Structural study proposes a tunnel-bridging mechanism for how CETP transfers cholesteryl ester between HDL and LDL (Nat Chem Biol 2012)

Using electron microscopy, single-particle image processing, and molecular dynamics simulation, researchers investigated the previously unknown mechanism by which CETP moves cholesteryl ester mass from atheroprotective HDL to atherogenic LDL. They found CETP bridges a ternary complex, with its N-terminal beta-barrel domain penetrating into HDL and its C-terminal domain interacting with LDL or VLDL. In their proposed model, the highly mobile lipoprotein-interacting regions of CETP form pores connecting to a hydrophobic central cavity, creating a continuous tunnel through which neutral lipids move from donor to acceptor lipoprotein. The authors present this tunnel-bridging mechanism as a molecular basis for the rational design of new CETP inhibitors. This tunnel-bridging model became the standard account of CETP mechanism for roughly a decade, and was subsequently contested: antibody-epitope work in 2016 found CETP interacts with HDL but not directly with LDL, concluding a ternary tunnel complex is not required.