期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 14, 期 9, 页码 861-868出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb1284
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资金
- NCRR NIH HHS [M01 RR018390] Funding Source: Medline
- NHLBI NIH HHS [HL066082, HL70621, P50 HL77107, P01 HL076491, P01 HL049373, HL 054176] Funding Source: Medline
- NIGMS NIH HHS [1R15 GM070469-01] Funding Source: Medline
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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