Exploring GPCR–Lipid Interactions by Molecular Dynamics Simulations: Excitements, Challenges, and the Way Forward

Sengupta, Durba; Prasanna, Xavier; Mohole, Madhura; Chattopadhyay, Amitabha

doi:10.1021/acs.jpcb.8b01657

Cited by 73 publications

(65 citation statements)

References 98 publications

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“…Despite substantial instances of lipid modulation, the mechanisms of allosteric modulation remain unclear. MD simulations could offer detailed insight into specific lipid-protein interactions and their effects (2,91), but so far only limited computational studies have been able to link these physical interactions to functional consequences of receptor activation/function. These studies have mostly focused on GPCRs due to their involvement in a multitude of physical processes, the acknowledged lipiddependency of GPCRs, and also the availability of several crystal structures, which make GPCRs viable for computational investigations.…”

Section: Lipids In Allosteric Modulation Of Receptor Activationmentioning

confidence: 99%

Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes

Manna

Nieminen

Vattulainen

2019

Annu. Rev. Biophys.

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Cell signaling controls essentially all cellular processes. While it is often assumed that proteins are the key architects coordinating cell signaling, recent studies have shown more and more clearly that lipids are also involved in signaling processes in a number of ways. Lipids do, for instance, act as messengers, modulate membrane receptor conformation and dynamics, and control membrane receptor partitioning. Further, through structural modifications such as oxidation, the functions of lipids as part of signaling processes can be modified. In this context, in this article we discuss the understanding recently revealed by atomistic and coarse-grained computer simulations of nanoscale processes and underlying physicochemical principles related to lipids’ functions in cellular signaling.

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Section: Lipids In Allosteric Modulation Of Receptor Activationmentioning

confidence: 99%

Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes

Manna

Nieminen

Vattulainen

2019

Annu. Rev. Biophys.

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“…In this context, the role of the plasma membrane lipid environment in the control of GPCR functional selectivity remains a relatively underexplored area, due primarily to the technical challenges associated with the study of lipid-protein cross-talk (7). Despite this, emerging evidence using newly developed methods places lipid nanodomains as key regulators of GPCR signaling (2, 5, 57-59).…”

Section: Discussionmentioning

confidence: 99%

Agonist binding affinity determines palmitoylation of the glucagon-like peptide-1 receptor and its functional interaction with plasma membrane nanodomains in pancreatic beta cells

Buenaventura

Laughlin

Bitsi

et al. 2018

Preprint

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30The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 31 2 diabetes and obesity, is known to undergo palmitoylation by covalent ligation of an 32 acyl chain to cysteine 438 in its carboxyl-terminal tail. Work with other GPCRs 33 indicates that palmitoylation can be dynamically regulated to allow receptors to 34 partition into plasma membrane nanodomains that act as signaling hotspots. Here, 35we demonstrate that the palmitoylated state of the GLP-1R is increased by agonist 36 binding, leading to its segregation and clustering into plasma membrane signaling 37 nanodomains before undergoing internalization in a clathrin-dependent manner. Both 38 GLP-1R signaling and trafficking are modulated by strategies targeting nanodomain 39 segregation and cluster formation, including depletion of cholesterol or expression of 40 a palmitoylation-defective GLP-1R mutant. Differences in receptor binding affinity 41 exhibited by biased GLP-1R agonists, and modulation of binding kinetics with the 42 positive allosteric modulator BETP, influence GLP-1R palmitoylation, clustering, 43 nanodomain signaling, and internalization. Downstream effects on insulin secretion 44 from pancreatic beta cells indicate that these processes are relevant to GLP-1R 45 physiological actions and might be therapeutically targetable. 46 47 48 49 50 51 52 53 54 55 56 Introduction 57 58 G protein-coupled receptors (GPCRs), the largest membrane receptor family in 59 eukaryotes (1), are integral membrane proteins and, as such, both their physical 60 organization and their signaling properties are modulated by the lipid composition of 61 the surrounding membrane (2, 3). The localization of GPCRs to dynamic membrane 62nanodomains has been widely reported (4-6). These nanodomains, or membrane 63 rafts, which cannot be directly observed in living cells with current methods (7), are 64 often described as highly organized detergent-resistant, liquid-ordered, 65 glycosphingolipid-and cholesterol-rich platforms where receptor-signaling complexes 66 become compartmentalized, facilitating efficient coupling with G proteins (5, 8, 9). 67Additionally, most GPCRs are modified post-translationally with one or more palmitic 68 acid chains linked covalently, but reversibly, via a thioester bond to cysteines within 69 the intracellular domain of the receptor, in a process known as palmitoylation (2, 10). 70The insertion of acyl chain(s) is regulated by families of acyltransferases (DHHCs) 71 and palmitoyl protein thioesterases (11, 12), and can be either constitutive or 72 modulated by agonist binding (13, 14). GPCR palmitoylation at or near the end of its 73 carboxyl-terminal (C-terminal) tail creates a new membrane anchor and a further 74 intracellular loop (15) that modifies the GPCR structure and its interactions with 75 specific intracellular partners, favoring receptor partitioning into plasma membrane 76 nanodomains (2, 16, 17). 78We have previously described how signaling responses of the glucagon-like peptide-79 1 receptor (GLP-1R), a ...

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“…Molecular dynamics (MD) simulations enable exploration of how the physical properties of a membrane (19) and/or direct lipid interactions (20,21) may alter the conformational dynamics of membrane proteins (15,22). For example, a crystal structure of the Class A GPCR β2-adrenegic receptor identified cholesterol bound to the intracellular region of TM4 (23), which was validated by observation of cholesterol binding to the same binding site in MD simulations (24).…”

Section: Introductionmentioning

confidence: 99%

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

Ansell

Song

Sansom

2020

Preprint

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The extracellular domain (ECD) of Class B1 G-protein coupled receptors (GPCRs) plays a central role in signal transduction and is uniquely positioned to sense both the extracellular and membrane environments. Whilst recent studies suggest a role for membrane lipids in the modulation of Class A and Class F GPCR signalling properties, little is known about the effect of lipids on Class B1 receptors. In this study, we employed multiscale molecular dynamics (MD) simulations to access the dynamics of the glucagon receptor (GCGR) ECD in the presence of native-like membrane bilayers.Simulations showed that the ECD could move about a hinge region formed by residues Q122-E126 to adopt both closed and open conformations relative to the TMD. ECD movements were modulated by binding of the glycosphingolipid GM3. These large-scale fluctuations in ECD conformation that may affect the ligand binding and receptor activation properties. We also identify a unique PIP2 interaction profile near ICL2/TM3 at the G-protein coupling interface, suggesting a mechanism of engaging G-proteins which may have a distinct dependence on PIP2 compared to Class A GPCRs.Given the structural conservation of Class B1 GPCRs, the modulatory effects of GM3 and PIP2 on GCGR may be conserved across these receptors, offering new insights into potential therapeutic targeting. Statement of SignificanceThe role of lipids in regulation of Class B GPCRs remains elusive, despite recent structural advances. In this study, multi-scale molecular dynamics simulations are used to evaluate lipid interactions with the glucagon receptor, a Class B1 GPCR. We find that the glycosphingolipid GM3 binds to the glucagon receptor extracellular domain (ECD), modulating the dynamics of the ECD and promoting movement away from the transmembrane domain . We also identify a unique PIP2 interaction fingerprint in a region known to be important for bridging G-protein coupling in Class A GPCRs. Thus, this study provides molecular insight into the behaviour of the glucagon receptor in a complex lipid bilayer environment which may aid understanding of glucagon receptor signalling properties.GCGR_main text v16 figs MS biorxiv.docx

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Exploring GPCR–Lipid Interactions by Molecular Dynamics Simulations: Excitements, Challenges, and the Way Forward

Cited by 73 publications

References 98 publications

Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes

Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes

Agonist binding affinity determines palmitoylation of the glucagon-like peptide-1 receptor and its functional interaction with plasma membrane nanodomains in pancreatic beta cells

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

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