Structure of dimeric apoA‐IV: basis for HDL model

A major contributing factor to cardiovascular disease is atherosclerosis and its progression is dramatically affected by HDL and LDL levels. HDL and LDL are lipoprotein complexes consisting of lipids and proteins from the apolipoprotein family. Apolipoprotein members have a unique detergent‐like property, which enable them to bind lipids and form large complexes such as chylomicrons, VLDL, LDL and HDL. Another key property of apolipoprotein is self‐association and elucidating this mechanism is key to understanding the functions of cardio‐protective lipoprotein complexes like HDL. The few solved structures of apolipoproteins have failed to provide insight into self‐association. We have determined the first dimeric structure of apoA‐IV, one of the largest of the apolipoproteins at 43kDa. From the structure, we observed a novel dimerization mechanism that buries over 11,000 Å 2 , forming an incredibly stable dimer that requires over 48 hours at 37°C to reach monomer:dimer equilibrium. This unique mechanism also maintains a four‐helical bundle upon dimerization and creats a hydrophobic core that stretches over 150Å and providing an ideal environment for sequestering lipids. Using this structure in conjunction with biochemical data, we have generated a model of apoA‐IV transitioning from a monomer to a HDL in three steps. The apoA‐IV HDL model is supported by previous observations and rectifies some conflicting biochemical data in the field. This structure not only reveals the mechanism for apolipoprotein self‐association, but also provides a clear picture that demonstrates the apoA‐IV structure as the basis for its biological function. We believe this transition model is a general mechanism and can extend to apoA‐I and apoA‐V, which also form HDL.