New insights into the determination of HDL structure by apolipoproteins

Abstract

This article is available online at http://www.jlr.orgThe purpose of this review is to summarize current understanding of how apolipoproteins (apoA-I in particular) determine the structures of HDL particles. The focus is on recent advances in the fi eld, so the coverage of the literature on HDL structure is not comprehensive. Knowledge of HDL structure at the molecular level is critical for understanding how this lipoprotein achieves the multiple functions elaborated in other reviews in this thematic series.In human plasma, HDL is a heterogeneous collection of particles ranging 7-12 nm in diameter and 1.063-1.21 g/ml in density ( 1-4 ). The predominant species of HDL are spherical microemulsion particles, in which a core of neutral cholesteryl ester (CE) and triacylglycerol (TG) is encapsulated by a monolayer of phospholipid (PL), unesterifi ed (free) cholesterol (FC), and protein ( 5 ). The protein and PL constituents comprise approximately 50 and 25%, respectively, of the mass of such particles, with the CE, FC, and TG components making up the remainder. Larger, less dense HDL particles have a higher lipidto-protein mass ratio. Approximately 70% of total plasma HDL protein is apoA-I (which is present in normolipidemic human plasma at ‫ف‬ 130 mg/dl), and it is located in essentially every HDL particle. The second most abundant protein is apoA-II, which comprises 15-20% of total plasma HDL protein, but this component is not present in all HDL particles. In human plasma, about 25% of apoA-I is present in HDL particles containing only apoA-I (LpA-I); the remaining HDL particles contain both apoA-I and apoA-II (LpA-I+A-II), typically in a molar ratio of 1-2/1 ( 6 ). ApoA-I and apoA-II are the "scaffold" proteins that primarily determine HDL particle structure. Other members of the exchangeable apolipoprotein gene family that are 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 ␣ -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 ␣ -helix formation. The lipid affi nity 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 s...

Is ABCA1 a lipid transfer protein?

“…The release of PL and FC from the PM involves PL bilayer solubilization due to the detergent-like properties of the apoA-I molecule (112,113). The solubilization process involves insertion of amphipathic α-helices between the PM PL molecules which destabilizes and fragments the bilayer (114).…”

Structure of serum amyloid A suggests a mechanism for selective lipoprotein binding and functions: SAA as a hub in macromolecular interaction networks

“…Fourth, extensive biophysical studies, including protein cross-linking followed by mass spectrometry and distance measurements using FRET or EPR, indicate that the 4-helix bundles in apoA-I, apoA-IV and apoE open up on the lipid to form two pairs of helices that wrap around the lipoprotein perimeter in an antiparallel “double-belt” conformation ([46–50] and references therein). Such a helix bundle opening exposes the apolar faces of the amphipathic apolipoprotein α-helices to the lipid surface (Fig.…”

Rapid identification of erythrocyte phospholipids in Sprague–Dawley rats by ultra high performance liquid chromatography with electrospray ionization quadrupole time‐of‐flight tandem mass spectrometry

“…Researchers indicated that the composition of plasma phospholipids in blood directly reflect short-term (several days) physiological changes (e.g. dietary fat intake) [13], while the erythrocytes have a half-life in circulation of approximately 120 days in blood and their membrane phospholipids are remodeled throughout the cell's life span by the ingestion of phospholipids from blood circulation [14,15]. Thus, the phospholipid compositions of erythrocyte membrane are thought to indirectly reflect physiological change over a period of months [16].…”