Abstract
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 β-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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Acknowledgements
We thank D.A. Agard, I. Bahar and K. Dill for valuable discussions and A. Cheng and J. Song for helpful comments. This work was supported by Basic Energy Sciences–US Department of Energy (DE-AC02-05CH11231) and the W. M. Keck Foundation (no. 011808); the Keygrant Project of the Chinese Ministry of Education no. 708082 (S.Z.); US National Institutes of Health grant NIH-HL077268 and Tobacco-Related Disease Research Program of California grant 16FT-0163 (M.O.).
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G.R., K.H.W. and X.Q. initiated and designed the project; X.Q. provided the soluble CETP; H.J.P. and R.M.K. contributed the LDL and VLDL; K.-A.R., M.O. and G.C. provided HDL; L.Z., F.Y. and G.R. collected the data; S.Z., D.L. and G.R. conducted the molecular simulation; G.R. solved the structure; G.R., L.Z., M.A.C. and X.Q. analyzed and interpreted the data; G.R. and S.Z. drafted the initial manuscript; M.A.C., H.J.P., K.H.W., K.-A.R., R.M.K., X.Q. and L.Z. discussed and revised the manuscript.
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Zhang, L., Yan, F., Zhang, S. et al. Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein. Nat Chem Biol 8, 342–349 (2012). https://doi.org/10.1038/nchembio.796
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DOI: https://doi.org/10.1038/nchembio.796
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