Rearrangement of the transmembrane domain interfaces associated with the activation of a GPCR hetero-oligomer.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 31235691.
- Also identified by DOI 10.1038/s41467-019-10834-5 and PMC identifier 6591306.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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<sub>B</sub> 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<sub>B1</sub>-GABA<sub>B2</sub>, as well as GABA<sub>B1</sub>-GABA<sub>B1</sub> interactions. Our data are consistent with an oligomer made of a row of GABA<sub>B1</sub>. 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.
Medical subject headings
- Models, Molecular
- Protein Domains
- Protein Multimerization
- Receptors, GABA-B