Molecular and cellular physiology of apolipoprotein A-I lipidation by the ATP-binding cassette transporter A1 (ABCA1)

被引:82
作者
Denis, M
Haidar, B
Marcil, M
Bouvier, M
Krimbou, L
Genest, J
机构
[1] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Cardiol Div,Cardiovasc Genet Lab, Montreal, PQ H3A 1A1, Canada
[2] Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada
关键词
D O I
10.1074/jbc.M306963200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The dynamics of ABCA1-mediated apoA-I lipidation were investigated in intact human fibroblasts induced with 22(R)-hydroxycholesterol and 9-cis-retinoic acid (stimulated cells). Specific binding parameters of I-125-apoA-I to ABCA1 at 37degreesC were determined: K-d=0.65 mug/ml, B-max=0.10 ng/mug cell protein. Lipid-free apoA-I inhibited the binding of I-125-apoA-I to ABCA1 more efficiently than pre-beta(1)-LpA-I, reconstituted HDL particles r(LpA-I), or HDL3 (IC50=0.35+/-1.14, apoA-I; 1.69+/-1.07, pre-beta(1)-LpA-I; 17.91+/-1.39, r(LpA-I); and 48.15+/-1.72 mug/ml, HDL3). Treatment of intact cells with either phosphatidylcholine-specific phospholipase C or sphingomyelinase affected neither I-125-apoA-I binding nor I-125-apoA-I/ABCA1 cross-linking. We next investigated the dynamics of apoA-I lipidation by monitoring the kinetic of apoA-I dissociation from ABCA1. The dissociation of I-125-apoA-I from normal cells at 37degreesC was rapid (t(1/2)=1.4+/-0.66 h; n=3) but almost completely inhibited at either 15 or 4degreesC. A time course analysis of apoA-I-containing particles released during the dissociation period showed nascent apoA-I-phospholipid complexes that exhibited alpha-electrophoretic mobility with a particle size ranging from 9 to 20 nm (designated alpha-LpA-I-like particles), whereas lipid-free apoA-I incubated with ABCA1 mutant (Q597R) cells was unable to form such particles. These results demonstrate that: 1) the physical interaction of apoA-I with ABCA1 does not depend on membrane phosphatidylcholine or sphingomyelin; 2) the association of apoA-I with lipids reduces its ability to interact with ABCA1; and 3) the lipid translocase activity of ABCA1 generates alpha-LpA-I-like particles. This process plays in vivo a key role in HDL biogenesis.
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页码:7384 / 7394
页数:11
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