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Structural basis of transfer between lipoproteins by cholesteryl ester transfer protein

Nature Chemical Biology volume 8, pages 342–349 (2012)Cite this article

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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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Figure 1: Three-dimensional reconstruction of CETP by cryo-PS-EM.
Figure 2: High-resolution CETP images by cryo-PS-EM.
Figure 3: Three-dimensional reconstruction of HDL–CETP complex by OpNS-EM.
Figure 4: Structural conformations of CETP bound to LDL or VLDL and CETP interactions between lipoproteins by OpNS-EM.
Figure 5: Analysis of HDL size change during incubation with CETP.
Figure 6: Analyses of the crystal structure of CETP.
Figure 7: Proposed mechanism for cholesteryl ester transfer by CETP.

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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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Author notes

  1. Lei Zhang and Feng Yan: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California, USA

    Lei Zhang & Gang Ren

  2. School of Medicine, University of California–San Francisco, San Francisco, California, USA

    Lei Zhang, Feng Yan, M Arthur Charles & Gang Ren

  3. Department of Applied Physics, Xi'an Jiaotong University, Xi'an, China

    Lei Zhang, Shengli Zhang, Dongsheng Lei & Gang Ren

  4. Children's Hospital Oakland Research Institute, Oakland, California, USA

    Giorgio Cavigiolio, Michael Oda & Ronald M Krauss

  5. Gladstone Institute of Neurological Disease, University of California–San Francisco, San Francisco, California, USA

    Karl H Weisgraber

  6. Lipid Research Group, The Heart Research Institute, Sydney, New South Wales, Australia

    Kerry-Anne Rye

  7. Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia

    Kerry-Anne Rye

  8. Department of Medicine, University of Melbourne, Victoria, Australia

    Kerry-Anne Rye

  9. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

    Henry J Pownall

  10. Pfizer Inc., Groton, Connecticut, USA

    Xiayang Qiu

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Contributions

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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Correspondence to Gang Ren.

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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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