Pathogenic mutations in the hydrophobic core of the human prion protein can promote structural instability and misfolding.
Pathogenic mutations in the hydrophobic core of the human prion protein can promote structural instability and misfolding.
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DOI：
10.1016/j.jmb.2010.09.060
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发表时间：
2010-12-10
影响因子：
5.6
通讯作者：
Daggett V
中科院分区：
文献类型：
--
作者：
van der Kamp MW;Daggett V
传染性海绵状脑病，或称PrP病，是由PrP蛋白的错误折叠和聚集引起的。这些疾病在人类中可能是遗传性的，许多与疾病相关的PrP错义突变中有四个位于疏水核心：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，并已知会导致不稳定。我们对这五个PrP突变体进行了广泛的分子动力学模拟，并将它们的动力学和构象与野生型PrP进行了比较。这些模拟突出了在引入突变时发生的变化，并有助于使实验结果合理化。突变可以发生在突变部位周围，但也可以远距离传播。特别是，F198S和T183A突变导致正常稳定的结构部分的灵活性增加，短β-折叠从蛋白质的其余部分移开。突变V180I、V210I和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。在一次V180I模拟中观察到早期错误折叠。总体而言，疏水核心的突变对PrP的动力学和稳定性有显著影响，包括错误折叠的倾向，这有助于解释它们在家族性PrP疾病发展中的作用。
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 have performed extensive molecular dynamics simulations of these five PrP mutants and compared their dynamics and conformations to 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 β-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.
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影响因子：
2.9
作者：
DeMarco, Mari L.;Silveira, Jay;Daggett, Valerie
通讯作者：
Daggett, Valerie
DOI：
10.1073/pnas.0809170106
发表时间：
2009-02-24
影响因子：
11.1
作者：
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9.9
作者：
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通讯作者：
Alpérovitch, A
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8
作者：
Julien, Olivier;Chatterjee, Subhrangsu;Sykes, Brian D.
通讯作者：
Sykes, Brian D.
影响因子：
2.5
作者：
Chasseigneaux, Stephanie;Haik, Stephane;Peoc'h, Katell
通讯作者：
Peoc'h, Katell