Structure of the antidiuretic hormone vasopressin receptor signalling complex
| Autor: | Julien Bous, Aurelie Ancelin, Nicolas Floquet, Hélène Orcel, Joséphine Lai-Kee-Him, Stefano Trapani, Julie Saint-Paul, Hélène Déméné, Sébastien Granier, Patrick Bron, Maxime Louet, Remy Sounier, Gérald Gaibelet, Bernard Mouillac, Cedric Leyrat |
|---|---|
| Přispěvatelé: | Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Déméné, Hélène, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Gs alpha subunit Chemistry [SDV]Life Sciences [q-bio] Protein subunit Aquaporin Cell biology [SDV] Life Sciences [q-bio] 03 medical and health sciences 0302 clinical medicine Arginine vasopressin receptor 2 Receptor Ternary complex 030217 neurology & neurosurgery Function (biology) 030304 developmental biology G protein-coupled receptor |
| DOI: | 10.1101/2020.12.22.424028 |
| Popis: | Arginine-vasopressin (AVP) is a neurohypophysial peptide known as the antidiuretic hormone. It forms an active signalling complex with the V2 receptor (V2R) and the Gs protein, promoting a cAMP/PKA-dependent aquaporin insertion in apical membranes of principal cells of the renal collecting ducts and ultimately, water reabsorption. Molecular mechanisms underlying activation of this critical G protein-coupled receptor (GPCR) signalling system are still unknown. To fill this gap of knowledge, we report here the structure of the AVP-V2R-Gs complex using cryo-electron microscopy (cryo-EM). Single-particle analysis revealed the presence of three different states. The two best maps were combined with computational and NMR spectroscopy constraints to reconstruct two structures of the ternary complex. These structures differ in AVP and Gs binding modes and could thus represent distinct complex conformations along the signalling activation pathway. Importantly, as compared to those of other class A GPCR-Gs complexes, the structures revealed an original receptor-Gs interface in which the Gsα subunit penetrates deeper into the active V2R, notably forming an ionic bond between its free C-terminal carboxylic function and the side chain of R137 in the V2R. Interestingly, the structures help to explain how V2R R137H or R137L/C variants can lead to two severe genetic diseases with opposite clinical outcomes, cNDI or NSIAD respectively. Our study thus provides important structural insights into the function of this clinically relevant GPCR signalling complex. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|