Conformational rearrangement during activation of a metabotropic glutamate receptor

Brandon Wey Hung Liauw, Hamid Samareh Afsari, Reza Vafabakhsh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

G protein-coupled receptors (GPCRs) relay information across cell membranes through conformational coupling between the ligand-binding domain and cytoplasmic signaling domain. In dimeric class C GPCRs, the mechanism of this process, which involves propagation of local ligand-induced conformational changes over 12 nm through three distinct structural domains, is unknown. Here, we used single-molecule FRET and live-cell imaging and found that metabotropic glutamate receptor 2 (mGluR2) interconverts between four conformational states, two of which were previously unknown, and activation proceeds through the conformational selection mechanism. Furthermore, the conformation of the ligand-binding domains and downstream domains are weakly coupled. We show that the intermediate states act as conformational checkpoints for activation and control allosteric modulation of signaling. Our results demonstrate a mechanism for activation of mGluRs where ligand binding controls the proximity of signaling domains, analogous to some receptor kinases. This design principle may be generalizable to other biological allosteric sensors. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)291-297
Number of pages7
JournalNature Chemical Biology
Volume17
Issue number3
DOIs
StatePublished - Mar 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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