Bone morphogenetic protein-1 (BMP-1) cleaves human proapolipoprotein A1 and regulates its activation for lipid binding
Bone morphogenetic protein-1 (BMP-1) cleaves human proapolipoprotein A1 and regulates its activation for lipid binding
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DOI：
10.1021/bi700028u
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发表时间：
2007-07-17
期刊：
影响因子：
2.9
通讯作者：
Fielding, Christopher J.
中科院分区：
文献类型：
--
作者：
Chau, Phuonglan;Fielding, Phoebe E.;Fielding, Christopher J.
载脂蛋白A1（apoA 1）是高密度脂蛋白的主要蛋白质，以前蛋白形式分泌，然后被一种未知的金属蛋白酶切割。在这里，这种酶被鉴定为C-末端前胶原蛋白内切酶/骨形态发生蛋白-1（BMP-1）。使用重组BMP-1、BMP-1抗体和BMP-1 siRNA进行的研究证实，该蛋白酶是稳定表达人载脂蛋白A1的人肝源性（HepG 2）细胞和CHO细胞分泌的主要或唯一的载脂蛋白A1转化活性。BMP-1刺激新分泌的proapo A1转化为其磷脂-（PL-）结合形式。通过这种方式，它促进功能性HDL的形成和胆固醇的逆向转运，同时抑制未裂解的前蛋白的过滤和清除。α（2）-巨球蛋白是一种作为先天免疫应答的一部分分泌的蛋白酶抑制剂，可抑制BMP-1活性并阻断proapo A1的成熟。作为炎症和感染反应特征的循环载脂蛋白A1水平的降低可能至少部分地通过这种新机制经由BMP-1介导。
Apolipoprotein A1 (apo A1), the major protein of high-density lipoprotein, is secreted as a proprotein and then cleaved by an uncharacterized metalloproteinase. Here this enzyme is identified as C-terminal procollagen endoproteinase/bone morphogenetic protein-1 (BMP-1). Studies with recombinant BMP-1, BMP-1 antibody, and BMP-1 siRNA establish this proteinase as the major or only apo A1-converting activity secreted by human liver-derived (HepG2) cells and CHO cells stably expressing human apo A1. BMP-1 stimulates the conversion of newly secreted proapo A1 to its phospholipid- (PL-) binding form. In this way it promotes formation of functional HDL and reverse cholesterol transport, while inhibiting filtration and clearance of uncleaved proprotein. alpha(2)-Macroglobulin, a protease inhibitor secreted as part of the innate immune response, inhibits BMP-1 activity and blocks the maturation of proapo A1. The decrease in circulating apo A1 levels that is characteristic of the response to inflammation and infection may be mediated, at least in part, via BMP-1 by this novel mechanism.