Open AccessConformational rearrangement during activation of a metabotropic glutamate receptor
Author(s) -
Brandon W. Liauw,
Hamid Samareh Afsari,
Reza Vafabakhsh
Publication year - 2021
Publication title -
nature chemical biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.412
H-Index - 216
eISSN - 1552-4469
pISSN - 1552-4450
DOI - 10.1038/s41589-020-00702-5
Subject(s) - allosteric regulation , g protein coupled receptor , chemistry , biophysics , metabotropic glutamate receptor , conformational change , förster resonance energy transfer , metabotropic glutamate receptor 2 , ligand (biochemistry) , allosteric enzyme , signal transduction , receptor , glutamate receptor , stereochemistry , biochemistry , biology , physics , quantum mechanics , fluorescence
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.