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首页> 外文期刊>Journal of Molecular Biology >Pathogenic mutations in the hydrophobic core of the human prion protein can promote structural instability and misfolding.
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Pathogenic mutations in the hydrophobic core of the human prion protein can promote structural instability and misfolding.

机译：人类病毒蛋白疏水核心的致病突变可促进结构不稳定和错误折叠。

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摘要

Transmissible spongiform encephalopathies, or prion diseases, are caused by misfolding and aggregation of the prion protein PrP. These diseases can be hereditary in humans and four of the many disease-associated missense mutants of PrP are in the hydrophobic core: V180I, F198S, V203I and V210I. The T183A mutation is related to the hydrophobic core mutants as it is close to the hydrophobic core and known to cause instability. We used extensive molecular dynamics simulations of these five PrP mutants to compare their dynamics and conformations to those of the wild type PrP. The simulations highlight the changes that occur upon introduction of mutations and help to rationalize experimental findings. Changes can occur around the mutation site, but they can also be propagated over long distances. In particular, the F198S and T183A mutations lead to increased flexibility in parts of the structure that are normally stable, and the short beta-sheet moves away from the rest of the protein. Mutations V180I, V210I and, to a lesser extent, V203I cause changes similar to those observed upon lowering the pH, which has been linked to misfolding. Early misfolding is observed in one V180I simulation. Overall, mutations in the hydrophobic core have a significant effect on the dynamics and stability of PrP, including the propensity to misfold, which helps to explain their role in the development of familial prion diseases.
机译：miss病毒蛋白PrP的错误折叠和聚集会导致传染性海绵状脑病或病毒疾病。这些疾病在人类中可能是遗传性的，PrP的许多与疾病相关的错义突变中的四个在疏水核心中：V180I，F198S，V203I和V210I。 T183A突变与疏水核心突变体有关，因为它靠近疏水核心且已知会引起不稳定性。我们使用了这五个PrP突变体的广泛分子动力学模拟，以比较它们与野生型PrP的动力学和构象。模拟突出显示了引入突变后发生的变化，并有助于合理化实验结果。变化可以在突变位点附近发生，但也可以长距离传播。特别是，F198S和T183A突变导致通常稳定的结构部分具有更大的柔韧性，而短的β-折叠会远离蛋白质的其余部分。突变V180I，V210I和较小程度的V203I引起的变化与降低pH时观察到的变化相似，这与错误折叠有关。在一个V180I模拟中观察到了早期的错折。总体而言，疏水核心的突变对PrP的动力学和稳定性具有重大影响，包括易折叠的倾向，这有助于解释其在家族性pr病毒疾病发展中的作用。

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