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首页> 外文期刊>Biochemistry >The H187R Mutation of the Human Prion Protein Induces Conversion of Recombinant Prion Protein to the PrPsc-like Form
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The H187R Mutation of the Human Prion Protein Induces Conversion of Recombinant Prion Protein to the PrPsc-like Form

机译：人类Pri病毒蛋白的H187R突变诱导重组Pri病毒蛋白转化为PrPsc样形式。

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摘要

Prion diseases are associated with a conformational switch in the prion protein (PrP) from its normal cellular form (denoted PrP~c) to a disease-associated "scrapie" form (PrP~(Sc)). A number of PrP~(Sc)-like conformations can be generated by incubating recombinant PrP~c at low pH, indicating that protonation of key residues is likely to destabilize PrP~c, facilitating its conversion to PrP~(Sc). Here, we examine the stability of human PrP~c with pH and find that PrP~c fold stability is significantly reduced by the protonation of two histidine residues, Hisl87 and His155. Mutation of Hisl87 to an arginine, which imposes a _permanently positively charged residue in this region of the protein, has a dramatic effect on the folding of PrP~C. resulting in a molecule that displays a markedly increased propensity to oligomerize. The oligomeric form is characterized by an increased β-sheet content, loss of fixed side chain interactions, and partial proteina se resistance. Hence, the protonation state of H187 appears to be crucial in determining the conformation of PrP, the unprotonated form favors native PrP~c, while the protonated form favors PrP~(Sc)-like conformations. These results are relevant to the pathogenic HI87R mutation found in humans,which is associated with an inherited prion disease [also termed Gerstmann-Straussler-Scheinker (GSS)syndrome] with unusual features such as childhood neuropsychiatric illness. Our data imply that the intrinsic instability of the PrP~c conformation in this variant is caused by a positive charge at this site in the protein. This mutation is distinct from all those associated with GSS, which have much more subtle physical consequences. The degree of instability might be the cause of the unusually early onset of mental disturbance in affected individuals.
机译：on病毒与with病毒蛋白（PrP）从其正常细胞形式（表示为PrP_c）到疾病相关的“ sc痒”形式（PrP〜（Sc））的构象转换有关。通过在低pH条件下孵育重组PrP〜c可以生成许多类似PrP〜（Sc）的构象，这表明关键残基的质子化可能会使PrP〜c不稳定，从而促进其转化为PrP〜（Sc）。在这里，我们检查了人类PrP〜c在pH值下的稳定性，发现PrP〜c的折叠稳定性由于两个组氨酸残基Hisl87和His155的质子化而大大降低。 His187突变为精氨酸，在该蛋白的这一区域施加了一个永久带正电的残基，对PrP〜C的折叠产生了显着影响。导致分子显示出明显更高的低聚倾向。寡聚形式的特征在于增加的β-折叠含量，丧失固定的侧链相互作用和部分的蛋白抵抗性。因此，H187的质子化状态似乎对确定PrP的构象至关重要，未质子化的形式有利于天然PrP〜c，而质子化的形式有利于PrP〜（Sc）样构象。这些结果与人类发现的致病性HI87R突变有关，该突变与遗传性with病毒疾病（也称为Gerstmann-Straussler-Scheinker（GSS）综合征）有关，具有儿童神经精神病等异常特征。我们的数据表明，此变体中PrP〜c构象的固有不稳定性是由蛋白质中此位点的正电荷引起的。这种突变不同于所有与GSS相关的突变，后者具有更为微妙的物理后果。不稳定程度可能是受影响个体异常早期精神障碍发作的原因。

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