Biophysical properties of apolipoprotein E4 variants: implications in molecular mechanisms of correction of hypertriglyceridemia.
Biophysical properties of apolipoprotein E4 variants: implications in molecular mechanisms of correction of hypertriglyceridemia.
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载脂蛋白 E4 变体的生物物理特性：对纠正高甘油三酯血症的分子机制的影响。
DOI：
10.1021/bi8015857
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发表时间：
2008
期刊：
影响因子：
2.9
通讯作者：
Atkinson,David
中科院分区：
文献类型：
--
作者：
Gorshkova,IrinaN;Kypreos,KyriakosE;Gantz,DonaldL;Zannis,VassilisI;Atkinson,David
在人类和动物模型中，载脂蛋白（apo）E的高血浆浓度与高脂血症相关。已经显示，在apoE缺陷小鼠中人野生型（WT）apoE 4的过表达诱导高脂血症。相反，apoE 4变体apoE 4-mut 1（apoE 4（L261 A、W264 A、F265 A、L268 A、V269 A））的过表达不诱导高胆固醇血症并纠正高胆固醇血症。此外，另一种变体apoE 4-mut 2（apoE 4（W276 A，L279 A，V280 A，V283 A））的过表达诱导轻度高胆固醇血症并且不纠正高胆固醇血症。为了更好地理解这些突变如何改善apoE 4的功能，我们研究了apoE 4-mut 1和apoE 4-mut 2的构象和稳定性，以及它们与二肉豆蔻酰磷脂酰胆碱（DMPC）囊泡和富含甘油三酯（TG）的乳剂颗粒的结合。我们发现，apoE 4-mut 1中引入的突变导致apoE 4的更稳定和更复杂的折叠构象。这些结构变化与apoE 4-mut 1溶解DMPC囊泡的速率较慢以及与WT apoE 4相比蛋白质与乳剂颗粒的结合减少有关。在apoE 4过表达的条件下，apoE 4-mut 1与富含TG的脂蛋白颗粒的结合减少，可能促进这些颗粒的脂解，并可能以有利于有效清除脂蛋白残余物的方式改变脂蛋白结合的apoE的构象。在apoE 4-mut 2中引入的突变导致与在apoE 4-mut 1中观察到的那些相比更小的结构改变。与WT apoE 4相比，apoE 4-mut 2的轻微改变的结构特性与该蛋白质与富含TG的脂蛋白颗粒的结合轻微减少和轻度高脂血症有关。
In humans and animal models, high plasma concentrations of apolipoprotein (apo) E are associated with hypertriglyceridemia. It has been shown that overexpression of human wild-type (WT) apoE4 in apoE-deficient mice induces hypertriglyceridemia. In contrast, overexpression of an apoE4 variant, apoE4-mut1 (apoE4(L261A, W264A, F265A, L268A, V269A)), does not induce hypertriglyceridemia and corrects hypercholesterolemia. Furthermore, overexpression of another variant, apoE4-mut2 (apoE4(W276A, L279A, V280A, V283A)), induces mild hypertriglyceridemia and does not correct hypercholesterolemia. To better understand how these mutations improve the function of apoE4, we investigated the conformation and stability of apoE4-mut1 and apoE4-mut2 and their binding to dimyristoyl phosphatidylcholine (DMPC) vesicles and to triglyceride (TG)-rich emulsion particles. We found that the mutations introduced in apoE4-mut1 lead to a more stable and compactly folded conformation of apoE4. These structural changes are associated with a slower rate of solubilization of DMPC vesicles by apoE4-mut1 and reduced binding of the protein to emulsion particles compared with WT apoE4. Under conditions of apoE4 overexpression, the reduced binding of apoE4-mut1 to TG-rich lipoprotein particles may facilitate the lipolysis of these particles and may alter the conformation of the lipoprotein-bound apoE in a way that favors the efficient clearance of the lipoprotein remnants. Mutations introduced in apoE4-mut2 result in smaller structural alterations compared with those observed in apoE4-mut1. The slightly altered structural properties of apoE4-mut2 are associated with slightly reduced binding of this protein to TG-rich lipoprotein particles and milder hypertriglyceridemia as compared with WT apoE4.