The roles of C-terminal helices of human apolipoprotein A-I in formation of high-density lipoprotein particles.
The roles of C-terminal helices of human apolipoprotein A-I in formation of high-density lipoprotein particles.
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DOI：
10.1016/j.bbalip.2013.10.005
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Saito H
中科院分区：
文献类型：
--
作者：
Nagao K;Hata M;Tanaka K;Takechi Y;Nguyen D;Dhanasekaran P;Lund-Katz S;Phillips MC;Saito H
载脂蛋白A-I （apoA-I）接受来自atp结合盒转运蛋白Al （ABCA1）表达细胞的胆固醇和磷脂，形成高密度脂蛋白（HDL）。人类apoA-I有两个三级结构域，其中c端结构域（约190-243个氨基酸）在脂质结合中起关键作用。尽管apoA-I c端结构域的高脂类亲和性区域（残基223-243）对HDL的形成至关重要，但低脂类亲和性区域（残基191-220）的功能尚不清楚。为了评估残基191-220的作用，我们分析了Δ191-220 apoA-I的结构、脂质结合特性和HDL形成活性，并与野生型和Δ223-243 apoA-I进行了比较。虽然残基191-220的缺失对apoA-I的三级结构有轻微的影响，但Δl91-220变体在疏水位点的形成和通过c端结构域的脂质相互作用方面表现出介于野生型和Δ223-243之间的中间行为。理化分析表明Δl91-220 apoA-I的脂质结合缺陷是由于形成α-螺旋结构的能力下降，而α-螺旋结构为脂质结合提供了能量来源。此外，在体外形成HDL颗粒和诱导ABC al表达Δ191-220 apoA-I细胞胆固醇外排的能力也介于野生型和Δ223-243 apoA-I之间。这些结果表明，尽管具有较低的脂质亲和力，但残基191-220在脂质相互作用时通过形成α-螺旋来增强apoA-I与脂质的结合和溶解能力。我们的研究结果表明，apoA-I的低脂亲和性区域和高脂亲和性区域的结合是有效的abca1依赖性HDL形成所必需的。
Apolipoprotein A-I (apoA-I) accepts cholesterol and phospholipids from ATP-binding cassette transporter Al (ABCA1)-expressing cells to form high-density lipoprotein (HDL). Human apoA-I has two tertiary structural domains and the C-terminal domain (approximately amino acids 190–243) plays a key role in lipid binding. Although the high lipid affinity region of the C-terminal domain of apoA-I (residues 223–243) is essential for the HDL formation, the function of low lipid affinity region (residues 191–220) remains unclear. To evaluate the role of residues 191–220, we analyzed the structure, lipid binding properties, and HDL formation activity of Δ191–220 apoA-I, in comparison to wild-type and Δ223–243 apoA-I. Although deletion of residues 191–220 has a slight effect on the tertiary structure of apoA-I, the Δl91–220 variant showed intermediate behavior between wild-type and Δ223–243 regarding the formation of hydrophobic sites and lipid interaction through the C-terminal domain. Physicochemical analysis demonstrated that defective lipid binding of Δl91–220 apoA-I is due to the decreased ability to form α-helix structure which provides the energetic source for lipid binding. In addition, the ability to form HDL particles in vitro and induce cholesterol efflux from ABC Al-expressing cells of Δ191–220 apoA-I was also intermediate between wild-type and Δ223–243 apoA-I. These results suggest that despite possessing low lipid affinity, residues 191–220 play a role in enhancing the ability of apoA-I to bind to and solubilize lipids by forming α-helix upon lipid interaction. Our results demonstrate that the combination of low lipid affinity region and high lipid affinity region of apoA-I is required for efficient ABCA1-dependent HDL formation.
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影响因子：
6.5
作者：
Kono, Momoe;Tanaka, Toshitaka;Saito, Hiroyuki
通讯作者：
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DOI：
10.1016/j.bbalip.2012.11.002
发表时间：
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