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Apolipoprotein A-I structural organization in high-density lipoproteins isolated from human plasma

Nature Structural & Molecular Biology volume 18, pages 416422 (2011) | Download Citation

Abstract

High-density lipoproteins (HDLs) mediate cholesterol transport and protection from cardiovascular disease. Although synthetic HDLs have been studied for 30 years, the structures of human plasma–derived HDL and its major protein apolipoprotein apoA-I are unknown. We separated normal human HDL into five density subfractions and then further isolated those containing predominantly apoA-I (LpA-I). Using cross-linking chemistry and mass spectrometry, we found that apoA-I adopts a structural framework in these particles that closely mirrors that in synthetic HDL. We adapted established structures for synthetic HDL to generate the first detailed models of authentic human plasma HDL in which apoA-I adopts a symmetrical cage-like structure. The models suggest that HDL particle size is modulated by means of a twisting motion of the resident apoA-I molecules. This understanding offers insights into how apoA-I structure modulates HDL function and its interactions with other apolipoproteins.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) 01 grant HL67093 (to W.S.D.), an American Heart Association Great Rivers Postdoctoral Fellowship to R.H. (3880030), NIH R01 grant HL48148 (to W.G.J.) and NIH Pathway to Independence Award (K99/R00) HL087561 from the National Heart, Lung, and Blood Institute (to R.A.G.D.S.). Negative stain EM was carried out in the Vanderbilt University Research Electron Microscopy Resource of the Cell Imaging Core. This resource is partially supported by NIH grants CA68485, DK20593 and DK58404. A.K. was supported by Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale en France. The images in Figure 6 were rendered by M. Hartsock (marcia@hartsockillustration.com). Any use of these images is subject to copyright law and should be negotiated with the artist. We also thank C. Smith for excellent administrative assistance.

Author information

Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA.

    • Rong Huang
    • , R A Gangani D Silva
    •  & W Sean Davidson
  2. Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

    • W Gray Jerome
  3. Université Pierre et Marie Curie-Paris 6, Paris, France.

    • Anatol Kontush
    •  & M John Chapman
  4. National Institute of Health and Medical Research, Dyslipoproteinemia and Atherosclerosis Research Unit, Paris, France.

    • Anatol Kontush
    •  & M John Chapman
  5. Assistance Publique–Hopitaux de Paris, Groupe hospitalier Pitié-Salpétrière, Paris, France.

    • Anatol Kontush
    •  & M John Chapman
  6. Department of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California, USA.

    • Linda K Curtiss
  7. Department of Mathematical Sciences, University of Cincinnati, Cincinnati, Ohio, USA.

    • Timothy J Hodges

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Contributions

R.H., M.J.C. and W.S.D. designed the research plan. R.H., R.A.G.D.S., L.K.C., W.G.J. and A.K. conducted experiments. R.H., W.S.D. and T.J.H. analyzed data, and R.H. and W.S.D. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to W Sean Davidson.

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DOI

https://doi.org/10.1038/nsmb.2028

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