Journal
NATURE CHEMICAL BIOLOGY
Volume 8, Issue 4, Pages 342-349Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.796
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Funding
- Basic Energy Sciences-US Department of Energy [DE-AC02-05CH11231]
- W. M. Keck Foundation [011808]
- Chinese Ministry of Education [708082]
- US National Institutes of Health [NIH-HL077268]
- Tobacco-Related Disease Research Program of California [16FT-0163]
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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 beta-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.
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