Hot spot of structural ambivalence in prion protein revealed by secondary structure principal component analysis.
Hot spot of structural ambivalence in prion protein revealed by secondary structure principal component analysis.
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DOI：
10.1021/jp5034245
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发表时间：
2014-08
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影响因子：
--
通讯作者：
Norifumi Yamamoto
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文献类型：
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作者：
Norifumi Yamamoto
蛋白质构象转化为易于聚集的形式是各种神经退行性疾病（包括阿尔茨海默病、亨廷顿病、帕金森病和朊病毒病）的共同特征。在朊病毒疾病的早期阶段，朊病毒蛋白（PrP）的二级结构转换导致β-折叠扩展，从而促进形成具有高含量β-折叠和强聚集倾向以形成淀粉样纤维的致病性同种型。在这里，我们提出了一个简单的方法来提取重要的信息，关于蛋白质的二级结构转换的分子模拟，命名为二级结构主成分分析（SSPCA）。根据SSPCA确定的主成分将蛋白质结构数据映射到约简空间中构建的自由能景观中，证实了具有增加的β-折叠结构的PrP异构体的确定存在。我们认为PrP中存在一个结构矛盾的“点”--螺旋2的C-末端部分--它缺乏强大的内在二级结构，从而促进了部分α-螺旋向β-折叠的转化。这一结果对于理解朊病毒疾病中PrP的致病性构象转换是如何启动的具有重要意义。SSPCA具有很大的潜力，以解决各种挑战，在研究高度灵活的分子系统，如内在无序的蛋白质，结构矛盾的肽，和变色龙序列。
The conformational conversion of proteins into an aggregation-prone form is a common feature of various neurodegenerative disorders including Alzheimer's, Huntington's, Parkinson's, and prion diseases. In the early stage of prion diseases, secondary structure conversion in prion protein (PrP) causing β-sheet expansion facilitates the formation of a pathogenic isoform with a high content of β-sheets and strong aggregation tendency to form amyloid fibrils. Herein, we propose a straightforward method to extract essential information regarding the secondary structure conversion of proteins from molecular simulations, named secondary structure principal component analysis (SSPCA). The definite existence of a PrP isoform with an increased β-sheet structure was confirmed in a free-energy landscape constructed by mapping protein structural data into a reduced space according to the principal components determined by the SSPCA. We suggest a "spot" of structural ambivalence in PrP-the C-terminal part of helix 2-that lacks a strong intrinsic secondary structure, thus promoting a partial α-helix-to-β-sheet conversion. This result is important to understand how the pathogenic conformational conversion of PrP is initiated in prion diseases. The SSPCA has great potential to solve various challenges in studying highly flexible molecular systems, such as intrinsically disordered proteins, structurally ambivalent peptides, and chameleon sequences.