Zhang, L.; Yan, F.; Zhang, S.; Lei, D.; Charles, M. A.; Cavigiolio, G.; Oda, M.; Krauss, R. M.; Weisgraber, K. H.; Rye, K.-A.; Pownall, H. J.; Qiu, X. & Ren, G. Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein. Nature chemical biology, 2012, 8, 342-349
Human cholesteryl ester transfer protein (CETP) mediates the net transfer of cholesteryl ester mass from atheroprotective high-density lipoproteins to atherogenic low-density lipoproteins by an unknown mechanism. Delineating this mechanism would be an important step toward the rational design of new CETP inhibitors for treating cardiovascular diseases. Using EM, single-particle image processing and molecular dynamics simulation, we discovered that CETP bridges a ternary complex with its N-terminal Î²-barrel domain penetrating into high-density lipoproteins and its C-terminal domain interacting with low-density lipoprotein or very-low-density lipoprotein. In our mechanistic model, the CETP lipoprotein-interacting regions, which are highly mobile, form pores that connect to a hydrophobic central cavity, thereby forming a tunnel for transfer of neutral lipids from donor to acceptor lipoproteins. These new insights into CETP transfer provide a molecular basis for analyzing mechanisms for CETP inhibition.