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.
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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.
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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