The conformational signature of ß-arrestin2 predicts its trafficking and signalling functions.
Nature
; 531(7596): 665-8, 2016 Mar 31.
Article
en En
| MEDLINE
| ID: mdl-27007854
ABSTRACT
Arrestins are cytosolic proteins that regulate G-protein-coupled receptor (GPCR) desensitization, internalization, trafficking and signalling. Arrestin recruitment uncouples GPCRs from heterotrimeric G proteins, and targets the proteins for internalization via clathrin-coated pits. Arrestins also function as ligand-regulated scaffolds that recruit multiple non-G-protein effectors into GPCR-based 'signalsomes'. Although the dominant function(s) of arrestins vary between receptors, the mechanism whereby different GPCRs specify these divergent functions is unclear. Using a panel of intramolecular fluorescein arsenical hairpin (FlAsH) bioluminescence resonance energy transfer (BRET) reporters to monitor conformational changes in ß-arrestin2, here we show that GPCRs impose distinctive arrestin 'conformational signatures' that reflect the stability of the receptor-arrestin complex and role of ß-arrestin2 in activating or dampening downstream signalling events. The predictive value of these signatures extends to structurally distinct ligands activating the same GPCR, such that the innate properties of the ligand are reflected as changes in ß-arrestin2 conformation. Our findings demonstrate that information about ligand-receptor conformation is encoded within the population average ß-arrestin2 conformation, and provide insight into how different GPCRs can use a common effector for different purposes. This approach may have application in the characterization and development of functionally selective GPCR ligands and in identifying factors that dictate arrestin conformation and function.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
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Arrestinas
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Receptores Acoplados a Proteínas G
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
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Humans
Idioma:
En
Año:
2016
Tipo del documento:
Article