Amyloid-Forming Properties of Human Apolipoproteins: Sequence Analyses and Structural Insights.
Amyloid-Forming Properties of Human Apolipoproteins: Sequence Analyses and Structural Insights.
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人类载脂蛋白的淀粉样蛋白形成特性：序列分析和结构见解。
DOI：
10.1007/978-3-319-17344-3_8
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发表时间：
2015
影响因子：
--
通讯作者：
Gursky O
中科院分区：
文献类型：
--
作者：
Das M;Gursky O
载脂蛋白是在循环中运输胆固醇和脂肪的脂蛋白的蛋白质成分，对心血管健康和疾病至关重要。可溶性载脂蛋白可以以一种不稳定的自由形式短暂地从脂蛋白表面解离，这种不稳定的自由形式可以错误折叠，可能导致淀粉样蛋白疾病。apoA-I、apoA-II和血清淀粉样蛋白A （SAA）的错误折叠导致系统性淀粉样变性，apoE4是阿尔茨海默病的关键危险因素，载脂蛋白错误折叠也与心血管疾病有关。为了解释为什么载脂蛋白在淀粉样变性中被过度代表，有人提出在该蛋白家族中形成脂质表面结合基序的两亲性α-螺旋具有高淀粉样变性倾向。在这里，我们使用12种基于序列的生物信息学方法来评估人类载脂蛋白的淀粉样蛋白形成潜力，并确定可能启动β聚集的片段。将这些片段映射到载脂蛋白的可用原子结构上，有助于解释为什么其中一些容易形成淀粉样蛋白，而另一些则不会。我们的分析表明，几乎所有的淀粉样蛋白片段：(i)大部分是疏水性的，（ii）位于可溶性载脂蛋白的天然结构中脂结合的两亲性α-螺旋中，（iii）预测在不溶性载脂蛋白的天然α-螺旋和β-片中，以及（iv）预测在淀粉样蛋白中形成平行的寄存器内β-片。这些预测大部分已经在apoC-II、apoA-I、apoA-II和SAA的实验中得到了验证。令人惊讶的是，形成淀粉样蛋白的氨基酸序列的排序顺序（apoB > apoA-II > apoA-II≥apoA-I, apoa - iii， SAA, apoA-I > apoA-IV, apoA-V, apoE）与蛋白参与淀粉样变性无关。相反，它与蛋白质-脂质结合的强度直接相关，这种强度随着蛋白质疏水性的增加而增加。因此，脂质表面结合功能和淀粉样蛋白形成倾向都植根于载脂蛋白的疏水性，提示功能限制使得难以完全消除致病性载脂蛋白错误折叠。我们认为载脂蛋白已经进化出了防止错误折叠的保护机制，例如通过天然的蛋白质-脂质和蛋白质-蛋白质相互作用来隔离淀粉样蛋白片段，这些相互作用涉及两亲性α-螺旋，在载脂蛋白ob的情况下，涉及β-薄片。
Apolipoproteins are protein constituents of lipoproteins that transport cholesterol and fat in circulation and are central to cardiovascular health and disease. Soluble apolipoproteins can transiently dissociate from the lipoprotein surface in a labile free form that can misfold, potentially leading to amyloid disease. Misfolding of apoA-I, apoA-II, and serum amyloid A (SAA) causes systemic amyloidoses, apoE4 is a critical risk factor in Alzheimer’s disease, and apolipoprotein misfolding is also implicated in cardiovascular disease. To explain why apolipoproteins are over- represented in amyloidoses, it was proposed that the amphipathic α-helices, which form the lipid surface-binding motif in this protein family, have high amyloid-forming propensity. Here, we use 12 sequence-based bioinformatics approaches to assess amyloid-forming potential of human apolipoproteins and to identify segments that are likely to initiate β-aggregation. Mapping such segments on the available atomic structures of apolipoproteins helps explain why some of them readily form amyloid while others do not. Our analysis shows that nearly all amyloidogenic segments: (i) are largely hydrophobic, (ii) are located in the lipid-binding amphipathic α-helices in the native structures of soluble apolipoproteins, (iii) are predicted in both native α-helices and β-sheets in the insoluble apoB, and (iv) are predicted to form parallel in-register β-sheet in amyloid. Most of these predictions have been verified experimentally for apoC-II, apoA-I, apoA-II and SAA. Surprisingly, the rank order of the amino acid sequence propensity to form amyloid (apoB > apoA-II > apoC-II ≥ apoA-I, apoC-III, SAA, apoC-I > apoA-IV, apoA-V, apoE) does not correlate with the proteins’ involvement in amyloidosis. Rather, it correlates directly with the strength of the protein-lipid association, which increases with increasing protein hydrophobicity. Therefore, the lipid surface-binding function and the amyloid-forming propensity are both rooted in apolipoproteins’ hydrophobicity, suggesting that functional constraints make it difficult to completely eliminate pathogenic apolipoprotein misfolding. We propose that apolipoproteins have evolved protective mechanisms against misfolding, such as the sequestration of the amyloidogenic segments via the native protein-lipid and protein-protein interactions involving amphipathic α-helices and, in case of apoB, β-sheets.
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作者：
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DOI：
10.1073/pnas.94.23.12291
发表时间：
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影响因子：
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DOI：
10.1111/j.1582-4934.2011.01271.x
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2011-12-01
影响因子：
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