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首页> 外文期刊>Biochemistry >The Pathogenic Mutation T182A Converts the Prion Protein into a Molten Globule-like Conformation Whose Misfolding to Oligomers but Not to Fibrils Is Drastically Accelerated
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The Pathogenic Mutation T182A Converts the Prion Protein into a Molten Globule-like Conformation Whose Misfolding to Oligomers but Not to Fibrils Is Drastically Accelerated

机译：病原性突变T182A将the病毒蛋白转化为融合为寡聚体而不是原纤维的熔融小球状构象，从而急剧加速

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Delineation of the effects of pathogenic mutations linked with familial prion diseases on the structure and misfolding of prion protein (PrP) will be useful in understanding the molecular mechanism of PrP misfolding. Here, it has been shown that the pathogenic mutation T182A causes a drastic reduction in the apparent cooperativity and enthalpy of unfolding of the mouse prion protein (moPrP) under misfolding-prone conditions by converting the protein into a molten globule (MG)-like conformation. Hydrogen deuterium exchange studies in conjunction with mass spectrometry indicate that the T182A mutation disrupts the core of the protein, thereby increasing overall structural dynamics. T182A moPrP is shown to misfold to oligomers very much faster than does wild-type (wt) moPrP but to misfold to fibrils at a rate similar to that of wt moPrP. This observation suggests that oligomers are unlikely to play a productive role in the direct pathway of aggregation from monomer to fibrils. The observation that fully folded T182A moPrP has a MG-like structure, and that it misfolds to oligomers much faster than does wt moPrP, suggests that a MG-like intermediate, whose structure resembles that of fully folded T182A moPrP, might be populated early on the pathway of misfolding of wt moPrP to oligomers.
机译：描绘与家族性pr病毒疾病有关的致病性突变对of病毒蛋白（PrP）的结构和错误折叠的影响将有助于理解PrP错误折叠的分子机制。在这里，已经表明，致病性突变T182A通过将易折叠蛋白条件下的蛋白转化为熔融小球（MG）样构象，导致表观协同性和小鼠病毒蛋白（moPrP）的展开焓急剧降低。 。氢氘交换研究与质谱联用表明，T182A突变破坏了蛋白质的核心，从而增加了整体结构动力学。已显示T182A moPrP与野生型（wt）moPrP错折叠到寡聚物的速度非常快，但与wt moPrP相似的错折叠到原纤维的速度。该观察结果表明，低聚物不太可能在从单体到原纤维的聚集的直接途径中发挥生产性作用。观察到完全折叠的T182A moPrP具有MG样结构，并且比wt moPrP错折叠到寡聚物的速度要快得多，这表明其结构类似于完全折叠的T182A moPrP的MG样中间体可能在早期就被填充。 wt moPrP错折叠为寡聚物的途径。

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