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

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. E...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications 2022-09, Vol.13 (1), p.5638-5638, Article 5638
Main Authors: Haider, Raphael S., Matthees, Edda S. F., Drube, Julia, Reichel, Mona, Zabel, Ulrike, Inoue, Asuka, Chevigné, Andy, Krasel, Cornelius, Deupi, Xavier, Hoffmann, Carsten
Format: Article
Language:English
Subjects:
14
14/19
631/1647/1888
631/45
631/80/313
631/80/86
96/10
96/95
Arrestin
Biosensors
Cells (biology)
Coupling
G protein-coupled receptors
Humanities and Social Sciences
Isoforms
Kinases
multidisciplinary
Parathyroid hormone
Phosphorylation
Receptors
Science
Science (multidisciplinary)
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. Here the authors present improved intramolecular sensors for β-arrestin2 and 1, which enable assessment of conformational changes of both isoforms in living cells. These reveal that the same GPCR induces differential conformational rearrangements that determine the functional diversity between the two β-arrestins.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-33307-8