Influence of pH on the human prion protein: insights into the early steps of misfolding.
Influence of pH on the human prion protein: insights into the early steps of misfolding.
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DOI：
10.1016/j.bpj.2010.07.063
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发表时间：
2010-10
影响因子：
3.4
通讯作者：
M. W. van der Kamp;V. Daggett
中科院分区：
文献类型：
--
作者：
M. W. van der Kamp;V. Daggett
传染性海绵状脑病，或称普恩疾病，是由普恩蛋白PrP的错误折叠和聚集引起的。从正常细胞形式(PrPC)或重组PrP(RecPrP)到错误折叠形式的转换对pH敏感，因为在较低的pH下更容易发生错误折叠和聚集。为了更深入地了解pH对PrP动力学的影响及其错误折叠的可能性，我们对重组PrP蛋白(残基90-230)在三种不同pH条件下的水中进行了广泛的分子动力学模拟：中性(或细胞质)pH(∼7.4)、中等(或内体)pH(∼5)和低pH(<；4)。我们提供了五个不同的模拟，每个pH区域各50 ns，总计750 ns的模拟时间。通过详细的分析和与实验的比较，验证了模拟结果，并对pH诱导错误折叠的机理有了新的见解。通过第一螺旋的位移和疏水核心的不稳定，球状结构域的迁移率随着pH的降低而增加。在中等pH下，也没有观察到错误折叠(类PrPSc)构象的转变。观察到的构象和稳定性的变化与实验数据一致，从而为错误折叠过程的初始步骤提供了分子基础。
Transmissible spongiform encephalopathies, or prion diseases, are caused by misfolding and aggregation of the prion protein PrP. Conversion from the normal cellular form (PrPC) or recombinant PrP (recPrP) to a misfolded form is pH-sensitive, in that misfolding and aggregation occur more readily at lower pH. To gain more insight into the influence of pH on the dynamics of PrP and its potential to misfold, we performed extensive molecular-dynamics simulations of the recombinant PrP protein (residues 90–230) in water at three different pH regimes: neutral (or cytoplasmic) pH (∼7.4), middle (or endosomal) pH (∼5), and low pH (<4). We present five different simulations of 50 ns each for each pH regime, amounting to a total of 750 ns of simulation time. A detailed analysis and comparison with experiment validate the simulations and lead to new insights into the mechanism of pH-induced misfolding. The mobility of the globular domain increases with decreasing pH, through displacement of the first helix and instability of the hydrophobic core. At middle pH, conversion to a misfolded (PrPSc-like) conformation is observed. The observed changes in conformation and stability are consistent with experimental data and thus provide a molecular basis for the initial steps in the misfolding process.