拓扑反转进行调节。
G protein-coupled receptors (GPCRs) are a family of proteins containing seven transmembrane helices, with the N- and C-terminus of the protein located at the extracellular space and cytosol, respectively. Here, we report that ceramide or related sphingolipids might invert the topology of many GPCRs that contain a GXXXN motif in their first transmembrane helix. The functional significance of this topological regulation is illustrated by the CCR5 chemokine receptor. In the absence of lipopolysaccharide (LPS), CCR5 adopts a topology consistent with that of GPCR, allowing mouse peritoneal macrophages to migrate toward its ligand CCL5. LPS stimulation results in increased production of dihydroceramide, which inverts the topology of CCR5, preventing macrophages from migrating toward CCL5. These results suggest that GPCRs may not always adopt the same topology and can be regulated through topological inversion.