Article abstract

Nature Structural & Molecular Biology 14, 861 - 868 (2007)
Published online: 5 August 2007 | Corrected online: 27 February 2008 | Corrected online: 22 May 2008 | doi:10.1038/nsmb1284



There is a Corrigendum (June 2008) associated with this Article.

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

Zhiping Wu1,2, Matthew A Wagner3, Lemin Zheng1,6, John S Parks4, Jacinto M Shy, III3, Jonathan D Smith1,5, Valentin Gogonea2,3 & Stanley L Hazen1,2,5

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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  1. Department of Cell Biology, Cleveland Clinic, 9500 Euclid Avenue, NE-10, Cleveland, Ohio 44195, USA.
  2. Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, 9500 Euclid Avenue, NE-10, Cleveland, Ohio 44195, USA.
  3. Chemistry Department, Cleveland State University, Cleveland, Ohio 44115, USA.
  4. Department of Pathology/Section on Lipid Sciences, Wake Forest University, School of Medicine, Winston-Salem, North Carolina 27157, USA.
  5. Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, NE-10, Cleveland, Ohio 44195, USA.
  6. Present address: PrognostiX, Inc.,10265 Carnegie Avenue, Cleveland, Ohio 44106, USA.

Correspondence to: Stanley L Hazen1,2,5 e-mail: hazens@ccf.org

* 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.

** 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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