Encoding the β-Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C-Tail-Independent Molecular Determinants in GPCRs.,ACS Pharmacology & Translational Science

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Encoding the β-Arrestin Trafficking Fate of Ghrelin Receptor GHSR1a: C-Tail-Independent Molecular Determinants in GPCRs.
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2019-06-03 , DOI: 10.1021/acsptsci.9b00018
Krisztian Toth _{1,

2} , Karim Nagi _{1,

3} , Lauren M Slosky ₁ , Lauren Rochelle ₁ , Caroline Ray ₁ , Suneet Kaur ₁ , Sudha K Shenoy _{1,

1} , Marc G Caron _{1,

1,

1} , Larry S Barak ₁

Affiliation

G-protein-coupled receptors (GPCRs) can bias signaling through distinct biochemical pathways that originate from G-protein/receptor and β-arrestin/receptor complexes. Receptor conformations supporting β-arrestin engagement depend on multiple receptor determinants. Using ghrelin receptor GHR1a, we demonstrate by bioluminescence resonance energy transfer and fluorescence microscopy a critical role for its second intracellular loop 2 (ICL2) domain in stabilizing β-arrestin/GHSR1a core interactions and determining receptor trafficking fate. We validate our findings in ICL2 gain- and loss-of-function experiments assessing β-arrestin and ubiquitin-dependent internalization of the CC chemokine receptor, CCR1. Like all CC and CXC subfamily chemokine receptors, CCR1 lacks a critical proline residue found in the ICL2 consensus domain of rhodopsin-family GPCRs. Our study indicates that ICL2, C-tail determinants, and the orthosteric binding pocket that regulates β-arrestin/receptor complex stability are sufficient to encode a broad repertoire of the trafficking fates observed for rhodopsin-family GPCRs, suggesting they provide the essential elements for regulating a large fraction of β-arrestin signaling bias.

中文翻译：

编码 Ghrelin 受体 GHSR1a 的 β-Arrestin 贩运命运：GPCR 中与 C-尾无关的分子决定因素。

G 蛋白偶联受体 (GPCR) 可以通过源自 G 蛋白/受体和 β-抑制素/受体复合物的不同生化途径偏向信号传导。支持 β-arrestin 参与的受体构象取决于多个受体决定因素。使用 ghrelin 受体 GHR1a，我们通过生物发光共振能量转移和荧光显微镜证明其第二个细胞内环 2 (ICL2) 结构域在稳定 β-arrestin/GHSR1a 核心相互作用和确定受体运输命运中的关键作用。我们在 ICL2 功能获得和功能丧失实验中验证了我们的发现，该实验评估了 CC 趋化因子受体 CCR1 的 β-抑制蛋白和泛素依赖性内化。像所有 CC 和 CXC 亚家族趋化因子受体一样，CCR1 缺乏在视紫红质家族 GPCR 的 ICL2 共有域中发现的关键脯氨酸残基。我们的研究表明 ICL2、C 尾决定簇和调节 β-抑制蛋白/受体复合物稳定性的正构结合口袋足以编码视紫红质家族 GPCR 观察到的广泛的运输命运，表明它们为调节大部分 β-arrestin 信号偏倚。

更新日期：2019-06-13

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