Arrestin recognizes GPCRs independently of the receptor state

• 成果类型: Article
• 署名作者: Petrovic, Ivana; Tatli, Meltem; Desai, Samit; Grahl, Anne; Ni, Dongchun; Stahlberg, Henning; Spang, Anne; Grzesiek, Stephan; Abiko, Layara Akemi
• 署名单位: University of Basel; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of Lausanne
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14057
• 发表日期: 2025-05-20
• 关键词: mechanism; software

摘要

Only two nonvisual arrestins recognize many hundreds of different, intracellularly phosphorylated G protein-coupled receptors (GPCRs). Due to the highly dynamic nature of GPCR center dot arrestin complexes, the critical determinants of GPCR-arrestin recognition have remained largely unclear. We show here that arrestin2 recruitment to the R1-adrenergic receptor (R1AR) can be induced by an arrestin-activating phosphopeptide that is not covalently linked to the receptor and that the recruitment is independent of the presence and type of the orthosteric receptor ligand. Apparently, the arrestin-receptor interaction is driven by the conformational switch within arrestin induced by the phosphopeptide, whereas the electrostatic attraction toward the receptor phosphosites may only play an auxiliary role. Extensive NMR observations show that in contrast to previous static GPCR center dot arrestin complex structures, the R1AR complex with the beta-blocker carvedilol and arrestin2 is in a G protein-inactive conformation. The insensitivity to the specific receptor conformation provides a rationale for arrestin's promiscuous recognition of GPCRs and explains the arrestin-biased agonism of carvedilol, which largely blocks G protein binding, while still enabling arrestin engagement.