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

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Item Type:Preprint
Title:Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors
Creators Name:Thibado, J. and Tano, J.Y. and Lee, J. and Salas-Estrada, L. and Provasi, D. and Strauss, A. and Lamim Ribeiro, J.M. and Xiang, G. and Broichhagen, J. and Filizola, M. and Lohse, M. 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 informs a working model of inter-TMD rearrangement that drives mGluR function.
Source:bioRxiv
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2021.02.04.429701
Date:6 February 2021
Official Publication:https://doi.org/10.1101/2021.02.04.429701
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https://edoc.mdc-berlin.de/20208/Final version

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