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Lipids modulate the dynamics of GPCR:β-arrestin interaction

Author

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  • Antoniel A. S. Gomes

    (Université de Montpellier, ENSCM
    Universidade Federal do)

  • 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)

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.

Suggested Citation

  • Antoniel A. S. Gomes & Michela Michele & Rita Ann Roessner & Marjorie Damian & Paulo M. Bisch & Nathalie Sibille & Maxime Louet & Jean-Louis Banères & Nicolas Floquet, 2025. "Lipids modulate the dynamics of GPCR:β-arrestin interaction," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59842-8
    DOI: 10.1038/s41467-025-59842-8
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