Structure of the prion protein and its gene: an analysis using bioinformatics and computer simulation.
Structure of the prion protein and its gene: an analysis using bioinformatics and computer simulation.
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DOI：
10.2174/138920310790848386
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发表时间：
2010-02
影响因子：
2.8
通讯作者：
A. Sakudo;Guangai Xue;N. Kawashita;Y. Ano;T. Takagi;H. Shintani;Yasuharu Tanaka;T. Onodera;K. Ikuta
中科院分区：
文献类型：
--
作者：
A. Sakudo;Guangai Xue;N. Kawashita;Y. Ano;T. Takagi;H. Shintani;Yasuharu Tanaka;T. Onodera;K. Ikuta
Prion蛋白(PrP)基因编码细胞PrP(PrPC)，一种糖基磷脂酰肌醇(GPI)锚定的细胞膜蛋白，是Prion感染所必需的，可引起人类的克雅氏病(CJD)、牛的牛海绵状脑病(BSE)和绵羊的瘙痒病。虽然已知PrPC在PrP感染后会转化为一种异常异构体(PrPSc)，并在Prion疾病中发挥重要作用，但其机制仍不清楚，部分原因是PrPSc的不溶性，这阻碍了实验的生化和生物物理分析。最近，随着计算机能力和方法的改进，计算机分析对Prion研究做出了更大的贡献。对PrP基因序列的比较发现，人类PrP基因的开放阅读框(ORF)与PrP疾病有关，存在突变和多态。尽管PrP基因启动子的插入/缺失(INS/Del)多态性与疯牛病的易感性有关，但在牛PrP基因的ORF中未发现与疯牛病易感性相关的突变或多态。我们的研究结果表明，PrP基因启动子的特异性蛋白1(Sp1)在启动子活性中起着重要作用，其活性受Sp1结合位点多态性的影响。用分子动力学(MD)和量子力学(QM)等计算方法对PrP的势能结构动力学进行了模拟。拟议的转换机制揭示了对普恩病毒疾病的新见解。在这篇综述中，我们将介绍基础和高级计算分析揭示的PrP的基因结构、多态性和潜在的结构动力学。讨论了这些方法对阐明PrPC致病机制和PrPC功能的可能贡献。
Prion protein (PrP) gene encodes cellular PrP (PrPC), a glycosylphosphatidylinositol (GPI)-anchored cell membrane protein indispensable for infections of prion, which causes Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. Although PrPC is known to be converted into an abnormal isoform (PrPSc) upon prion infection and play an important role in prion diseases, the mechanisms involved remain unclear, partly due to the insolubility of PrPSc, which prevents experimental biochemical and biophysical analyses. Recently, with improvements in computer power and methods, computer analyses have been contributing more to prion studies. A comparison of PrP gene sequences revealed mutations and polymorphisms in the open reading frame (ORF) of the human PrP gene related to prion diseases. In contrast, little mutations or polymorphisms related to susceptibility to BSE were found in the ORF of the bovine PrP gene, though relationships between insertion/deletion (Ins/Del) polymorphisms of the PrP gene promoter and susceptibility to BSE have been found. Our results have shown that the specific protein 1 (Sp1) plays important role in the activity of PrP gene promoter, which is influenced by polymorphisms in the Sp1 binding sites. The potential structural dynamics of PrP have been simulated by computational methods such as molecular dynamics (MD) and quantum mechanics (QM). The proposed mechanisms of conversion have revealed new insights in prion diseases. In this review, we will introduce the gene structure, polymorphisms, and potential structural dynamics of PrP revealed by basic and advanced computational analyses. The possible contribution of these methods to elucidation of the pathogenicity of prion diseases and functions of PrPC is discussed.