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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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