title: Molecular organization and dynamics of the melatonin MT₁ receptor/RGS20/G(i) protein complex reveal asymmetry of receptor dimers for RGS and G(i) coupling.
abstract: Functional asymmetry of G-protein-coupled receptor (GPCR) dimers has been reported for an increasing number of cases, but the molecular architecture of signalling units associated to these dimers remains unclear. Here, we characterized the molecular complex of the melatonin MT₁ receptor, which directly and constitutively couples to G(i) proteins and the regulator of G-protein signalling (RGS) 20. The molecular organization of the ternary MT₁/G(i)/RGS20 complex was monitored in its basal and activated state by bioluminescence resonance energy transfer between probes inserted at multiple sites of the complex. On the basis of the reported crystal structures of G(i) and the RGS domain, we propose a model wherein one G(i) and one RGS20 protein bind to separate protomers of MT₁ dimers in a pre-associated complex that rearranges upon agonist activation. This model was further validated with MT₁/MT₂ heterodimers. Collectively, our data extend the concept of asymmetry within GPCR dimers, reinforce the notion of receptor specificity for RGS proteins and highlight the advantage of GPCRs organized as dimers in which each protomer fulfils its specific task by binding to different GPCR-interacting proteins.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Maurice
authors.forename: Avais M
authors.initials: AM
authors.lastname: Daulat
authors.forename: Rostislav
authors.initials: R
authors.lastname: Turecek
authors.forename: Klara
authors.initials: K
authors.lastname: Ivankova-Susankova
authors.forename: Francesco
authors.initials: F
authors.lastname: Zamponi
authors.forename: Maud
authors.initials: M
authors.lastname: Kamal
authors.forename: Nathalie
authors.initials: N
authors.lastname: Clement
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Guillaume
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.forename: Céline
authors.initials: C
authors.lastname: Galès
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D004594:Electrophysiology; D004735:Energy Transfer; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008550:Melatonin / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D020710:RGS Proteins; D044122:Receptor, Melatonin, MT1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020710:RGS Proteins; C115120:RGS20 protein, human; D044122:Receptor, Melatonin, MT1; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D008550:Melatonin