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

Jordana Thibado, Jean-Yves Tano, Joon Lee, Leslie Salas-Estrada, Davide Provasi, Alexa Strauss, Joao Marcelo Lamim Ribeiro, Guoqing Xiang, Johannes Broichhagen, Marta Filizola, Martin Lohse, Joshua Levitz
2021 biorxiv/medrxiv   pre-print
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
more » ... e 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.
doi:10.1101/2021.02.04.429701 fatcat:a6n4vy5vbjh6xcl5mlhjb4kc3y