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神经降压素受体1与β-arrestin1的复合物结构获解析
2020-01-22 13:31

美国斯坦福大学医学院Brian K. Kobilka、Georgios Skiniotis等研究人员合作解析了神经降压素受体1与β-arrestin1的复合物结构。相关论文2020年1月16日在线发表于《自然》。

研究人员报道了全长人类神经降压素受体1(NTSR1)与人类截断的人β-arrestin1(βarr1ΔCT)结合的冷冻电镜结构。研究人员发现,NTSR1的磷酸化对于与βarr1ΔCT形成稳定复合物至关重要,并且在第三个细胞内环和C末端均发现了可能促进这种相互作用的磷酸化位点。此外,研究人员观察到磷脂酰肌醇-4,5-双磷酸(PI(4,5)P2)分子在NTSR1跨膜片段1和4的膜侧与arrestin蛋白的C叶之间形成桥梁。与视紫红质-arrestin-1的结构相比,这一结构表明arrestin相对于受体旋转了约85°。这些发现既强调了保守的方面,又强调了arrestin与受体相互作用的可塑性。
 
据介绍,arrestin蛋白与活跃的磷酸化G蛋白偶联受体(GPCR)结合,从而阻止G蛋白偶联,触发受体內吞并影响各种下游信号传导途径。尽管有大量的结构信息描述了GPCR与G蛋白之间的相互作用,但对于抑制蛋白如何与GPCR结合的了解却很少。
 
附:英文原文

Title: Structure of the neurotensin receptor 1 in complex with β-arrestin 1

Author: Weijiao Huang, Matthieu Masureel, Qu Qianhui, John Janetzko, Asuka Inoue, Hideaki E. Kato, Michael J. Robertson, Khanh C. Nguyen, Jeffrey S. Glenn, Georgios Skiniotis, Brian K. Kobilka

Issue&Volume: 2020-01-16

Abstract: Arrestin proteins bind to active, phosphorylated G-protein-coupled receptors (GPCRs), thereby preventing G-protein coupling, triggering receptor internalization, and affecting various downstream signalling pathways1,2. Although there is a wealth of structural information delineating the interactions between GPCRs and G proteins, less is known about how arrestins engage GPCRs. Here we report a cryo-EM structure of full-length human neurotensin receptor 1 (NTSR1) in complex with truncated human β-arrestin 1 (βarr1ΔCT). We found that phosphorylation of NTSR1 was critical for obtaining a stable complex with βarr1ΔCT, and identified phosphorylated sites in both the third intracellular loop and the C terminus that may promote this interaction. In addition, we observed a phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) molecule forming a bridge between the membrane side of NTSR1 transmembrane segments 1 and 4 and the C-lobe of arrestin. Compared to a structure of rhodopsin-arrestin-1, our structure displays an approximately 85° rotation of arrestin relative to the receptor. These findings highlight both conserved aspects but also the plasticity of arrestin–receptor interactions.

DOI: 10.1038/s41586-020-1953-1

Source: https://www.nature.com/articles/s41586-020-1953-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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