title: Major ligand-induced rearrangement of the heptahelical domain interface in a GPCR dimer.
abstract: G protein-coupled receptors (GPCRs) are major players in cell communication. Although they form functional monomers, increasing evidence indicates that GPCR dimerization has a critical role in cooperative phenomena that are important for cell signal integration. However, the structural bases of these phenomena remain elusive. Here, using well-characterized receptor dimers, the metabotropic glutamate receptors (mGluRs), we show that structural changes at the dimer interface are linked to receptor activation. We demonstrate that the main dimer interface is formed by transmembrane α helix 4 (TM4) and TM5 in the inactive state and by TM6 in the active state. This major change in the dimer interface is required for receptor activity because locking the TM4-TM5 interface prevents activation by agonist, whereas locking the TM6 interface leads to a constitutively active receptor. These data provide important information on the activation mechanism of mGluRs and improve our understanding of the structural basis of the negative cooperativity observed in these GPCR dimers.
authors.affiliation: 1] Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. [2] CNRS, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France. [3] INSERM, U661, Montpellier, France. [4] Université Montpellier 1 &2, Montpellier, France.
authors.forename: Li
authors.initials: L
authors.lastname: Xue
authors.affiliation: 1] CNRS, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France. [2] INSERM, U661, Montpellier, France. [3] Université Montpellier 1 &2, Montpellier, France.
authors.forename: Xavier
authors.identifier: 0000000297649927
authors.initials: X
authors.lastname: Rovira
authors.affiliation: 1] CNRS, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France. [2] INSERM, U661, Montpellier, France. [3] Université Montpellier 1 &2, Montpellier, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Scholler
authors.affiliation: Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, School of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1] CNRS, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France. [2] INSERM, U661, Montpellier, France. [3] Université Montpellier 1 &2, Montpellier, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
authors.affiliation: 1] CNRS, UMR5203, Institut de Génomique Fonctionnelle, Montpellier, France. [2] INSERM, U661, Montpellier, France. [3] Université Montpellier 1 &2, Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rondard
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000737:chemistry / Q000235:genetics; D018080:Receptors, GABA-B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000737:chemistry* / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: C578937:Grm5 protein, rat; D008024:Ligands; D021122:Protein Subunits; D064529:Receptor, Metabotropic Glutamate 5; D018080:Receptors, GABA-B; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C104077:metabotropic glutamate receptor type 1; D003545:Cysteine; D000409:Alanine