Helix 8 is the essential structural motif of mechanosensitive GPCRs
Helix 8 is the essential structural motif of mechanosensitive GPCRs
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DOI：
10.1038/s41467-019-13722-0
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发表时间：
2019-12-19
影响因子：
16.6
通讯作者：
Mederos y Schnitzler, Michael
中科院分区：
文献类型：
--
作者：
Erdogmus, Serap;Storch, Ursula;Mederos y Schnitzler, Michael
G蛋白偶联受体（GPCR）是化学刺激的多功能细胞传感器，但也用作参与各种（病理）生理环境如血管调节、心脏肥大和先兆子痫的机械传感器。然而，机械诱导的GPCR活化的分子机制仍然难以捉摸。在这里，我们表明，机械敏感性组胺H-1受体（H（1）Rs）是流体剪切应力的内皮传感器，并有助于流动诱导的血管舒张。在分子水平上，我们观察到H（1）Rs经历刺激特异性构象变化模式，表明机械力和激动剂诱导不同的活性受体构象。缺乏C-末端螺旋8（H8）的GPCR不是机械敏感性的，并且将H8转移到非响应性GPCR赋予机械敏感性，而去除H8则排除机械敏感性。此外，通过氨基酸交换破坏H8结构完整性会损害机械敏感性。总之，H8是赋予GPCR机械敏感性的基本结构基序。这些发现提供了一个机械的基础，更好地理解机械敏感GPCR的作用（病理）生理学。
G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H-1 receptors (H(1)Rs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation. At the molecular level, we observe that H(1)Rs undergo stimulus-specific patterns of conformational changes suggesting that mechanical forces and agonists induce distinct active receptor conformations. GPCRs lacking C-terminal helix 8 (H8) are not mechanosensitive, and transfer of H8 to non-responsive GPCRs confers, while removal of H8 precludes, mechanosensitivity. Moreover, disrupting H8 structural integrity by amino acid exchanges impairs mechanosensitivity. Altogether, H8 is the essential structural motif endowing GPCRs with mechanosensitivity. These findings provide a mechanistic basis for a better understanding of the roles of mechanosensitive GPCRs in (patho)physiology.