Influence of the pathogenic mutations T188K/R/A on the structural stability and misfolding of human prion protein: Insight from molecular dynamics simulations
Influence of the pathogenic mutations T188K/R/A on the structural stability and misfolding of human prion protein: Insight from molecular dynamics simulations
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致病性突变 T188K/R/A 对人类朊病毒蛋白结构稳定性和错误折叠的影响：来自分子动力学模拟的见解。
DOI：
10.1016/j.bbagen.2011.11.013
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发表时间：
2012-02-01
影响因子：
3
通讯作者：
Yao, Xiaojun
中科院分区：
文献类型：
--
作者：
Guo, Jingjing;Ning, Lulu;Yao, Xiaojun
背景：Prion病与PrP从PrPC到PrPSC的构象转换有关。许多基因突变与PrP疾病有关，例如带有fCJD的T188K/R/A突变。综述范围：对WT PrP及其突变体进行MD模拟，以探索T188突变对人类PrP的潜在动态影响。虽然球状结构域相当保守，但这三个突变对PIT的动力学性质有不同的影响，包括H1的移动，天然β-折叠的延长和S2-H2环向3(10)螺旋的转变。主要结论：我们的研究表明，PrP的三个突变可能经历了不同的致病机制，现实的原子模拟可以深入了解疾病相关突变对PrP动力学和稳定性的影响。我们目前的研究有助于了解T188K/R/A突变对人PrP的影响：尽管这三种致病突变几乎不改变PrP的天然结构，但会扰乱其稳定性。这种不稳定性可能进一步调节齐聚途径，并决定PrPSC组装的特征。(C)2011爱思唯尔B.V.保留所有权利。
Background: Prion diseases are associated with a conformational switch for PrP from PrPC to PrPSC. Many genetic mutations are linked with prion diseases, such as mutations T188K/R/A with fCJD.Scope of review: MD simulations for the WT PrP and its mutants were performed to explore the underlying dynamic effects of T188 mutations on human PrP. Although the globular domains are fairly conserved, the three mutations have diverse effects on the dynamics properties of PIT, including the shift of H1, the elongation of native beta-sheet and the conversion of S2-H2 loop to a 3(10) helix.Major conclusions: Our present study indicates that the three mutants for PrP may undergo different pathogenic mechanisms and the realistic atomistic simulations can provide insights into the effects of disease-associated mutations on PrP dynamics and stability, which can enhance our understanding of how mutations induce the conversion from PrPC to PrPSC.General significanceOur present study helps to understand the effects of T188K/R/A mutations on human PrP: despite the three pathogenic mutations almost do not alter the native structure of PrP, but perturb its stability. This instability may further modulate the oligomerization pathways and determine the features of the PrPSC assemblies. (C) 2011 Elsevier B.V. All rights reserved.