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Updated: Sep 17, 2025

Monitoring GPCR-β-arrestin1/2 Interactions in Real Time Living Systems to Accelerate Drug Discovery
Published on: June 28, 2019
Helix-bundle and C-terminal GPCR domains differentially influence GRK-specific functions and β-arrestin-mediated
Edda S F Matthees1, Raphael S Haider1,2,3, Laura Klement1
1Institut für Molekulare Zellbiologie, CMB - Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena, Jena, Germany.
None:
G protein-coupled receptors (GPCRs) orchestrate diverse physiological responses via signaling through G proteins, GPCR kinases (GRKs), and arrestins. While most G protein functions are well-established, the contributions of GRKs and arrestins remain incompletely understood. Here, we investigate the influence of β-arrestin-interacting GPCR domains (helix-bundle/C-terminus) on β-arrestin conformations and functions using refined biosensors and advanced cellular knockout systems. Focusing on prototypical class A (b2AR) and B (V2R) receptors and their chimeras (b2V2/V2b2), we show that most N-domain β-arrestin conformational changes are mediated by receptor C-terminus-interactions, while C-domain conformations respond to the helix-bundle or an individual combination of interaction interfaces. Moreover, we demonstrate that ERK1/2 signaling responses are governed by the GPCR helix-bundle, while β-arrestin co-internalization depends on the receptor C-terminus. However, receptor internalization is controlled via the overall GPCR configuration. Our findings elucidate how individual GPCR domains dictate downstream signaling events, shedding light on the structural basis of receptor-specific signaling.
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