Adsorption of apolipoprotein A-I to biological membranes. A statistical mechanical model

Abstract

Apolipoprotein A-I (apo A-I), the main protein component of high-density lipoprotein (HDL), reduces the risk for atherosclerosis by removing cholesterol from the membrane of foam cells. Experiments with model membrane systems have indicated, however, that membrane cholesterol reduces apo A-I binding to the membrane. Foam cells resolve this discrepancy electrostatically by co-inserting negatively charged phospholipids in their membrane. Here we present a statistical mechanical model to account for the effect of cholesterol. Our model is based on the Haugen and May model which takes into account the dipolar nature of the zwitterionic phospholipid head group in the membrane, in which the positive end of the zwitterionic dipole moment can move randomly on a hemispherical surface with a radius equal to the arm of the dipole moment and with the negative end fixed at the hydrocarbon layer. Adsorption of a positively charged apo A-I macroion to the surface of the membrane modifies the electric field within the head group region and induces lateral demixing of phospholipid molecules in the membrane. Results from numerical integration of model equations show that i) as a result of the strong charge-dipole electrostatic coupling, the positive end of the dipoles tilts away from the adsorbed macroion in a cooperative manner; and ii) cholesterol reduces macroion adsorption to the membrane by reducing the surface area of the membrane and restricting the dipoles range of rotation. Model predictions for the change in free energy of adsorption to zwitterionic membrane are in good agreement with previously reported experimental data with liposomes. The model can assist in designing new mimetic peptides.

ABCA1 Mediates Unfolding of Apolipoprotein AI N Terminus on the Cell Surface Before Lipidation and Release of Nascent High-Density Lipoprotein

“…The next transition is sharply uphill and leads to the insertion of apoAI into the fatty acyl chains of the plasma membrane to yield the lipidated cell surface (L C ) state. This step probably involves the creation of phospholipid head group packing discontinuities, with increased efficiency due to ABCA1 mediated plasma membrane remodeling, and which may in part be in response to the positive charges of apoAI leading to phospholipid headgroup lateral demixing, as recently suggested by Gross 29 . However, this L C state is not stable and rapidly resolves with a large drop in free energy by the release of apoAI in nascent HDL (nHDL) from the cells into the surrounding interstitial space.…”