Lipids modulate the dynamics of GPCR:β-arrestin interaction
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 orientati...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59842-8 |
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| author | Antoniel A. S. Gomes Michela Di Michele Rita Ann Roessner Marjorie Damian Paulo M. Bisch Nathalie Sibille Maxime Louet Jean-Louis Banères Nicolas Floquet |
| author_facet | Antoniel A. S. Gomes Michela Di Michele Rita Ann Roessner Marjorie Damian Paulo M. Bisch Nathalie Sibille Maxime Louet Jean-Louis Banères Nicolas Floquet |
| author_sort | Antoniel A. S. Gomes |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-682e45578c524f4c8c041ce63b528fb3 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-682e45578c524f4c8c041ce63b528fb32025-08-20T02:03:31ZengNature PortfolioNature Communications2041-17232025-05-0116111610.1038/s41467-025-59842-8Lipids modulate the dynamics of GPCR:β-arrestin interactionAntoniel A. S. Gomes0Michela Di Michele1Rita Ann Roessner2Marjorie Damian3Paulo M. Bisch4Nathalie Sibille5Maxime Louet6Jean-Louis Banères7Nicolas Floquet8Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCMInstitut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCMInstitut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCMInstitut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCMLaboratório de Física Biológica, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal doCentre de Biologie Structurale (CBS), CNRS, Université de Montpellier, InsermInstitut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCMInstitut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCMInstitut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCMAbstract 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.https://doi.org/10.1038/s41467-025-59842-8 |
| spellingShingle | Antoniel A. S. Gomes Michela Di Michele Rita Ann Roessner Marjorie Damian Paulo M. Bisch Nathalie Sibille Maxime Louet Jean-Louis Banères Nicolas Floquet Lipids modulate the dynamics of GPCR:β-arrestin interaction Nature Communications |
| title | Lipids modulate the dynamics of GPCR:β-arrestin interaction |
| title_full | Lipids modulate the dynamics of GPCR:β-arrestin interaction |
| title_fullStr | Lipids modulate the dynamics of GPCR:β-arrestin interaction |
| title_full_unstemmed | Lipids modulate the dynamics of GPCR:β-arrestin interaction |
| title_short | Lipids modulate the dynamics of GPCR:β-arrestin interaction |
| title_sort | lipids modulate the dynamics of gpcr β arrestin interaction |
| url | https://doi.org/10.1038/s41467-025-59842-8 |
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