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

作者：Xue Li, Qian Sun, Han Zhao, Xavier Rovira, Siyu Gai, Qianwen He, Jean‐Philippe Pin, Jianfeng Liu, Philippe Rondard · 发表于：Nature Communications · 年份：2019 · DOI：10.1038/s41467-019-10834-5 · 被引用次数：58 · 研究领域：Receptor Mechanisms and Signaling、Neuroscience and Neuropharmacology Research、Neuropeptides and Animal Physiology

Abstract 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.