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Nat Struct Mol Biol. 2007 Sep;14(9):861-8. Epub 2007 Aug 5.

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

Author information

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

Erratum in

  • Nat Struct Mol Biol. 2008 Jun;15(6):651.
  • Nat Struct Mol Biol. 2008 Mar;15(3):330.

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.

PMID:
17676061
DOI:
10.1038/nsmb1284
[Indexed for MEDLINE]

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