Lipids modulate the dynamics of GPCR:β-arrestin interaction

Antoniel A. S. Gomes, Michela Michele, Rita Ann Roessner, Marjorie Damian, Paulo M. Bisch, Nathalie Sibille, Maxime Louet, Jean-Louis Banères and Nicolas Floquet ()
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Antoniel A. S. Gomes: Université de Montpellier, ENSCM
Michela Michele: Université de Montpellier, ENSCM
Rita Ann Roessner: Université de Montpellier, ENSCM
Marjorie Damian: Université de Montpellier, ENSCM
Paulo M. Bisch: Universidade Federal do
Nathalie Sibille: Université de Montpellier, Inserm
Maxime Louet: Université de Montpellier, ENSCM
Jean-Louis Banères: Université de Montpellier, ENSCM
Nicolas Floquet: Université de Montpellier, ENSCM

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

Abstract: Abstract β-arrestins are key molecular partners of G Protein-Coupled Receptors (GPCRs), triggering not only their desensitization but also intracellular signaling. Existing structural data point to high conformational plasticity of GPCR:β-arrestin interaction, with two completely different orientations between receptor and β-arrestin. Combining molecular dynamics simulations and fluorescence spectroscopy, we show that β-arrestin 1 interacts with membranes even in the absence of a receptor, an interaction that is enhanced by PI(4,5)P2, presumably holding the β-arrestin 1 C-edge loop into the lipid bilayer. This key interaction helps β-arrestin 1 to adopt a “receptor-ready” orientation and consequently favors its coupling to the ghrelin receptor (GHSR). In addition, we show that the GHSR:β-arrestin 1 assembly is a dynamic complex where β-arrestin can adopt several orientations. PI(4,5)P2 decreases the dynamics of the complex and shifts the equilibrium between the different arrangements, favoring one of them. Taken together, our results highlight how PI(4,5)P2 plays a true third-player role in the GPCR:β-arrestin interaction, not only by preparing β-arrestin for its further interaction with receptors but also by modulating its orientation once the protein:protein complex is formed.

Date: 2025
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DOI: 10.1038/s41467-025-59842-8

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