DETERMINATION OF THE TRANSBILAYER DISTRIBUTION OF PLASMA MEMBRANE CHOLESTEROL

The transbilayer distribution of plasma membrane cholesterol remains uncertain despite repeated analysis. Here we propose a new mechanism driving cholesterol sidedness: sterols form simple stoichiometric complexes with phospholipids. The model postulates that the phospholipids in the plasma membrane bilayer are fully complexed with cholesterol. The sterol in each leaflet is then the product of the abundance of its phospholipid and its sterol stoichiometry. Notably, lipid affinities are not relevant. Using literature values for the composition, abundance and sterol stoichiometry of the phospholipid in each leaflet, the model predicts that two thirds of the cholesterol in the human erythrocyte membrane bilayer is located in its outer leaflet, an exofacial to endofacial ratio of 2:1. The model also predicts that the cholesterol content of the bilayer as a whole is 0.75 mole/mole phospholipid; this matches literature values. The model suggests, furthermore, that the areas of its two leaflets are about the same. The concordance of prediction with observation validates the model and the values used for the parameters. The sterol in the exofacial leaflet of the plasma membrane of any cell is predicted to exceed that on its contralateral side when its phospholipids have a higher sterol stoichiometry and are fully complexed.