Allosteric modulation of ghrelin receptor signaling by lipids

Marjorie Damian (1) , Maxime Louet (1) , Antoniel Augusto Severo Gomes (2) , Céline M’kadmi (1) , Séverine Denoyelle (1) , Sonia Cantel (1) , Sophie Mary (1) , Paulo M Bisch (2) , Jean-Alain Fehrentz (1) , Laurent J Catoire (3) , Nicolas Floquet (1) , Jean‐louis Baneres (1)

1 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
2 UFRJ - Universidade Federal do Rio de Janeiro [Brasil] = Federal University of Rio de Janeiro [Brazil] = Université fédérale de Rio de Janeiro [Brésil]
3 LBPC-PM (UMR_7099) - Laboratoire de biologie physico-chimique des protéines membranaires

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.

Domaines: Biophysique

Marjorie Damian, Maxime Louet, Antoniel Augusto Severo Gomes, Céline M’kadmi, Séverine Denoyelle, et al.. Allosteric modulation of ghrelin receptor signaling by lipids. Nature Communications, 2021, 12 (1), pp.3938. ⟨10.1038/s41467-021-23756-y⟩. ⟨hal-03407522⟩