Molecular mechanism for changes in proteoglycan binding on compositional changes of the core and the surface of low-density lipoprotein-containing human apolipoprotein B100
Molecular mechanism for changes in proteoglycan binding on compositional changes of the core and the surface of low-density lipoprotein-containing human apolipoprotein B100
复制标题
DOI：
10.1161/01.atv.0000117174.19078.85
复制
发表时间：
2004-03-01
影响因子：
8.7
通讯作者：
Borén, J
中科院分区：
文献类型：
--
作者：
Flood, C;Gustafsson, M;Borén, J
目的-本研究的目的是研究与动脉粥样硬化相关的LDL中两种成分变化的蛋白聚糖结合和LDL受体亲和力变化的分子机制：核心的胆固醇富集和表面的分泌型II A族磷脂酶A2（sPLA（2））修饰。方法和结果-表达重组载脂蛋白（apo）B和sPLA（2）的转基因小鼠产生了。分离重组LDL并测试其蛋白聚糖和LDL受体结合活性。结果显示apoB 100中的位点A（残基3148-3158）在sPLA（2）修饰的LDL中变得有功能，并且位点A与位点B（残基3359-3369）（天然LDL中的主要蛋白聚糖结合位点）在sPLA（2）修饰的LDL与蛋白聚糖的结合中协同作用。我们的研究结果还表明，胆固醇富集的LDL与蛋白聚糖和LDL受体的亲和力增加。结论apoB 100的A位点在sPLA（2）修饰的LDL中发挥作用，并与B位点协同作用，从而提高蛋白聚糖结合活性。胆固醇富集LDL的蛋白聚糖结合增加仅依赖于位点B。
Objective - The aim of this study was to investigate the molecular mechanism for changes in proteoglycan binding and LDL receptor affinity on two compositional changes in LDL that have been associated with atherosclerosis: cholesterol enrichment of the core and modification by secretory group IIA phospholipase A2 (sPLA(2)) of the surface.Methods and Results - Transgenic mice expressing recombinant apolipoprotein (apo) B and sPLA(2) were generated. Recombinant LDL were isolated and tested for their proteoglycan and LDL receptor-binding activity. The results show site A ( residues 3148-3158) in apoB100 becomes functional in sPLA(2)-modified LDL and that site A acts cooperatively with site B ( residues 3359-3369), the primary proteoglycan-binding site in native LDL, in the binding of sPLA(2)-modified LDL to proteoglycans. Our results also show that cholesterol enrichment of LDL is associated with increased affinity for proteoglycans and for the LDL receptor. This mechanism is likely mediated by a conformational change of site B and is independent of site A in apoB100.Conclusion - Site A in apoB100 becomes functional in sPLA(2)-modified LDL and acts cooperatively with site B resulting in increased proteoglycan-binding activity. The increased binding for proteoglycans of cholesterol-enriched LDL is solely dependent on site B.