Molecular organization and dynamics of the melatonin MT1 receptor/RGS20/Gi protein complex reveal asymmetry of receptor dimers for RGS and Gi coupling |
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Authors: | Pascal Maurice Avais M Daulat Rostislav Turecek Klara Ivankova-Susankova Francesco Zamponi Maud Kamal Nathalie Clement Jean-Luc Guillaume Bernhard Bettler C��line Gal��s Philippe Delagrange Ralf Jockers |
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Institution: | 1. Department of Biomedicine, Institute of Physiology, University of Basel, Basel, Switzerland;2. Institute of Experimental Medicine ASCR, Prague, Czech Republic;3. CNRS UMR 8549, Laboratoire de Physique Théorique, Ecole Normale Supérieure, Paris, France;4. Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France;5. Inserm, Paris, France;6. Inserm U858‐I2MR, Toulouse, France;7. Institut de Recherches SERVIER, Suresnes, France |
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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 Gi proteins and the regulator of G‐protein signalling (RGS) 20. The molecular organization of the ternary MT1/Gi/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 Gi and the RGS domain, we propose a model wherein one Gi 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. |
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Keywords: | G protein G‐protein‐coupled receptor heterodimerization molecular organization RGS |
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