Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors
- Weill Cornell Graduate School of Medical Sciences, United States
- Max Delbrück Center for Molecular Medicine, Germany
- Weill Cornell Medicine, United States
- Icahn School of Medicine at Mount Sinai, United States
- Forschungsinstitut für Molekulare Pharmakologie, Germany
Abstract
The metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G protein-coupled receptors that contain both a seven-helix transmembrane domain (TMD) and a large extracellular ligand-binding domain (LBD) which enables stable dimerization. While numerous studies have revealed variability across subtypes in the initial activation steps at the level of LBD dimers, an understanding of inter-TMD interaction and rearrangement remains limited. Here we use a combination of single molecule fluorescence, molecular dynamics, functional assays, and conformational sensors to reveal that distinct TMD assembly properties drive differences between mGluR subtypes. We uncover a variable region within transmembrane helix 4 (TM4) that contributes to homo- and heterodimerization in a subtype-specific manner and tunes orthosteric, allosteric and basal activation. We also confirm a critical role for a conserved inter-TM6 interface in stabilizing the active state during orthosteric or allosteric activation. Together this study shows that inter-TMD assembly and dynamic rearrangement drive mGluR function with distinct properties between subtypes.
Data availability
We have provided source data files for all relevant figures.
Article and author information
Author details
Johannes Broichhagen
Funding
National Institute of General Medical Sciences (R35 GM124731)
- Joshua Levitz
National Science Foundation (GRFP)
- Jordana K Thibado
National Institute on Drug Abuse (DA038882)
- Marta Filizola
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Janice L Robertson, Washington University in St Louis, United States
Version history
- Received: January 29, 2021
- Accepted: April 19, 2021
- Accepted Manuscript published: April 21, 2021 (version 1)
- Version of Record published: May 6, 2021 (version 2)
Copyright
© 2021, Thibado et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors
eLife 10:e67027.
https://doi.org/10.7554/eLife.67027
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