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

• DOI: 10.7554/elife.67027
• Publication Date: 2021-04-21T12:22:01Z
• Authors: Jordana K Thibado; Jean-Yves Tano; Joon Lee; Leslie Salas-Estrada; Davide Provasi; Alexa Strauss; Joao Marcelo Lami...; Guoqing Xiang; Johannes Broichhagen; Marta Filizola; Martin J Lohse; Joshua Levitz
• Keywords: Helix (gastropod)

The metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G-protein-coupled that contain both seven-helix transmembrane domain (TMD) and large extracellular ligand-binding (LBD) which enables stable dimerization. Although numerous studies have revealed variability across subtypes in the initial activation steps at level LBD dimers, an understanding inter-TMD interaction rearrangement remains limited. Here, we use combination single molecule fluorescence, molecular dynamics, functional assays, conformational sensors to reveal distinct TMD assembly properties drive differences between mGluR subtypes. We uncover variable region within helix 4 (TM4) contributes homo- heterodimerization subtype-specific manner tunes orthosteric, allosteric, basal activation. also confirm critical role for conserved inter-TM6 interface stabilizing active state during orthosteric or allosteric Together this study shows dynamic function with