Abstract
Apolipoprotein (apo)A-I is the principal protein component of HDL, and because of its conformational adaptability, it can stabilize all HDL subclasses. The amphipathic α-helix is the structural motif that enables apoA-I to achieve this functionality. In the lipid-free state, the helical segments unfold and refold in seconds and are located in the N-terminal two thirds of the molecule where they are loosely packed as a dynamic, four-helix bundle. The C-terminal third of the protein forms an intrinsically disordered domain that mediates initial binding to phospholipid surfaces, which occurs with coupled α-helix formation. The lipid affinity of apoA-I confers detergent-like properties; it can solubilize vesicular phospholipids to create discoidal HDL particles with diameters of approximately 10 nm. Such particles contain a segment of phospholipid bilayer and are stabilized by two apoA-I molecules that are arranged in an anti-parallel, double-belt conformation around the edge of the disc, shielding the hydrophobic phospholipid acyl chains from exposure to water. The apoA-I molecules are in a highly dynamic state, and they stabilize discoidal particles of different sizes by certain segments forming loops that detach reversibly from the particle surface. The flexible apoA-I molecule adapts to the surface of spherical HDL particles by bending and forming a stabilizing trefoil scaffold structure. The above characteristics of apoA-I enable it to partner with ABCA1 in mediating efflux of cellular phospholipid and cholesterol and formation of a heterogeneous population of nascent HDL particles. Novel insights into the structure-function relationships of apoA-I should help reveal mechanisms by which HDL subclass distribution can be manipulated.