The Affinity of Sterols for Different Phospholipid Classes and Its Impact on Lateral Segregation

Nyholm, Thomas K.M.; Jaikishan, Shishir; Engberg, Oskar; Hautala, Victor; Slotte, J. Peter

doi:10.1016/j.bpj.2018.11.3135

Cited by 36 publications

(42 citation statements)

References 67 publications

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“…These interactions are driven by van der Waals contacts, hydrogen bonds, and the shielding of the apolar sterol rings from water by the polar head groups of the phospholipids, a hydrophobic effect 19,20 . The absolute affinities of different membrane phospholipids for cholesterol are not known, but it has been shown that they vary over about an order of magnitude 2,21‐24 . Their complexes have stoichiometries that range from 1:1 for high‐affinity (long chain, saturated) species to two phospholipids per cholesterol for less avid lipids 3,18,20,23,25 .…”

Section: Cholesterol Complexes With Phospholipidsmentioning

confidence: 99%

Active cholesterol 20 years on

Lange

Steck

2020

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This review considers the following hypotheses, some well‐supported and some speculative. Almost all of the sterol molecules in plasma membranes are associated with bilayer phospholipids in complexes of varied strength and stoichiometry. These complexes underlie many of the material properties of the bilayer. The small fraction of cholesterol molecules exceeding the binding capacity of the phospholipids is thermodynamically active and serves diverse functions. It circulates briskly among the cell membranes, particularly through contact sites linking the organelles. Active cholesterol provides the upstream feedback signal to multiple mechanisms governing plasma membrane homeostasis, pegging the sterol level to a threshold set by its phospholipids. Active cholesterol could also be the cargo for various inter‐organelle transporters and the form excreted from cells by reverse transport. Furthermore, it is integral to the function of caveolae; a mediator of Hedgehog regulation; and a ligand for the binding of cytolytic toxins to membranes. Active cholesterol modulates a variety of plasma membrane proteins—receptors, channels and transporters—at least in vitro.

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Section: Cholesterol Complexes With Phospholipidsmentioning

confidence: 99%

Active cholesterol 20 years on

Lange

Steck

2020

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“…Segregation of lipid into lateral domains is a process that seems to be driven by many different forces (10,17,18,59). One factor that has been observed to influence the formation of ordered domains in the membrane plane is the interactions between cholesterol and the different phospholipids present (9,10). An increased relative affinity of cholesterol for the saturated phospholipids, as compared to the unsaturated phospholipids, has been observed to decrease the solubility of PSM in the L d phase and thereby promote the formation of ordered domains.…”

Section: Lateral Segregationmentioning

confidence: 99%

“…Among the saturated phospholipids, cholesterol further seems to have an especially strong affinity for sphingomyelin (6)(7)(8). In bilayers composed of different phospholipids, the presence of cholesterol may influence the lateral organization in the membrane by interacting preferentially with saturated lipids such as sphingomyelin (9)(10)(11). This may lead to the formation of L o domains.…”

Section: Introductionmentioning

confidence: 99%

Impact of Acyl Chain Mismatch on the Formation and Properties of Sphingomyelin-Cholesterol Domains

Nyholm

Engberg

Hautala

et al. 2019

Biophysical Journal

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Lateral segregation and the formation of lateral domains are well-known phenomena in ternary lipid bilayers composed of an unsaturated (low gel-to-liquid phase transition temperature (T m)) phospholipid, a saturated (high-T m) phospholipid, and cholesterol. The formation of lateral domains has been shown to be influenced by differences in phospholipid acyl chain unsaturation and length. Recently, we also showed that differential interactions of cholesterol with low-and high-T m phospholipids in the bilayer can facilitate phospholipid segregation. Now, we have investigated phospholipid-cholesterol interactions and their role in lateral segregation in ternary bilayers composed of different unsaturated phosphatidylcholines (PCs) with varying acyl chain lengths, N-palmitoyl-D-erythro-sphingomyelin (PSM), and cholesterol. Using deuterium NMR spectroscopy, we determined how PSM was influenced by the acyl chain composition in surrounding PC environments and correlated this with the affinity of cholestatrienol (a fluorescent cholesterol analog) for PSM in the different PC environments. Results from a combination of time-resolved fluorescence measurements of trans-parinaric acid and Fö rster resonance energy transfer experiments showed that the relative affinity of cholesterol for phospholipids determined the degree to which the sterol promoted domain formation. From Fö rster resonance energy transfer, deuterium NMR, and differential scanning calorimetry results, it was clear that cholesterol also influenced both the thermostability of the domains and the degree of order in and outside the PSM-rich domains. The results of this study have shown that the affinity of cholesterol for both low-T m and high-T m phospholipids and the effects of low-and high-T m phospholipids on each other influence both lateral structure and domain properties in complex bilayers. We envision that similar effects also contribute to lateral heterogeneity in even more complex biological membranes.

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“…In addition, according to the umbrella model [99], phospholipid head groups in the membrane shield nonpolar cholesterol bodies from the aqueous phase. PS with a large headgroup has a higher affinity for cholesterol than other phospholipids [48, 101]. Therefore, ergosterol, which is also enriched in the cytoplasmic leaflet [102], loses favorable interacting partners in the triple mutant.…”

Section: Discussionmentioning

confidence: 99%

Phospholipid flippases and Sfk1 are essential for the retention of ergosterol in the plasma membrane

Kishimoto

Mioka

Itoh

et al. 2020

Preprint

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Sterols are important lipid components of the plasma membrane (PM) in eukaryotic cells, but it is unknown how the PM retains sterols at a high concentration. Phospholipids are asymmetrically distributed in the PM, and phospholipid flippases play an important role in generating this phospholipid asymmetry. Here, we provide evidence that phospholipid flippases are essential for retaining ergosterol in the PM of yeast. A mutant in three flippases, Dnf1-Lem3, Dnf2-Lem3, and Dnf3-Crf1, and a membrane protein, Sfk1, showed a severe growth defect. We recently identified Sfk1 as a PM protein involved in phospholipid asymmetry. The PM of this mutant showed high permeability and low density, and many nutrient transporters failed to localize to the PM. Staining with the sterol probe filipin and the expression of a sterol biosensor revealed that ergosterol was not retained in the PM. Instead, ergosterol accumulated in an esterified form in lipid droplets. We propose that ergosterol is retained in the PM by the asymmetrical distribution of phospholipids and the action of Sfk1. Once phospholipid asymmetry is severely disrupted, sterols might be exposed on the cytoplasmic leaflet of the PM and actively transported to the endoplasmic reticulum by sterol transfer proteins.

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The Affinity of Sterols for Different Phospholipid Classes and Its Impact on Lateral Segregation

Cited by 36 publications

References 67 publications

Active cholesterol 20 years on

Active cholesterol 20 years on

Impact of Acyl Chain Mismatch on the Formation and Properties of Sphingomyelin-Cholesterol Domains

Phospholipid flippases and Sfk1 are essential for the retention of ergosterol in the plasma membrane

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