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

Autor: Haider RS; Institut für Molekulare Zellbiologie, CMB-Center for Molecular Biomedicine, Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., Matthees ESF; Institut für Molekulare Zellbiologie, CMB-Center for Molecular Biomedicine, Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., Drube J; Institut für Molekulare Zellbiologie, CMB-Center for Molecular Biomedicine, Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., Reichel M; Institut für Molekulare Zellbiologie, CMB-Center for Molecular Biomedicine, Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany., Zabel U; Institut für Pharmakologie und Toxikologie, Universität Würzburg, Versbacherstraße 9, D-97078, Würzburg, Germany., Inoue A; Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, 980-8578, Japan.; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Saitama, 332-0012, Japan., Chevigné A; Immuno-Pharmacology and Interactomics, Department of Infection and Immunity, Luxembourg Institute of Health (LIH), Esch-sur-Alzette, Luxembourg., Krasel C; Philipps-Universität Marburg; Fachbereich Pharmazie; Institut für Pharmakologie und Klinische Pharmazie, Karl-von-Frisch-Str. 1, 35043, Marburg, Germany., Deupi X; Laboratory of Biomolecular Research, Paul Scherrer Institute, CH-5232, Villigen, Switzerland.; Condensed Matter Theory Group, Paul Scherrer Institute, CH-5232, Villigen, Switzerland., Hoffmann C; Institut für Molekulare Zellbiologie, CMB-Center for Molecular Biomedicine, Universitätsklinikum Jena; Friedrich-Schiller-Universität Jena, Hans-Knöll-Straße 2, D-07745, Jena, Germany. carsten.hoffmann@med.uni-jena.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Sep 26; Vol. 13 (1), pp. 5638. Date of Electronic Publication: 2022 Sep 26.
DOI: 10.1038/s41467-022-33307-8
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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