β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle

Nuber, S., Zabel, U., Lorenz, K., Nuber, A., Milligan, G. , Tobin, A. B. , Lohse, M. J. and Hoffmann, C. (2016) β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle. Nature, 531, pp. 661-664. (doi: 10.1038/nature17198) (PMID:27007855)

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Abstract

(β-)Arrestins are important regulators of G-protein-coupled receptors (GPCRs)1, 2, 3. They bind to active, phosphorylated GPCRs and thereby shut off ‘classical’ signalling to G proteins3, 4, trigger internalization of GPCRs via interaction with the clathrin machinery5, 6, 7 and mediate signalling via ‘non-classical’ pathways1, 2. In addition to two visual arrestins that bind to rod and cone photoreceptors (termed arrestin1 and arrestin4), there are only two (non-visual) β-arrestin proteins (β-arrestin1 and β-arrestin2, also termed arrestin2 and arrestin3), which regulate hundreds of different (non-visual) GPCRs. Binding of these proteins to GPCRs usually requires the active form of the receptors plus their phosphorylation by G-protein-coupled receptor kinases (GRKs)1, 3, 4. The binding of receptors or their carboxy terminus as well as certain truncations induce active conformations of (β-)arrestins that have recently been solved by X-ray crystallography8, 9, 10. Here we investigate both the interaction of β-arrestin with GPCRs, and the β-arrestin conformational changes in real time and in living human cells, using a series of fluorescence resonance energy transfer (FRET)-based β-arrestin2 biosensors. We observe receptor-specific patterns of conformational changes in β-arrestin2 that occur rapidly after the receptor–β-arrestin2 interaction. After agonist removal, these changes persist for longer than the direct receptor interaction. Our data indicate a rapid, receptor-type-specific, two-step binding and activation process between GPCRs and β-arrestins. They further indicate that β-arrestins remain active after dissociation from receptors, allowing them to remain at the cell surface and presumably signal independently. Thus, GPCRs trigger a rapid, receptor-specific activation/deactivation cycle of β-arrestins, which permits their active signalling.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Milligan, Professor Graeme and Tobin, Andrew
Authors: Nuber, S., Zabel, U., Lorenz, K., Nuber, A., Milligan, G., Tobin, A. B., Lohse, M. J., and Hoffmann, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN:0028-0836
ISSN (Online):1476-4687

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