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 and Tano, J.Y. and Lee, J. and Salas-Estrada, L. and Provasi, D. and Strauss, A. and Ribeiro, J.M.L. and Xiang, G. and Broichhagen, J. and Filizola, M. and 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:

Page Range:

e67027

Date:

21 April 2021

Official Publication: