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.
Highlights
ApolipoproteinA-I is the principal protein component of HDL, and because of its conformational adaptability, it can stabilize all HDL subclasses
A conformation that would promote ready dissociation of apoA-I molecules is depicted in Fig. 4 in which the N-terminal helix bundle is closed and only the C-terminal domain is interacting with the HDL particle surface
Significant progress is being made in understanding the structures of human exchangeable apolipoproteins, especially apoA-I and apoE
Summary
Human exchangeable apolipoproteins (apoA, apoC, apoE) have the same genomic structure and are members of a multigene family that probably evolved from a common ancestor [13]. A longstanding question has been the relationship of the helix locations and overall helix content derived from analysis of the amino acid sequence (Fig. 1A) to the secondary structure of the monomeric lipid-free apoA-I molecule in aqueous solution. Relative to random coil structure, helices are protected against HX and the degree of protection (slowing of amide HX) gives a measure of helix stability (free energy of unfolding). This approach has yielded the locations and stabilities of helices in the apoA-I molecule. Helix cross-linking [21] and fluorescence
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