Molecular insights into atypical modes of β-arrestin interaction with seven transmembrane receptors

• 成果类型: Article
• 署名作者: Maharana, Jagannath; Sano, Fumiya K.; Sarma, Parishmita; Yadav, Manish K.; Duan, Longhan; Stepniewski, Tomasz M.; Chaturvedi, Madhu; Ranjan, Ashutosh; Singh, Vinay; Saha, Sayantan; Mahajan, Gargi; Chami, Mohamed; Shihoya, Wataru; Selent, Jana; Chung, Ka Young; Banerjee, Ramanuj; Nureki, Osamu; Shukla, Arun K.
• 署名单位: Indian Institute of Technology System (IIT System); Indian Institute of Technology (IIT) - Kanpur; University of Tokyo; Sungkyunkwan University (SKKU); Hospital del Mar Research Institute; Hospital del Mar; Pompeu Fabra University; University of Basel
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12063
• DOI: 10.1126/science.adj3347
• 发表日期: 2024-01-05
• 页码: 101-108
• 关键词: conformational-changes; crystal-structure; biased agonism; mechanism; domain; beta-arrestin1; Visualization; RECRUITMENT; activation; expression

摘要

beta-arrestins (beta arrs) are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor activation and phosphorylation. Here, we present seven cryo-electron microscopy structures of beta arrs either in the basal state, activated by the muscarinic receptor subtype 2 (M2R) through its third intracellular loop, or activated by the beta arr-biased decoy D6 receptor (D6R). Combined with biochemical, cellular, and biophysical experiments, these structural snapshots allow the visualization of atypical engagement of beta arrs with 7TMRs and also reveal a structural transition in the carboxyl terminus of beta arr2 from a beta strand to an alpha helix upon activation by D6R. Our study provides previously unanticipated molecular insights into the structural and functional diversity encoded in 7TMR-beta arr complexes with direct implications for exploring novel therapeutic avenues.