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首页> 外文期刊>Journal of Molecular Biology >Phospholipid interaction induces molecular-level polymorphism in apolipoprotein C-II amyloid fibrils via alternative assembly pathways
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Phospholipid interaction induces molecular-level polymorphism in apolipoprotein C-II amyloid fibrils via alternative assembly pathways

机译：磷脂相互作用通过替代组装途径诱导载脂蛋白C-II淀粉样蛋白原纤维的分子水平多态性

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A common feature of many of the most important and prominent amyloid forming proteins is their ability to bind lipids and lipid complexes. Lipids are ubiquitous components of disease-associated amyloid plaques and deposits in humans, yet the specific roles of lipid in the process of amyloid fibril formation are poorly understood. This study investigated the effect of phospholipids on amyloid fibril formation by human apolipoprotein (apo) C-II using phosphatidylcholine derivatives comprising acyl chains of up to 14 carbon atoms. Submicellar concentrations of short-chain phospholipids increase the rate of apoC-II fibril formation in an acyl-chain-length- and concentration-dependent fashion, while high micellar concentrations of phospholipids completely inhibited amyloid formation. At lower concentrations of soluble phospholipid complexes, fibril formation by apoC-II was only partially inhibited, and under these conditions, aggregation followed a two-phase process. Electron microscopy showed that the fibrils resulting from the second phase of aggregation were straight, cablelike, and about 13 nm wide, in contrast to the homogeneous twisted-ribbon morphology of apoC-II fibrils formed under lipid-free conditions. Seeding experiments showed that this alternative fibril structure could be templated both in the presence and in the absence of lipid complex, suggesting that the two morphologies result from distinct assembly pathways. Circular dichroism spectroscopy studies indicated that the secondary structural conformation within the straight-type and ribbon-type fibrils were distinct, further suggesting divergent assembly pathways. These studies show that phospholipid complexes can change the structural architecture of mature fibrils and generate new fibril morphologies with the potential to alter the in vivo behaviour of amyloid. Such lipid interactions may play a role in defining the structural features of fibrils formed by diverse amyloidogenic proteins. (c) 2007 Elsevier Ltd. All rights reserved.
机译：许多最重要和最重要的淀粉样蛋白形成蛋白的共同特征是它们结合脂质和脂质复合物的能力。脂质是人类与疾病相关的淀粉样蛋白斑块和沉积物中普遍存在的成分，但人们对脂质在淀粉样蛋白原纤维形成过程中的具体作用了解甚少。这项研究使用包含多达14个碳原子的酰基链的磷脂酰胆碱衍生物，研究了磷脂对人载脂蛋白（apo）C-II形成淀粉样蛋白原纤维的影响。亚胶束浓度的短链磷脂以酰基链长度和浓度依赖性方式增加apoC-II原纤维形成的速率，而高胶束浓度的磷脂则完全抑制淀粉样蛋白的形成。在较低浓度的可溶性磷脂复合物中，apoC-II形成的原纤维仅被部分抑制，在这些条件下，聚集遵循两相过程。电子显微镜显示，与在无脂质条件下形成的apoC-II原纤维的均匀扭曲丝带形态相反，第二阶段聚集产生的原纤维是直的，缆状的，约13 nm宽。播种实验表明，在存在和不存在脂质复合物的情况下，都可以对这种替代的原纤维结构进行模板化，这表明这两种形态是由不同的组装途径产生的。圆二色性光谱研究表明，在直型和带状原纤维中的二级结构构象是不同的，这进一步表明了不同的组装途径。这些研究表明，磷脂复合物可以改变成熟原纤维的结构结构，并产生新的原纤维形态，从而可能改变淀粉样蛋白的体内行为。此类脂质相互作用可能在定义由多种淀粉样蛋白形成的蛋白质形成的原纤维的结构特征中起作用。 （c）2007 Elsevier Ltd.保留所有权利。

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