Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling
Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling
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DOI：
10.1126/sciadv.abb8368
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发表时间：
2020-09-01
期刊：
影响因子：
13.6
通讯作者：
Shukla, Arun K.
中科院分区：
文献类型：
--
作者：
Dwivedi-Agnihotri, Hemlata;Chaturvedi, Madhu;Shukla, Arun K.
激动剂诱导的G蛋白偶联受体（gpcr）的磷酸化是它们与β -抑制素（β - arrs）相互作用和随后的功能反应的关键决定因素。因此，破译不同受体磷酸化位点在控制β - arr相互作用和功能结果中的作用和相互作用是很重要的。在这里，我们发现人抗利尿激素受体（V2R）中的几个磷酸化位点，无论是单独定位还是集群定位，都对β - arr的募集、运输和ERK1/2激活有不同的贡献。即使是V2R中的单个磷酸化位点，在与β - arrs中的关键残基进行适当的串导时，也对β - arr的募集起决定性作用，其突变导致强烈的g蛋白偏倚。分子动力学模拟提供了这一关键磷酸化位点在控制β - arr相互作用稳定性和调节β - arr结构域间旋转中的关键作用的机制见解。我们的发现揭示了重要的结构方面，以更好地理解gpcr - β - arr相互作用和偏倚信号的框架。
Agonist-induced phosphorylation of G protein-coupled receptors (GPCRs) is a key determinant for their interaction with beta-arrestins (beta arrs) and subsequent functional responses. Therefore, it is important to decipher the contribution and interplay of different receptor phosphorylation sites in governing beta arr interaction and functional outcomes. Here, we find that several phosphorylation sites in the human vasopressin receptor (V2R), positioned either individually or in clusters, differentially contribute to beta arr recruitment, trafficking, and ERK1/2 activation. Even a single phosphorylation site in V2R, suitably positioned to cross-talk with a key residue in beta arrs, has a decisive contribution in beta arr recruitment, and its mutation results in strong G-protein bias. Molecular dynamics simulation provides mechanistic insights into the pivotal role of this key phosphorylation site in governing the stability of beta arr interaction and regulating the interdomain rotation in beta arrs. Our findings uncover important structural aspects to better understand the framework of GPCR-beta arr interaction and biased signaling.