TY - JOUR TI - Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors AU - Thibado, Jordana K AU - Tano, Jean-Yves AU - Lee, Joon AU - Salas-Estrada, Leslie AU - Provasi, Davide AU - Strauss, Alexa AU - Marcelo Lamim Ribeiro, Joao AU - Xiang, Guoqing AU - Broichhagen, Johannes AU - Filizola, Marta AU - Lohse, Martin J AU - Levitz, Joshua A2 - Robertson, Janice L A2 - Swartz, Kenton J A2 - Hébert, Terry VL - 10 PY - 2021 DA - 2021/04/21 SP - e67027 C1 - eLife 2021;10:e67027 DO - 10.7554/eLife.67027 UR - https://doi.org/10.7554/eLife.67027 AB - 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. Although 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. KW - GPCR KW - single molecule fluorescence KW - conformational dynamics KW - dimerization KW - metabotropic glutamate receptor KW - molecular dynamics JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -