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Allosteric modulation of ghrelin receptor signaling by lipids

Author

Listed:
  • Marjorie Damian

    (Université de Montpellier, ENSCM)

  • Maxime Louet

    (Université de Montpellier, ENSCM)

  • Antoniel Augusto Severo Gomes

    (Université de Montpellier, ENSCM
    Universidade Federal do Rio de Janeiro)

  • Céline M’Kadmi

    (Université de Montpellier, ENSCM)

  • Séverine Denoyelle

    (Université de Montpellier, ENSCM)

  • Sonia Cantel

    (Université de Montpellier, ENSCM)

  • Sophie Mary

    (Université de Montpellier, ENSCM)

  • Paulo M. Bisch

    (Universidade Federal do Rio de Janeiro)

  • Jean-Alain Fehrentz

    (Université de Montpellier, ENSCM)

  • Laurent J. Catoire

    (Université de Paris, Institut de Biologie Physico-Chimique (FRC 550))

  • Nicolas Floquet

    (Université de Montpellier, ENSCM)

  • Jean-Louis Banères

    (Université de Montpellier, ENSCM)

Abstract

The membrane is an integral component of the G protein-coupled receptor signaling machinery. Here we demonstrate that lipids regulate the signaling efficacy and selectivity of the ghrelin receptor GHSR through specific interactions and bulk effects. We find that PIP2 shifts the conformational equilibrium of GHSR away from its inactive state, favoring basal and agonist-induced G protein activation. This occurs because of a preferential binding of PIP2 to specific intracellular sites in the receptor active state. Another lipid, GM3, also binds GHSR and favors G protein activation, but mostly in a ghrelin-dependent manner. Finally, we find that not only selective interactions but also the thickness of the bilayer reshapes the conformational repertoire of GHSR, with direct consequences on G protein selectivity. Taken together, this data illuminates the multifaceted role of the membrane components as allosteric modulators of how ghrelin signal could be propagated.

Suggested Citation

  • Marjorie Damian & Maxime Louet & Antoniel Augusto Severo Gomes & Céline M’Kadmi & Séverine Denoyelle & Sonia Cantel & Sophie Mary & Paulo M. Bisch & Jean-Alain Fehrentz & Laurent J. Catoire & Nicolas , 2021. "Allosteric modulation of ghrelin receptor signaling by lipids," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23756-y
    DOI: 10.1038/s41467-021-23756-y
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    Cited by:

    1. Alexandre Pozza & François Giraud & Quentin Cece & Marina Casiraghi & Elodie Point & Marjorie Damian & Christel Le Bon & Karine Moncoq & Jean-Louis Banères & Ewen Lescop & Laurent J. Catoire, 2022. "Exploration of the dynamic interplay between lipids and membrane proteins by hydrostatic pressure," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Fabian Bumbak & James B. Bower & Skylar C. Zemmer & Asuka Inoue & Miquel Pons & Juan Carlos Paniagua & Fei Yan & James Ford & Hongwei Wu & Scott A. Robson & Ross A. D. Bathgate & Daniel J. Scott & Pau, 2023. "Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Woori Ko & Euna Lee & Jung-Eun Kim & Hyun-Ho Lim & Byung-Chang Suh, 2024. "The plasma membrane inner leaflet PI(4,5)P2 is essential for the activation of proton-activated chloride channels," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Junke Liu & Hengmin Tang & Chanjuan Xu & Shengnan Zhou & Xunying Zhu & Yuanyuan Li & Laurent Prézeau & Tao Xu & Jean-Philippe Pin & Philippe Rondard & Wei Ji & Jianfeng Liu, 2022. "Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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