Influence of domain stability on the properties of human apolipoprotein E3 and E4 and mouse apolipoprotein E.
Influence of domain stability on the properties of human apolipoprotein E3 and E4 and mouse apolipoprotein E.
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域稳定性对人载脂蛋白E3和E4和小鼠载脂蛋白E的特性的影响。
DOI：
10.1021/bi500340z
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发表时间：
2014-06-24
期刊：
影响因子：
2.9
通讯作者：
Lund-Katz S
中科院分区：
文献类型：
--
作者：
Nguyen D;Dhanasekaran P;Nickel M;Mizuguchi C;Watanabe M;Saito H;Phillips MC;Lund-Katz S
人载脂蛋白（apo）E4亚型与野生型apoE 3的不同之处在于单个氨基酸取代C112 R，与心血管疾病和阿尔茨海默病的风险升高有关，但亚型之间这种变异的分子基础尚不清楚。人apoE是一种双结构域蛋白，包括N-末端螺旋束和单独折叠的C-末端区域。在这里，我们研究的概念，蛋白质结合到脂质表面的能力是由这些域的稳定性（或准备展开）的影响。无脂质的结构和能力，结合脂质和脂蛋白颗粒的一系列人类和小鼠的载脂蛋白E变体与不同的结构域稳定性和结构域之间的相互作用进行了比较。如尿素变性所评估的，这两个结构域在apoE 4中比在apoE 3中更不稳定。为了区分每个域的不稳定性的贡献更大的脂质结合能力的apoE 4，apoE 4的R61 T和E255 A的变体，具有相同的螺旋束稳定性，但改变C-末端结构域的稳定性的属性进行了比较。在这些情况下，对脂质结合特性的影响相对较小，表明螺旋束结构域的不稳定是apoE 4增强脂质结合能力的主要原因。与人apoE不同，小鼠apoE基本上表现为单一结构域，其脂质结合特征与apoE 4更相似。总之，结果表明，整个apoE分子的整体稳定性对其脂质和脂蛋白结合特性产生重大影响。
The human apolipoprotein (apo) E4 isoform, which differs from wild-type apoE3 by the single amino acid substitution C112R, is associated with elevated risk of cardiovascular and Alzheimer’s diseases, but the molecular basis for this variation between isoforms is not understood. Human apoE is a two-domain protein comprising an N-terminal helix bundle and a separately folded C-terminal region. Here, we examine the concept that the ability of the protein to bind to lipid surfaces is influenced by the stability (or readiness to unfold) of these domains. The lipid-free structures and abilities to bind to lipid and lipoprotein particles of a series of human and mouse apoE variants with varying domain stabilities and domain–domain interactions are compared. As assessed by urea denaturation, the two domains are more unstable in apoE4 than in apoE3. To distinguish the contributions of the destabilization of each domain to the greater lipid-binding ability of apoE4, the properties of the apoE4 R61T and E255A variants, which have the same helix bundle stabilities but altered C-terminal domain stabilities, are compared. In these cases, the effects on lipid-binding properties are relatively minor, indicating that the destabilization of the helix bundle domain is primarily responsible for the enhanced lipid-binding ability of apoE4. Unlike human apoE, mouse apoE behaves essentially as a single domain, and its lipid-binding characteristics are more similar to those of apoE4. Together, the results show that the overall stability of the entire apoE molecule exerts a major influence on its lipid- and lipoprotein-binding properties.
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影响因子：
2.9
作者：
Nguyen D;Dhanasekaran P;Nickel M;Nakatani R;Saito H;Phillips MC;Lund-Katz S
通讯作者：
Lund-Katz S
影响因子：
6.5
作者：
Getz, Godfrey S.;Reardon, Catherine A.
通讯作者：
Reardon, Catherine A.
DOI：
10.1073/pnas.201279298
发表时间：
2001-09-25
影响因子：
11.1
作者：
Raffaï, RL;Dong, LM;Weisgraber, KH
通讯作者：
Weisgraber, KH
影响因子：
2.9
作者：
Garai, Kanchan;Baban, Berevan;Frieden, Carl
通讯作者：
Frieden, Carl
影响因子：
2.9
作者：
Garai, Kanchan;Frieden, Carl
通讯作者：
Frieden, Carl