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

eLife

Joon Lee¹  Guoqing Xiang¹  Leslie Salas-Estrada²  Davide Provasi²  Joao Marcelo Lamim Ribeiro²  Marta Filizola²  Johannes Broichhagen³  Jean-Yves Tano⁴  Martin J Lohse⁵  Jordana K Thibado⁶  Joshua Levitz⁷  Alexa Strauss⁸ 

[1] Department of Biochemistry, Weill Cornell Medicine, New York, United States;Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States;Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany;Max Delbrück Center for Molecular Medicine, Berlin, Germany;Max Delbrück Center for Molecular Medicine, Berlin, Germany;ISAR Bioscience Institute, Planegg-Munich, Germany;Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States;Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States;Department of Biochemistry, Weill Cornell Medicine, New York, United States;Tri-Institutional PhD Program in Chemical Biology, New York, United States;Tri-Institutional PhD Program in Chemical Biology, New York, United States;

关键词: GPCR;    single molecule fluorescence;    conformational dynamics;    dimerization;    metabotropic glutamate receptor;    molecular dynamics;    None;   

DOI  :  10.7554/eLife.67027

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY