A basic model for the association of ligands with membrane cholesterol: application to cytolysin binding

Lange, Yvonne; Tabei, S. M. Ali; Steck, Theodore L.

doi:10.1016/j.jlr.2023.100344

Cited by 8 publications

(35 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We assumed that the cytoplasmic endomembranes, taken as a whole, have a very low cholesterol content (namely, ≤ 10 mol%) and phospholipids of very low cholesterol affinity. 24, 25 It appears that proteins with modest cholesterol affinity (namely, those characterized in Figures 1-3) would be partially filled with cholesterol in such membranes while the oligomers with high affinity and cooperativity would be essentially saturated. Of course, individual organelles such as the endoplasmic reticulum and distal Golgi membranes differ in their cholesterol content; also, the maturation and modifications of these proteins may vary among organelles.…”

Section: Resultsmentioning

confidence: 99%

“…It resembles an earlier model that treats the binding of water-soluble ligands such as cytolysins to membrane sterols. 24 In contrast, the present version places the ligand in the same membrane compartment as the sterol and the phospholipid. We assume that a ligand (L) associates with cholesterol (C) in competition with the membrane phospholipids (P).…”

Section: Methodsmentioning

confidence: 95%

“…We assumed that the cytoplasmic endomembranes, taken as a whole, have a very low cholesterol content (namely,  10 mol%) and phospholipids of very low cholesterol affinity. 24,25 It appears that proteins with modest cholesterol affinity (namely, those characterized in Figures 1-3) would be partially filled with cholesterol in such membranes while the oligomers with high affinity and cooperativity would for five of the transporters studied above and endomembranes that contained a 30/70 mixture of two phospholipids with stoichiometries of C:P = 1:1 and 1:2 and sterol association constants KP = 21 and 10, respectively. 24 The characteristics of the proteins are given in Table 8.…”

Section: Nicotinic Acetylcholine Receptor (Achr)mentioning

confidence: 99%

“…The cytoplasmic endomembranes, taken as a whole, appear to have a very low cholesterol content (namely,  10 mol%) and phospholipids of very low cholesterol affinity. 23,24 In Figure 8, we simulated the association of the sterol with five of the integral membrane Figure 8. Simulation of the association of cholesterol with proteins in membranes with the overall phospholipid characteristics of hypothetical endomembranes.…”

Section: Nicotinic Acetylcholine Receptor (Achr)mentioning

confidence: 99%

“…At the other extreme, very weak proteins bind cholesterol poorly until the phospholipids become saturated with sterol at their stoichiometric equivalence point and the uncomplexed excess sterol becomes increasingly available to the protein. 25 Between these extremes, proteins have sigmoidal sterol dependence curves with shapes and thresholds determined by the attributes both of the ligands and the phospholipids (see Results). We assume that two forms of cholesterol are available to the protein: (a) that extracted from membrane phospholipid complexes by strong competition; and (b) that readily available beyond the stoichiometric equivalence point of the complexes.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

Steck,

Tabei,

Lange

2023

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 95%