Cholesterol in Class C GPCRs: Role, Relevance, and Localization

Isu, Ugochi; Badiee, Shadi A.; Khodadadi, Ehsaneh; Moradi, Mahmoud

doi:10.3390/membranes13030301

Cited by 14 publications

(14 citation statements)

References 192 publications

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“…Our findings contribute to the understanding of cholesterol’s critical role in GPCR function and regulation. 4,16,69–71 Cholesterol interacts with specific regions of GPCRs, such as the cholesterol recognition amino acid consensus (CRAC) motif, modulating their structural and functional properties. 72–75 The preferential impact of cholesterol on mGluR1’s transmembrane helices aligns with cholesterol-mediated GPCR regulation, emphasizing the significance of considering the lipid environment in investigating GPCR dynamics and function.…”

Section: Resultsmentioning

confidence: 99%

“…24,27,28 Moreover, cholesterol has been implicated in the localization and trafficking of mGluRs, with cholesterol-rich lipid rafts serving as platforms for mGluR signaling complexes. 16,29–32 These findings suggest a potential role for lipid-protein interactions in fine tuning mGluR signaling.…”

Section: Introductionmentioning

confidence: 90%

“…Recent studies have shed light on the significance of membrane lipids, particularly cholesterol, in modulating mGluR structure and function. 4,16,24–26 For instance, cholesterol depletion has been shown to impair the function of mGluR1 in hippocampal neurons, leading to reduced calcium signaling and altered synaptic plasticity. 24,27,28 Moreover, cholesterol has been implicated in the localization and trafficking of mGluRs, with cholesterol-rich lipid rafts serving as platforms for mGluR signaling complexes.…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol Dependence of the Conformational Changes in Metabotropic Glutamate Receptor 1

Isu,

Badiee,

Polasa

et al. 2024

Preprint

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Metabotropic glutamate receptors (mGluRs) are class C G protein-coupled receptors that function as obligate dimers in regulating neurotransmission and synaptic plasticity in the central nervous system. The mGluR1 subtype has been shown to be modulated by the membrane lipid environment, particularly cholesterol, though the molecular mechanisms remain elusive. In this study, we employed all-atom molecular dynamics simulations to investigate the effects of cholesterol on the conformational dynamics of the mGluR1 seven transmembrane (7TM) domain in an inactive state model. Simulations were performed with three di erent cholesterol concentrations (0%, 10%, and 25%) in a palmitoyl-oleoyl phosphatidylcholine (POPC) lipid bilayer system. Our results demonstrate that cholesterol induces conformational changes in the mGluR1 dimer more significantly than in the individual protomers. Notably, cholesterol modulates the dynamics and conformations of the TM1 and TM2 helices at the dimer interface. Interestingly, an intermediate cholesterol concentration of 10% elicits more pronounced conformational changes compared to both cholesterol-depleted (0%) and cholesterol-enriched (25%) systems. Specific electrostatic interaction unique to the 10% cholesterol system further corroborate these conformational differences. Given the high sequence conservation of the 7TM domains across mGluR subtypes, the cholesterol-dependent effects observed in mGluR1 are likely applicable to other members of this receptor family. Our findings provide atomistic insights into how cholesterol modulates the conformational landscape of mGluRs, which could impact their function and signaling mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Cholesterol Dependence of the Conformational Changes in Metabotropic Glutamate Receptor 1

Isu,

Badiee,

Polasa

et al. 2024

Preprint

Self Cite

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“…These associations have been characterized by various techniques, including X-ray, cryo-EM, NMR, molecular computation and functional analysis. [1][2][3][4][5][6][7][8][9][10] Two cardinal features of the interaction of the proteins and sterols are the strength of their association and their binding stoichiometry. We have found only one experimental determination in the literature of the affinity of cholesterol for an integral membrane protein in situ.…”

Section: Introductionmentioning

confidence: 99%

A Method For Estimating The Cholesterol Affinity Of Integral Membrane Proteins From Experimental Data

Steck,

Tabei,

Lange

2023

Preprint

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The cholesterol affinities of many integral plasma membrane proteins have been estimated by molecular simulation techniques. However, these values lack experimental confirmation. We therefore developed a simple mathematical model to extract sterol affinity constants and stoichiometries from published isotherms for the dependence of the activity of such proteins on membrane cholesterol concentration. The model assumes competition for cholesterol between the proteins and the phospholipids. This competition makes the binding isotherms of the proteins sigmoidal with strongly-lagged thresholds. Using sterol association constants and stoichiometries for the phospholipids taken from the literature, we matched computed isotherms to experimental curves. Three oligomeric transporters were found to bind cholesterol without cooperativity with dimensionless association constants of 35 for Kir3.4* and 100 for both Kir2 and a GAT transporter. (The corresponding ΔG° values are -8.8, -11.4 and -11.4 KJ/mol, respectively.) These association constants are significantly lower than those for the phospholipids, which range from ~100 to 6,000. The BK channel, the nicotinic acetylcholine receptor and the M192I mutant of Kir3.4* appear to bind multiple cholesterol molecules strongly and cooperatively with subunit affinities of 563, 950 and 700, respectively. The model predicts that the three less avid transporters are approximately half-saturated in their native plasma membranes; hence, sensitive to variations in cholesterol in vivo. The more avid proteins would be nearly saturated in vivo. The method can be applied to any integral protein or other ligand in any bilayer of phospholipids for which reasonable estimates of sterol affinities and stoichiometries can be assigned.

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“…Cholesterol is bound to many plasma membrane proteins, affecting their disposition and activity in diverse ways. These associations have been characterized by various techniques, including X-ray, cryo-EM, NMR, molecular computation, and functional analysis. − Two cardinal features of the interaction of the proteins and sterols are the strength of their association and their binding stoichiometry. We have found only one experimental determination in the literature of the affinity of cholesterol for an integral membrane protein in situ .…”

Section: Introductionmentioning

confidence: 99%

Estimating the Cholesterol Affinity of Integral Membrane Proteins from Experimental Data

Steck,

Ali Tabei,

Lange

2023

Biochemistry

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The cholesterol affinities of many integral plasma membrane proteins have been estimated by molecular computation. However, these values lack experimental confirmation. We therefore developed a simple mathematical model to extract sterol affinity constants and stoichiometries from published isotherms for the dependence of the activity of such proteins on the membrane cholesterol concentration. The binding curves for these proteins are sigmoidal, with strongly lagged thresholds attributable to competition for the cholesterol by bilayer phospholipids. The model provided isotherms that matched the experimental data using published values for the sterol association constants and stoichiometries of the phospholipids. Three oligomeric transporters were found to bind cholesterol without cooperativity, with dimensionless association constants of 35 for Kir3.4* and 100 for both Kir2 and a GAT transporter. (The corresponding ΔG°values were −8.8, −11.4, and −11.4 kJ/mol, respectively). These association constants are significantly lower than those for the phospholipids, which range from ∼100 to 6000. The BK channel, the nicotinic acetylcholine receptor, and the M192I mutant of Kir3.4* appear to bind multiple cholesterol molecules cooperatively (n = 2 or 4), with subunit affinities of 563, 950, and 700, respectively. The model predicts that the three less avid transporters are approximately half-saturated in their native plasma membranes; hence, they are sensitive to variations in cholesterol in vivo. The more avid proteins would be nearly saturated in vivo. The method can be applied to any integral protein or other ligands in any bilayer for which there are reasonable estimates of the sterol affinities and stoichiometries of the phospholipids.

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Cholesterol in Class C GPCRs: Role, Relevance, and Localization

Cited by 14 publications

References 192 publications

Cholesterol Dependence of the Conformational Changes in Metabotropic Glutamate Receptor 1

Cholesterol Dependence of the Conformational Changes in Metabotropic Glutamate Receptor 1

A Method For Estimating The Cholesterol Affinity Of Integral Membrane Proteins From Experimental Data

Estimating the Cholesterol Affinity of Integral Membrane Proteins from Experimental Data

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