Diverse effects on the native β-sheet of the human prion protein due to disease-associated mutations.
Diverse effects on the native β-sheet of the human prion protein due to disease-associated mutations.
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DOI：
10.1021/bi101449f
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发表时间：
2010-11-16
期刊：
影响因子：
2.9
通讯作者：
Daggett, Valerie
中科院分区：
文献类型：
--
作者：
Chen, Wei;van der Kamp, Marc W.;Daggett, Valerie
朊病毒疾病是致命的神经退行性疾病，涉及朊病毒蛋白（PrPC）的正常细胞形式转化为错误折叠的致病形式（PrPSc）。PrP基因的许多突变与人类朊病毒病有关。这些点突变中的三个位于人PrP中天然β折叠的第一链：G131 V、S132 I和A133 V。为了了解这些致病突变对人类蛋白质的潜在结构和动态影响，我们对野生型和突变的人PrP进行了分子动力学研究。结果表明，这些突变诱导了不同的效应，但它们都与天然β折叠的错误折叠有关：G131 V导致天然β折叠的延长，A133 V破坏天然β折叠，S132 I将天然β折叠转化为α折叠。观察到的变化是由于引入突变后侧链-侧链相互作用的重定向。此外，所有突变都损害了天然β折叠上结构保守的水位点。我们的工作表明，各种错误折叠途径的人PrP突变。
Prion diseases are fatal neurodegenerative disorders that involve the conversion of the normal cellular form of the prion protein (PrPC) to a misfolded pathogenic form (PrPSc). There are many genetic mutations of PrP associated with human prion diseases. Three of these point mutations are located at the first strand of the native β-sheet in human PrP: G131V, S132I and A133V. To understand the underlying structural and dynamic effects of these disease-causing mutations on the human protein, we performed molecular dynamics of wild-type and mutated human PrP. The results indicate that the mutations induced different effects but they were all related to misfolding of the native β-sheet: G131V caused the elongation of the native β-sheet, A133V disrupted the native β-sheet, and S132I converted the native β-sheet to an α-sheet. The observed changes were due to the reorientation of side chain-side chain interactions upon introducing the mutations. In addition, all mutations impaired a structurally conserved water site at the native β-sheet. Our work suggests various misfolding pathways for human PrP in response to mutation.
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DOI：
10.1073/pnas.0502068102
发表时间：
2005-09-20
影响因子：
11.1
作者：
Armen, RS;Bernard, BM;Daggett, V
通讯作者：
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影响因子：
16.6
作者：
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DOI：
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发表时间：
2004-08-10
影响因子：
11.1
作者：
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通讯作者：
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DOI：
10.1073/pnas.0307178101
发表时间：
2004-02-24
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
2.9
作者：
DeMarco, Mari L.;Daggett, Valerie
通讯作者：
Daggett, Valerie