Allosteric modulation of ghrelin receptor signaling by lipids

Marjorie Damian,Nicolas Floquet,Laurent J Catoire,Sonia Cantel,Céline M’Kadmi,Sophie Mary,Maxime Louet,Jean-Alain Fehrentz,Antoniel Augusto Severo Gomes,Séverine Denoyelle,Jean-Louis Banères,Paulo M Bisch

doi:10.1038/s41467-021-23756-y

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.

Highlights

The membrane is an integral component of the G protein-coupled receptor signaling machinery
There are some differences that likely result from the diversity in protein sequence, most of the residues in the PIP2binding sites of growth hormone secretagogue receptor (GHSR) are homologous to those proposed to play a similar role in NTS1R and A2AR9,17
This could explain the increase in PIP2:GHSR FRET signal observed when cholesterol was included in the nanodiscs, as this sterol appeared to stabilize the active state of GHSR (Supplementary Fig. 10)

Summary

Introduction

The membrane is an integral component of the G protein-coupled receptor signaling machinery. We find that selective interactions and 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. The cell membrane does provide the physiological environment necessary for the stability of the native fold of membrane proteins but it modulates their function through an impact on their conformational dynamics. This makes the lipid and proteins intricated components of a single molecular machine[4]. This receptor is expressed in a variety of tissues and cell types, both at the central and peripheral levels[12]

Methods

Results

Conclusion