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

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

doi:10.1101/2021.02.04.429701

bioRxiv · 10.1101/2021.02.04.429701

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

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

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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 informs a working model of inter-TMD rearrangement that drives mGluR function.

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Thibado, J., Tano, J.-Y., Lee, J., Salas-Estrada, L., Provasi, D., Strauss, A., Marcelo Lamim Ribeiro, J., Xiang, G., Broichhagen, J., Filizola, M., Lohse, M., Levitz, J.. 2021-02-06. Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors. https://doi.org/10.1101/2021.02.04.429701

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