Cargando…

Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor

The structural plasticity of G-protein coupled receptors (GPCRs) enables the long-range transmission of conformational changes induced by specific orthosteric site ligands and other pleiotropic factors. Here, we demonstrate that the ligand binding cavity in the sphingosine 1-phosphate receptor S1PR1...

Descripción completa

Detalles Bibliográficos
Autores principales: Patrone, Marco, Cammarota, Eugenia, Berno, Valeria, Tornaghi, Paola, Mazza, Davide, Degano, Massimo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962373/
https://www.ncbi.nlm.nih.gov/pubmed/31941999
http://dx.doi.org/10.1038/s42003-020-0752-4
_version_ 1783488152020713472
author Patrone, Marco
Cammarota, Eugenia
Berno, Valeria
Tornaghi, Paola
Mazza, Davide
Degano, Massimo
author_facet Patrone, Marco
Cammarota, Eugenia
Berno, Valeria
Tornaghi, Paola
Mazza, Davide
Degano, Massimo
author_sort Patrone, Marco
collection PubMed
description The structural plasticity of G-protein coupled receptors (GPCRs) enables the long-range transmission of conformational changes induced by specific orthosteric site ligands and other pleiotropic factors. Here, we demonstrate that the ligand binding cavity in the sphingosine 1-phosphate receptor S1PR1, a class A GPCR, is in allosteric communication with both the β-arrestin-binding C-terminal tail, and a receptor surface involved in oligomerization. We show that S1PR1 oligomers are required for full response to different agonists and ligand-specific association with arrestins, dictating the downstream signalling kinetics. We reveal that the active form of the immunomodulatory drug fingolimod, FTY720-P, selectively harnesses both these intramolecular networks to efficiently recruit β-arrestins in a stable interaction with the receptor, promoting deep S1PR1 internalization and simultaneously abrogating ERK1/2 phosphorylation. Our results define a molecular basis for the efficacy of fingolimod for people with multiple sclerosis, and attest that GPCR signalling can be further fine-tuned by the oligomeric state.
format Online
Article
Text
id pubmed-6962373
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-69623732020-01-22 Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor Patrone, Marco Cammarota, Eugenia Berno, Valeria Tornaghi, Paola Mazza, Davide Degano, Massimo Commun Biol Article The structural plasticity of G-protein coupled receptors (GPCRs) enables the long-range transmission of conformational changes induced by specific orthosteric site ligands and other pleiotropic factors. Here, we demonstrate that the ligand binding cavity in the sphingosine 1-phosphate receptor S1PR1, a class A GPCR, is in allosteric communication with both the β-arrestin-binding C-terminal tail, and a receptor surface involved in oligomerization. We show that S1PR1 oligomers are required for full response to different agonists and ligand-specific association with arrestins, dictating the downstream signalling kinetics. We reveal that the active form of the immunomodulatory drug fingolimod, FTY720-P, selectively harnesses both these intramolecular networks to efficiently recruit β-arrestins in a stable interaction with the receptor, promoting deep S1PR1 internalization and simultaneously abrogating ERK1/2 phosphorylation. Our results define a molecular basis for the efficacy of fingolimod for people with multiple sclerosis, and attest that GPCR signalling can be further fine-tuned by the oligomeric state. Nature Publishing Group UK 2020-01-15 /pmc/articles/PMC6962373/ /pubmed/31941999 http://dx.doi.org/10.1038/s42003-020-0752-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Patrone, Marco
Cammarota, Eugenia
Berno, Valeria
Tornaghi, Paola
Mazza, Davide
Degano, Massimo
Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor
title Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor
title_full Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor
title_fullStr Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor
title_full_unstemmed Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor
title_short Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor
title_sort combinatorial allosteric modulation of agonist response in a self-interacting g-protein coupled receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962373/
https://www.ncbi.nlm.nih.gov/pubmed/31941999
http://dx.doi.org/10.1038/s42003-020-0752-4
work_keys_str_mv AT patronemarco combinatorialallostericmodulationofagonistresponseinaselfinteractinggproteincoupledreceptor
AT cammarotaeugenia combinatorialallostericmodulationofagonistresponseinaselfinteractinggproteincoupledreceptor
AT bernovaleria combinatorialallostericmodulationofagonistresponseinaselfinteractinggproteincoupledreceptor
AT tornaghipaola combinatorialallostericmodulationofagonistresponseinaselfinteractinggproteincoupledreceptor
AT mazzadavide combinatorialallostericmodulationofagonistresponseinaselfinteractinggproteincoupledreceptor
AT deganomassimo combinatorialallostericmodulationofagonistresponseinaselfinteractinggproteincoupledreceptor