β-arrestin1 and 2 exhibit distinct phosphorylation-dependent conformations when coupling to the same GPCR in living cells

Raphael S. Haider, Edda S. F. Matthees, Julia Drube, Mona Reichel, Ulrike Zabel, Asuka Inoue, Andy Chevigné, Cornelius Krasel, Xavier Deupi and Carsten Hoffmann ()
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Raphael S. Haider: Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena
Edda S. F. Matthees: Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena
Julia Drube: Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena
Mona Reichel: Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena
Ulrike Zabel: Universität Würzburg
Asuka Inoue: Tohoku University
Andy Chevigné: Luxembourg Institute of Health (LIH)
Cornelius Krasel: Philipps-Universität Marburg; Fachbereich Pharmazie; Institut für Pharmakologie und Klinische Pharmazie
Xavier Deupi: Paul Scherrer Institute
Carsten Hoffmann: Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract β-arrestins mediate regulatory processes for over 800 different G protein-coupled receptors (GPCRs) by adopting specific conformations that result from the geometry of the GPCR–β-arrestin complex. However, whether β-arrestin1 and 2 respond differently for binding to the same GPCR is still unknown. Employing GRK knockout cells and β-arrestins lacking the finger-loop-region, we show that the two isoforms prefer to associate with the active parathyroid hormone 1 receptor (PTH1R) in different complex configurations (“hanging” and “core”). Furthermore, the utilisation of advanced NanoLuc/FlAsH-based biosensors reveals distinct conformational signatures of β-arrestin1 and 2 when bound to active PTH1R (P-R*). Moreover, we assess β-arrestin conformational changes that are induced specifically by proximal and distal C-terminal phosphorylation and in the absence of GPCR kinases (GRKs) (R*). Here, we show differences between conformational changes that are induced by P-R* or R* receptor states and further disclose the impact of site-specific GPCR phosphorylation on arrestin-coupling and function.

Date: 2022
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DOI: 10.1038/s41467-022-33307-8

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