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Catalytic activation of β-arrestin by GPCRs

β-arrestins are critical regulator and transducer proteins for G protein-coupled receptors (GPCRs). Cellular β-arrestin function is presently thought to require stable and stoichiometric GPCR/β-arrestin scaffold complex formation driven by the phosphorylated GPCR tail. We demonstrate a distinct and...

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Detalles Bibliográficos
Autores principales: Eichel, Kelsie, Jullié, Damien, Barsi-Rhyne, Benjamin, Latorraca, Naomi R., Masureel, Matthieu, Sibarita, Jean-Baptiste, Dror, Ron O., von Zastrow, Mark
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058965/
https://www.ncbi.nlm.nih.gov/pubmed/29720660
http://dx.doi.org/10.1038/s41586-018-0079-1
Descripción
Sumario:β-arrestins are critical regulator and transducer proteins for G protein-coupled receptors (GPCRs). Cellular β-arrestin function is presently thought to require stable and stoichiometric GPCR/β-arrestin scaffold complex formation driven by the phosphorylated GPCR tail. We demonstrate a distinct and additional mechanism that does not require stable GPCR/β-arrestin scaffolding or the GPCR tail. Instead, it is activated by transient engagement of the GPCR core that destabilizes a conserved inter-domain charge network in β-arrestin. This promotes capture of β-arrestin at the plasma membrane and accumulation in clathrin-coated endocytic structures (CCSs) after GPCR dissociation, requiring a series of β-arrestin interactions with membrane phosphoinositides and CCS lattice proteins. β-arrestin clustering in CCSs without its upstream activating GPCR is associated with a β-arrestin-dependent component of the cellular ERK (Extracellular signal-regulated kinase) response. These results delineate a discrete mechanism of cellular β-arrestin function that is activated catalytically by GPCRs.