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The refined structure of nascent HDL reveals a key functional domain for particle maturation and dysfunction

Nature Structural & Molecular Biology volume 14, pages 861–868 (2007)Cite this article

A Corrigendum to this article was published on 01 June 2008

A Corrigendum to this article was published on 01 March 2008

This article has been updated

Abstract

The cardioprotective function of high-density lipoprotein (HDL) is largely attributed to its ability to facilitate transport of cholesterol from peripheral tissues to the liver. However, HDL may become dysfunctional through oxidative modification, impairing cellular cholesterol efflux. Here we report a refined molecular model of nascent discoidal HDL, determined using hydrogen-deuterium exchange mass spectrometry. The model reveals two apolipoprotein A1 (apoA1) molecules arranged in an antiparallel double-belt structure, with residues 159–180 of each apoA1 forming a protruding solvent-exposed loop. We further show that this loop, including Tyr166, a preferred target for site-specific oxidative modification within atheroma, directly interacts with and activates lecithin cholesterol acyl transferase. These studies identify previously uncharacterized structural features of apoA1 in discoidal HDL that are crucial for particle maturation, and elucidate a structural and molecular mechanism for generating a dysfunctional form of HDL in atherosclerosis.

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Figure 1: Solvent accessibility of lipid-free apoA1 and apoA1 within recombinant human discoidal HDL, revealed by hydrogen-deuterium exchange mass spectrometry.
Figure 2: The solar-flares model of discoidal HDL.
Figure 3: Residues Leu159–Leu170 of apoA1 in discoidal HDL directly interact with LCAT.
Figure 4: Peptide Leu159–Leu170 and Tyr166 of apoA1 are important for the activation of LCAT and are selectively targeted for MPO-catalyzed oxidative inactivation under physiological conditions.
Figure 5: Refined solar-flares model of discoidal HDL, illustrating sites of known protein-protein interactions and site-specific oxidative modifications reported within human atherosclerotic plaque.

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Change history

  • 27 February 2008

    In the version of this article initially published, Figures 2c,d,e and 5 showed an incorrect model for discoidal HDL, with the apoA1 molecules in a clockwise orientation, in contrast with their counterclockwise orientation in the final mode described in the text. The correct model is deposited under the same accession number, PM0074956, at http://mi.caspur.it/PMDB/main.php. The error has been corrected in the PDF and HTML versions of the article.

  • 22 May 2008

    In the version of this article initially published, the legend text for Figure 2c was incorrect, with the terms “clockwise” and “counterclockwise” swapped. The error has been corrected in the PDF and HTML versions of the article.

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Acknowledgements

This work was supported by US National Institutes of Health grants P01 HL076491, P50 HL77107, HL70621, HL066082, 1R15 GM070469-01, P01 HL049373 and HL 054176, and the Cleveland Clinic Foundation General Clinical Research Center (M01 RR018390). Z.W. was partially supported by an American Heart Association Fellowship Award.

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Author notes

  1. Lemin Zheng

    Present address: Present address: PrognostiX, Inc.,10265 Carnegie Avenue, Cleveland, Ohio 44106, USA.,

Authors and Affiliations

  1. Department of Cell Biology, Cleveland Clinic, 9500 Euclid Avenue, NE-10, Cleveland, 44195, Ohio, USA

    Zhiping Wu, Lemin Zheng, Jonathan D Smith & Stanley L Hazen

  2. Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, 9500 Euclid Avenue, NE-10, Cleveland, 44195, Ohio, USA

    Zhiping Wu, Valentin Gogonea & Stanley L Hazen

  3. Chemistry Department, Cleveland State University, Cleveland, 44115, Ohio, USA

    Matthew A Wagner, Jacinto M Shy III & Valentin Gogonea

  4. Department of Pathology/Section on Lipid Sciences, Wake Forest University, School of Medicine, Winston-Salem, 27157, North Carolina, USA

    John S Parks

  5. Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, NE-10, Cleveland, 44195, Ohio, USA

    Jonathan D Smith & Stanley L Hazen

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Contributions

Z.W. and S.L.H. designed all studies and prepared the manuscript. Z.W. carried out all biochemical studies. V.G., M.A.W. and J.M.S. performed computational modeling. J.D.S. and J.S.P. assisted in generation of recombinant proteins. L.Z. and Z.W. performed all proteomic studies.

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Correspondence to Stanley L Hazen.

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Wu, Z., Wagner, M., Zheng, L. et al. The refined structure of nascent HDL reveals a key functional domain for particle maturation and dysfunction. Nat Struct Mol Biol 14, 861–868 (2007). https://doi.org/10.1038/nsmb1284

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