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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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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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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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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DOI: https://doi.org/10.1038/nsmb1284
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