Journal Article

G-protein activation by a metabotropic glutamate receptor

Mathiesen, Jesper M., Schelshorn, Dominik, Robertson, Michael J., Barros-Álvarez, Ximena, Gao, Yang, de Lapeyrière, Marine, Papasergi-Scott, Makaía M., Meyerowitz, Justin G., Nwokonko, Robert M., Kobilka, Brian K., Seven, Alpay B., Rocher, Jean-Philippe, Zhang, Chensong, Skiniotis, Georgios

2021

Overview

Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism 1 . Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G i . Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6–TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound G i can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6–TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation. Cryo-electron microscopy structures show that metabotropic glutamate receptor 2 forms a dimer to which only one G protein is coupled, revealing the basis for asymmetric signal transduction.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/45/612/194 / 631/535/1258/1259 / 82 / 82/80 / 82/83 / 96 / Asymmetry / C-Terminus / Cell Membrane - chemistry / Cell Membrane - metabolism / Dimers / Domains / Free form / G protein-coupled receptors / G proteins / Glutamate / Glutamate receptors / Glutamic acid receptors (metabotropic) / GTP-Binding Protein alpha Subunits, Gi-Go - chemistry / GTP-Binding Protein alpha Subunits, Gi-Go - metabolism / Heterotrimeric GTP-Binding Proteins - chemistry / Heterotrimeric GTP-Binding Proteins - metabolism / Humanities and Social Sciences / Humans / Ligands / Metabotropic glutamate receptors / Models, Molecular / multidisciplinary / Nucleotides / Physiological aspects / Protein Multimerization / Proteins / Receptors / Receptors, Metabotropic Glutamate - chemistry / Receptors, Metabotropic Glutamate - metabolism / Science / Science (multidisciplinary) / Transmembrane domains