Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex.,Nature Structural & Molecular Biology

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Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex.
Nature Structural & Molecular Biology ( IF 12.5 ) Pub Date : 2019-11-18 , DOI: 10.1038/s41594-019-0330-y
Anthony H Nguyen _{1,

2} , Alex R B Thomsen _{1,

3} , Thomas J Cahill _{1,

2} , Rick Huang ₄ , Li-Yin Huang ₁ , Tara Marcink _{5,

6} , Oliver B Clarke _{7,

8,

9} , Søren Heissel ₁₀ , Ali Masoudi ₁ , Danya Ben-Hail ₁₁ , Fadi Samaan ₁₁ , Venkata P Dandey ₁₂ , Yong Zi Tan _{12,

13} , Chuan Hong ₄ , Jacob P Mahoney _{14,

15} , Sarah Triest _{16,

17} , John Little ₂ , Xin Chen ₁₈ , Roger Sunahara _{14,

19} , Jan Steyaert ₁₆ , Henrik Molina ₁₀ , Zhiheng Yu ₄ , Amedee des Georges _{11,

20,

21} , Robert J Lefkowitz _{1,

2,

22}

Affiliation

Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Department of Biochemistry, Duke University Medical Center, Durham, NC, USA.
Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA.
Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA, USA.
Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
Center for Host-Pathogen Interaction, Columbia University Irving Medical Center, New York, NY, USA.
Department of Anesthesiology, Columbia University Irving Medical Center, New York, NY, USA.
Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
The Irving Center for Clinical and Translational Research, Columbia University Irving Medical Center, New York, NY, USA.
Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
Structural Biology Initiative, CUNY Advanced Science Research Center, New York, NY, USA.
The National Resource for Automated Molecular Microscopy, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA.
Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA.
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Department of Structural Biology, Stanford University, Stanford, CA, USA.
Structural Biology Brussels, Vrije Universiteit Brussels, Brussels, Belgium.
Structural Biology Research Center, Vlaams Instituut voor Biotechnologie, Brussels, Belgium.
School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China.
Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
Department of Chemistry and Biochemistry, City College of New York, New York, NY, USA.
Biochemistry and Chemistry PhD Programs, Graduate Center, City University of New York, New York, NY, USA.
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA.

Classically, G-protein-coupled receptors (GPCRs) are thought to activate G protein from the plasma membrane and are subsequently desensitized by β-arrestin (β-arr). However, some GPCRs continue to signal through G protein from internalized compartments, mediated by a GPCR-G protein-β-arr 'megaplex'. Nevertheless, the molecular architecture of the megaplex remains unknown. Here, we present its cryo-electron microscopy structure, which shows simultaneous engagement of human G protein and bovine β-arr to the core and phosphorylated tail, respectively, of a single active human chimeric β2-adrenergic receptor with the C-terminal tail of the arginine vasopressin type 2 receptor (β2V2R). All three components adopt their canonical active conformations, suggesting that a single megaplex GPCR is capable of simultaneously activating G protein and β-arr. Our findings provide a structural basis for GPCR-mediated sustained internalized G protein signaling.

中文翻译：

内体信号转导 GPCR-G 蛋白-β-抑制蛋白巨复合体的结构。

传统上，G 蛋白偶联受体 (GPCR) 被认为可以激活质膜上的 G 蛋白，随后被 β-arrestin (β-arr) 脱敏。然而，一些 GPCR 继续通过 G 蛋白从内化区室发出信号，由 GPCR-G 蛋白-β-arr 'megaplex' 介导。然而，megaplex 的分子结构仍然未知。在这里，我们展示了它的低温电子显微镜结构，它显示了人 G 蛋白和牛 β-arr 同时分别与单个活性人嵌合 β2-肾上腺素能受体的核心和磷酸化尾部结合，其 C 末端尾部为精氨酸加压素 2 型受体 (β2V2R)。所有三个组件都采用其规范的活性构象，表明单个 megaplex GPCR 能够同时激活 G 蛋白和 β-arr。我们的研究结果为 GPCR 介导的持续内化 G 蛋白信号传导提供了结构基础。

更新日期：2019-11-18

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