How Cholesterol Could Be Drawn to the Cytoplasmic Leaf of the Plasma Membrane by Phosphatidylethanolamine

Abstract

In the mammalian plasma membrane, cholesterol can translocate rapidly between the exoplasmic and cytoplasmic leaves, so that its distribution between them should be given by the equality of its chemical potential in the leaves. Due to its favorable interaction with sphingomyelin, which is almost entirely in the outer leaf, one expects the great majority of cholesterol to be there also. Experimental results do not support this, implying that there is some mechanism attracting cholesterol to the inner leaf. We hypothesize that it is drawn there to reduce the bending free energy of the membrane caused by the presence of PE (phosphatidylethanolamine). It does this in two ways: first by simply diluting the amount of PE in the inner leaf, and second by ordering the tails of the PE to reduce its spontaneous curvature. Incorporating this mechanism into a model free energy for the bilayer, we find that between 50 and 60% of the total cholesterol should be in the inner leaf of human erythrocytes.

Interleaflet Coupling, Pinning, and Leaflet Asymmetry—Major Players in Plasma Membrane Nanodomain Formation

“…Its optical properties are not favorable for imaging, but a study using dehydroergosterol showed its enrichment in the inner leaflet (Mondal et al, 2009), which is in accordance with theoretical considerations (Giang and Schick, 2014; Falkovich et al, 2016). In contrast, preferential distribution of cholesterol to the outer leaflet of the human erythrocyte membrane was shown by biochemical analysis of a phospholipid monolayer obtained by freeze-fracture (Fisher, 1976).…”

Nonadditive Compositional Curvature Energetics of Lipid Bilayers

“…The difference is critical for interpreting the influence of curvature stress on, for example, relative lipid composition of the inner and outer leaflets of the plasma membrane (see Ref. [17] in which F H,g was used). Although not apparent from F̄ ′(0), it follows from our proposed local molecular mechanisms that it is the local lipid composition that determines energetics, rather than the global concentration.…”

“…In applications of the Helfrich Hamiltonian to membrane bending, the additivity assumption for c 0 is ubiquitous, see e.g., Refs. [16] and [17]. For a mixture of two lipids A and B with fractions f A and f B , and spontaneous curvatures $c_0^{\mathrm{A}}$ and $c_0^{\mathrm{B}}$, the spontaneous curvature is $$c_0^{\text{mix}}=f^{\mathrm{A}}{c}_0^{\mathrm{A}}+f^{\mathrm{B}}{c}_0^{\mathrm{B}}.$$ Violation of Eq.…”

Role of Aminophospholipids in the Formation of Lipid Rafts in Model Membranes

“…It's in accordance with the relation found out between the affinity of cholesterol and glycerophospholipids [6], the lower the cholesterol affinity is, the higher the temperature of L o /L d immiscibility will be. Moreover, it has been suggested that there is some mechanism attracting CHOL to the inner leaflet [33,1]. The authors hypothesized that CHOL is drown to the inner leaflet to reduce the bending free energy of the membrane caused by the presence of PE.…”

“…While the choline-containing phospholipids, phosphatidylcholine (PC) and sphingomyelin (SM), form extracellular lipid leaflet, cholesterol (CHOL) is considered to be distributed equally between both leaflets in the most of cell types [1]. The lipids in plasma membranes do not mix ideally in the membrane bilayer and they are organized in specialized lipid domains.…”