Arrestin recruitment to CCR5: potent CCL5 analogs reveal differences in dependence on receptor phosphorylation and isoform-specific recruitment bias.,Molecular Pharmacology

当前位置： X-MOL 学术 › Mol. Pharmacol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Arrestin recruitment to CCR5: potent CCL5 analogs reveal differences in dependence on receptor phosphorylation and isoform-specific recruitment bias.
Molecular Pharmacology ( IF 3.2 ) Pub Date : 2020-11-01 , DOI: 10.1124/molpharm.120.000036
Elsa Martins ₁ , Hellena Brodier ₁ , Irène Rossitto-Borlat ₁ , Ilke Ilgaz ₁ , Mélanie Villard ₁ , Oliver Hartley ₂

Affiliation

C-C chemokine receptor 5 (CCR5) is a chemokine receptor belonging to the G protein–coupled receptor (GPCR) superfamily. An established anti–human immunodeficiency virus drug target, CCR5 is attracting significant additional interest in both cancer and neuroinflammation. Several N-terminally engineered analogs of C-C chemokine ligand 5 (CCL5), a natural ligand of CCR5, are highly potent CCR5 inhibitors. The inhibitory mechanisms of certain analogs relate to modulation of receptor desensitization, but the cellular and molecular mechanisms have not been fully elucidated. Here we made use of a collection of CCR5 phosphorylation mutants and arrestin variants to investigate how CCL5 analogs differ from CCL5 in their capacity to elicit both CCR5 phosphorylation and arrestin recruitment, with reference to the current “core” and “tail” interaction model for arrestin-GPCR interaction. We showed that CCL5 recruits both arrestin 2 and arrestin 3 to CCR5 with recruitment, particularly of arrestin 2, strongly dependent on the arrestin tail interaction. 5P12–RANTES does not elicit receptor phosphorylation or arrestin recruitment. In contrast, PSC-RANTES induces CCR5 hyperphosphorylation, driving enhanced arrestin recruitment with lower dependence on the arrestin tail interaction. 5P14-RANTES induces comparable levels of receptor phosphorylation to CCL5, but arrestin recruitment is absolutely dependent on the arrestin tail interaction, and in one of the cellular backgrounds used, recruitment showed isoform bias toward arrestin 3 versus arrestin 2. No evidence for ligand-specific differences in receptor phosphorylation patterns across the four implicated serine residues was observed. Our results improve understanding of the molecular pharmacology of CCR5 and help further elucidate the inhibitory mechanisms of a group of potent inhibitors.

中文翻译：

Arrestin募集至CCR5：有效的CCL5类似物揭示了对受体磷酸化和异构体特异性募集偏倚的依赖性差异。

CC趋化因子受体5（CCR5）是一种趋化因子受体，属于G蛋白偶联受体（GPCR）超家族。已建立的抗人类免疫缺陷病毒药物靶标CCR5在癌症和神经炎症方面也引起了极大的兴趣。CC趋化因子配体5（CCL5）（CCR5的天然配体）的几种N端工程改造类似物是高效的CCR5抑制剂。某些类似物的抑制机制与受体脱敏的调节有关，但尚未完全阐明细胞和分子机制。在这里，我们利用了CCR5磷酸化突变体和抑制蛋白变体的集合来研究CCL5类似物在引发CCR5磷酸化和抑制蛋白募集的能力上与CCL5有何不同，参照目前用于抑制蛋白-GPCR相互作用的“核心”和“尾巴”相互作用模型。我们显示，CCL5会在CCR5募集（尤其是抑制蛋白2的）募集抑制蛋白2和抑制蛋白3，这在很大程度上取决于抑制蛋白尾巴的相互作用。5P12–RANTES不会引起受体磷酸化或抑制蛋白的募集。相反，PSC-RANTES诱导CCR5过度磷酸化，从而增强了抑制蛋白的募集，而对抑制蛋白尾巴相互作用的依赖性较低。5P14-RANTES诱导的受体磷酸化水平与CCL5相当，但抑制蛋白的募集绝对取决于抑制蛋白尾巴的相互作用，在所用的细胞背景之一中，募集显示出同种型偏向于抑制蛋白3与抑制蛋白2。没有证据表明在四个牵连的丝氨酸残基的受体磷酸化模式中存在配体特异性差异。我们的结果提高了对CCR5分子药理学的理解，并有助于进一步阐明一组有效抑制剂的抑制机制。

更新日期：2020-10-27

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11