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

Li Xue, Qian Sun, Han Zhao, Xavier Rovira, Siyu Gai, Qianwen He, Jean-Philippe Pin (), Jianfeng Liu () and Philippe Rondard
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Li Xue: Huazhong University of Science and Technology
Qian Sun: Huazhong University of Science and Technology
Han Zhao: Huazhong University of Science and Technology
Xavier Rovira: Université de Montpellier
Siyu Gai: Huazhong University of Science and Technology
Qianwen He: Huazhong University of Science and Technology
Jean-Philippe Pin: Université de Montpellier
Jianfeng Liu: Huazhong University of Science and Technology
Philippe Rondard: Université de Montpellier

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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 GABAB 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 GABAB1-GABAB2, as well as GABAB1-GABAB1 interactions. Our data are consistent with an oligomer made of a row of GABAB1. 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.

Date: 2019
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DOI: 10.1038/s41467-019-10834-5

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