Lipid Modulation of a Class B GPCR: Elucidating the Modulatory Role of PI(4,5)P₂ Lipids

Abstract

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) lipids have been shown to stabilize an active conformation of class A G-protein coupled receptors (GPCRs) through a conserved binding site, not present in class B GPCRs. For class B GPCRs, previous molecular dynamics (MD) simulation studies have shown PI(4,5)P 2 interacting with the Glucagon receptor (GCGR), which constitutes an important target for diabetes and obesity therapeutics. In this work, we applied MD simulations supported by native mass spectrometry (nMS) to study lipid interactions with GCGR. We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P 2 lipids to GCGR. Specifically, we find the PI(4,5)P 2 lipids to have a higher affinity toward the inactive conformation of GCGR. Interestingly, we find that in contrast to class A GPCRs, PI(4,5)P 2 appear to stabilize the inactive conformation of GCGR through a binding site conserved across class B GPCRs but absent in class A GPCRs. This suggests differences in the regulatory function of PI(4,5)P 2 between class A and class B GPCRs.

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“…Martini has been heavily used to study specific protein–lipid interactions, particularly the protein’s lipid “fingerprint”, i.e., the unique local lipid environment around a protein when inserted in a complex membrane . Some examples of this are the extensive work done on a variety of G protein-coupled receptors (GPCRs), − several pores and transmembrane channels, − and peripheral membrane proteins, ,− among many others. − …”

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“…Phosphoinositides (PIPs), phosphorylated derivatives of phosphatidylinositol (PI), are essential components of eukaryotic cell membranes. PIPs play important roles in cell membrane dynamics, focal adhesion, action organization, and intracellular signaling and serve as modulators of GPCRs, ion channels, and transporters . The hydroxyl groups on the inositol ring of PI can be phosphorylated at the 3, 4, and 5 positions by specific kinases, giving rise to a group of structurally related PIPs, such as PI-monophosphate (PI3P, PI4P, and PI5P), PI- bis phosphate (PI­(3,4)­P 2 , PI­(3,5)­P 2 , and PI­(4,5)­P 2 ), and PI- tris phosphate (PI­(3,4,5)­P 3 ) …”

“…To elucidate PIP 2 binding on the glucagon receptor, a class B GPCR protein, Kjo̷lbye et al used MD simulations to examine the binding of three types of PI­(4,5)­P 2 lipids with varying tails to the receptor . The simulations show that the three PIP 2 lipids have different binding profiles on the receptor.…”

“…(C) PIP 2 binding in the glucagon receptor, a class B GPCR protein, and the conformation preference of PIP 2 binding to the inactive state. Adapted with permission from ref . Copyright 2022 American Chemical Society.…”

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“…The findings show that PI­(4,5)­P2 lipids stabilize the inactive conformation of GCGR through a binding site, which is conserved across class B GPCRs but is absent in class A GPCRs. This suggests differences in the regulatory function of PI­(4,5)­P2 between class A and class B GPCRs …”