Combinatorial allosteric modulation of agonist response in a self-interacting G-protein coupled receptor
| Autor: | Valeria Berno, Marco Patrone, Eugenia Cammarota, Massimo Degano, Paola Tornaghi, Davide Mazza |
|---|---|
| Přispěvatelé: | Patrone, M, Cammarota, E, Berno, V, Tornaghi, P, Mazza, D, Degano, M |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Agonist Models Molecular medicine.drug_class Protein Conformation media_common.quotation_subject Allosteric regulation Medicine (miscellaneous) Biochemistry General Biochemistry Genetics and Molecular Biology Article Cell Line Receptors G-Protein-Coupled Multiple sclerosis 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Allosteric Regulation medicine Humans Lipid signalling Phosphorylation Receptor Internalization lcsh:QH301-705.5 S1PR1 beta-Arrestins G protein-coupled receptor media_common Chemistry Fingolimod Hydrochloride Cell Membrane Serine Endopeptidases Fingolimod Kinetics Protein Transport 030104 developmental biology lcsh:Biology (General) Biophysics lipids (amino acids peptides and proteins) Proprotein Convertases Molecular modelling Protein Multimerization General Agricultural and Biological Sciences 030217 neurology & neurosurgery medicine.drug Protein Binding Signal Transduction |
| Zdroj: | Communications Biology, Vol 3, Iss 1, Pp 1-12 (2020) Communications Biology |
| Popis: | 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. Patrone et al study the mechanism by which fingolimod, a drug used for multiple sclerosis, and agonist to G-coupled receptor S1PR1, compared to the endogenous ligand S1P. They find that whereas S1P binds a S1PR1 dimer, the action of fingolimod is dependent on receptor oligomerisation, which affects β-arrestin binding, internalisation and signaling. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|