Helix-bundle and C-terminal GPCR domains differentially influence GRK-specific functions and β-arrestin-mediated regulation

Edda S. F. Matthees, Raphael S. Haider, Laura Klement, Mona Reichel, Nina K. Blum, Verena Weitzel, Thimea Trüpschuch, Carla Ziegler, Julia Drube, Stefan Schulz and Carsten Hoffmann ()
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Edda S. F. Matthees: CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena
Raphael S. Haider: CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena
Laura Klement: CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena
Mona Reichel: CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena
Nina K. Blum: Friedrich-Schiller-Universität Jena
Verena Weitzel: CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena
Thimea Trüpschuch: CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena
Carla Ziegler: CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena
Julia Drube: CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena
Stefan Schulz: Friedrich-Schiller-Universität Jena
Carsten Hoffmann: CMB – Center for Molecular Biomedicine, Universitätsklinikum Jena, Friedrich-Schiller-Universität Jena

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-61281-4

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