Rearrangement of the transmembrane domain interfaces associated with the activation of a GPCR hetero-oligomer

• Published in: Nature communications 2019-06, Vol.10 (1), p.2765-12, Article 2765
• Main Authors: Xue, Li, Sun, Qian, Zhao, Han, Rovira, Xavier, Gai, Siyu, He, Qianwen, Pin, Jean-Philippe, Liu, Jianfeng, Rondard, Philippe
• Format: Article
• Language: English
• Subjects: 631/378/340; 631/45; 631/45/612/194; 631/57; 82/29; 96/34; 96/95; Activation; Allosteric properties; Allosteric Regulation - drug effects; Allosteric Regulation - physiology; Allosteric Site - drug effects; Allosteric Site - physiology; Brain; Cross-Linking Reagents - chemistry; Crosslinking; Dimers; G protein-coupled receptors; GABA-B Receptor Agonists - pharmacology; gamma-Aminobutyric Acid - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Interfaces; Laboratories; Ligands; Models, Molecular; multidisciplinary; Mutation; Oligomers; Protein Binding - drug effects; Protein Binding - physiology; Protein Domains - drug effects; Protein Domains - physiology; Protein Multimerization - drug effects; Protein Multimerization - physiology; Proteins; Receptors; Receptors, GABA-B - metabolism; Science; Science (multidisciplinary); Transmembrane domains; γ-Aminobutyric acid B receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10834-5

G protein-coupled receptors (GPCRs) can integrate extracellular signals via allosteric interactions within dimers and higher-order oligomers. However, the structural bases of these interactions remain unclear. Here, we use the GABA B receptor heterodimer as a model as it forms large complexes in the brain. It is subjected to genetic mutations mainly affecting transmembrane 6 (TM6) and involved in human diseases. By cross-linking, we identify the transmembrane interfaces involved in GABA B1 -GABA B2 , as well as GABA B1 -GABA B1 interactions. Our data are consistent with an oligomer made of a row of GABA B1 . We bring evidence that agonist activation induces a concerted rearrangement of the various interfaces. While the GB1-GB2 interface is proposed to involve TM5 in the inactive state, cross-linking of TM6s lead to constitutive activity. These data bring insight for our understanding of the allosteric interaction between GPCRs within oligomers. G protein-coupled receptors (GPCRs), such as GABA B , can integrate extracellular signals via allosteric interactions within dimers and oligomers. Here authors use crosslinking and identify two transmembrane interfaces in GABA B which undergo a concerted rearrangement upon agonist activation.