Palmitoylation of the Glucagon-like Peptide-1 Receptor Modulates Cholesterol Interactions at the Receptor–Lipid Microenvironment

Naglekar, Amit; Chattopadhyay, Amitabha; Sengupta, Durba

doi:10.1021/acs.jpcb.3c05930

Cited by 3 publications

(1 citation statement)

References 97 publications

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“…It is important to mention that the possible presence of tail-to-tail cholesterol dimers [65] (mirror code [34]) is consistent with a functional coupling of the outer and inner leaflets of the plasma membrane via the TM domains of a membrane receptor [34]. Finally, GPCRs have been suggested to act as scramblases able to mediate phospholipid and cholesterol flip-flop [15,66,67]. The transbilayer transfer of cholesterol may also affect the geometry of TM domains in the membrane core during the propagation of the conformational wave.…”

Section: Conformational Rearrangements Following Ligand Bindingmentioning

confidence: 81%

Fundamental Mechanisms in Membrane Receptology: Old Paradigms, New Concepts and Perspectives

Fantini

2024

Receptors

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Receptology, the science of receptors, is a multidimensional field of research which can be dissected into biosynthesis, membrane sorting, ligand binding and signal transduction. Plasma membrane receptors connect the cells with their environment and transmit signals that are translated into biological information. The historical paradigm of ligand–receptor interactions is the lock-and-key model. This model presupposes that both partners have a precise 3D shape that perfectly fits together to form the ligand–receptor complex. However, this simple model suffers from severe limitations due to several levels of simplifications: (i) water molecules and membrane lipids are not considered; (ii) not all ligands have a stable 3D structure; (iii) the ligand-binding pocket of the receptor is often flexible and conformationally rearranged after the initial binding step (induced fit mechanism) and/or subjected to conformational selection by the ligand; (iv) there are signal transduction mechanisms which can be either purely mechanical (conformational change of the receptor induced after binding of the ligand), lipid-assisted (e.g., by raft lipids such as cholesterol or gangliosides), or in some instances of quantic nature (detection of odorant molecules). The aim of the present review is to challenge the old paradigms and present new concepts of membrane receptology that consider the impact of critical parameters such as water molecules, membrane lipids, electrostatic surface potential and quantum mechanisms.

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Section: Conformational Rearrangements Following Ligand Bindingmentioning

confidence: 81%

Fundamental Mechanisms in Membrane Receptology: Old Paradigms, New Concepts and Perspectives

Fantini

2024

Receptors

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Probing the energy landscape of the lipid interactions of the serotonin1A receptor

Mohole,

Naglekar,

Sengupta

et al. 2024

Biophysical Chemistry

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Human class B1 GPCR modulation by plasma membrane lipids

Chao,

Wong,

Oqua

et al. 2024

Preprint

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The class B1 G protein-coupled receptor (GPCR) subfamily is a class of receptors known for their regulatory roles in metabolism and neuronal activity important as drug targets. Lipids play key functional roles in modulation of GPCR signalling, yet our understanding of the molecular level detail of specific lipid interactions with class B1 GPCRs remains limited. Here we present coarse-grained molecular dynamics (MD) simulations of the active and inactive states of 15 human class B1 family members and use aiida-gromacs to capture full provenance for the set-up of simulations in complex plasma membranes. Receptors exhibit state-dependent lipid interactions with the regulatory sterol cholesterol and phospholipid phosphatidylinositiol-4,5-bisphosphate [PI(4,5)P2] at defined locations on the receptor surface. Global analysis of trends across the subfamily reveals conserved patterns of lipid interaction dynamics. The glycosphingolipid GM3 exerts a modulatory influence on the dynamics of class B1 extracellular domains in both simulations andin vitrotime-resolved FRET assays.TeaserCharacterisation of regulatory lipid interactions with all class B1 GPCRs.

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Palmitoylation of the Glucagon-like Peptide-1 Receptor Modulates Cholesterol Interactions at the Receptor–Lipid Microenvironment

Cited by 3 publications

References 97 publications

Fundamental Mechanisms in Membrane Receptology: Old Paradigms, New Concepts and Perspectives

Fundamental Mechanisms in Membrane Receptology: Old Paradigms, New Concepts and Perspectives

Probing the energy landscape of the lipid interactions of the serotonin1A receptor

Human class B1 GPCR modulation by plasma membrane lipids

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