Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors

Thibado, J.K; Tano, J.Y.; Lee, J.; Salas-Estrada, L.; Provasi, D.; Strauss, A.; Ribeiro, J.M.L.; Xiang, G.; Broichhagen, J.; Filizola, M.; Lohse, M.J.; Levitz, J.

Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors

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Item Type:	Article
Title:	Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors
Creators Name:	Thibado, J.K, Tano, J.Y., Lee, J., Salas-Estrada, L., Provasi, D., Strauss, A., Ribeiro, J.M.L., Xiang, G., Broichhagen, J., Filizola, M., Lohse, M.J. and Levitz, J.
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.
Keywords:	Calcium Signaling, Fluorescence Resonance Energy Transfer, Glutamic Acid, HEK293 Cells, Membrane Potentials, Fluorescence Microscopy, Molecular Dynamics Simulation, Mutation, alpha-Helical Protein Conformation, Protein Domains, Protein Multimerization, Metabotropic Glutamate Receptors, Single Molecule Imaging, Structure-Activity Relationship, Time Factors
Source:	eLife
ISSN:	2050-084X
Publisher:	eLife Sciences Publications
Volume:	10
Page Range:	e67027
Date:	21 April 2021
Official Publication:	https://doi.org/10.7554/eLife.67027
PubMed:	View item in PubMed

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