Abstract
Not long ago, high density lipoproteins (HDL)2 were second class citizens with regard to therapeutic strategies for lowering the risk of atherosclerosis and coronary artery disease (CAD). To date, most successful approaches have focused on the better understood pathways of cholesterol synthesis and low density lipoprotein (LDL) production, the “forward” cholesterol transport pathway. For example, the statin class of cholesterol synthesis inhibitors significantly reduces LDL levels resulting in a less atherogenic plasma lipoprotein profile. However, the relatively modest improvements in mortality conferred by these drugs suggest that other factors also play significant roles in defining CAD risk. The recent discoveries of HDL-interacting cell surface proteins such as scavenger receptor BI (SR-BI) and ATP-binding cassette transporters A1 (ABCA1) and G1 (for recent reviews see Refs. 1 and 2) have helped define the steps of reverse cholesterol transport (RCT), i.e. the movement of cholesterol from the periphery to the liver for catabolism (3, 4). Additionally, there is growing evidence that HDL anti-inflammatory properties may contribute significant protective effects (5), apparently via specific cell signaling pathways (6). These discoveries have fueled a new interest in HDL as a target for CAD treatment (7). Unfortunately, a complete understanding ofHDL function has been hampered by a lack of information on its structure and the molecular basis of its interactions with other proteins. This review summarizes the latest efforts in understanding the structure of the defining protein component of HDL, apoA-I, in the various stages of the RCT pathway.
Highlights
ApoA-I comprises roughly 70% of the high density lipoproteins (HDL) protein mass and apoA-II another 15–20%
HDL can be separated by major apolipoprotein species using immunoaffinity chromatography into apoA-I-containing particles that lack apoA-II (LpA-I) and those that contain both apoA-I and apoA-II (LpA-I/A-II) [9]
There are many examples of antiatherogenic properties of apoA-II. As it comprises the majority of the protein mass, structural studies of human plasma HDL must first focus on apoA-I
Summary
ApoA-I comprises roughly 70% of the HDL protein mass and apoA-II another 15–20%. The remainder is made up of amphipathic proteins including the apoCs, apoE, apoD, apoM, apoA-IV, paroxonase and many other proteins as identified in a recent proteomics study [8]. MINIREVIEW: ApoA-I Structure in HDL helical bundle, whereas the crystal structure shows one contiguous helix Beyond that, both models show the C-terminal residues from about 186 to 191 form a separate. The authors interpreted a third cross-link to indicate that the apoA-I N terminus forms a hairpin turn centered around residue 44 in order to interact with the C-terminal portion of the second apoA-I molecule that has doubled back on itself (Fig. 2C). This organization differs in that it no longer forms a closed loop encapsulating the lipid bilayer. More work will be required to tackle this intriguing issue
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