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 language | English (US) |
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Pages (from-to) | 291-297 |
Number of pages | 7 |
Journal | Nature Chemical Biology |
Volume | 17 |
Issue number | 3 |
DOIs | |
State | Published - Mar 2021 |
Funding
We thank M.R. Schamber, D. Badong, D. May and A.Y. Pen for technical assistance, M. Gallio, J. Marko, A. Mondragon and K. Ragunathan for critical reading of the manuscript, and J. Fei (University of Chicago) for providing MATLAB scripts. This work was supported by the National Institutes of Health grant R01GM140272 (to R.V.) and by The Searle Leadership Fund for the Life Sciences at Northwestern University and by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust (to R.V.). B.W.L. was supported by the National Institute of General Medical Sciences (NIGMS) Training Grant T32GM-008061. This work used resources of the Keck Biophysics Facility supported in part by the NCI CCSG P30 CA060553 grant awarded to the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology