Alonso D O, DeArmond S J, Cohen F E, Daggett V
Department of Medicinal Chemistry, University of Washington, Seattle, WA 98195-7610, USA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):2985-9. doi: 10.1073/pnas.061555898. Epub 2001 Feb 27.
Under certain conditions, the prion protein (PrP) undergoes a conformational change from the normal cellular isoform, PrP(C), to PrP(Sc), an infectious isoform capable of causing neurodegenerative diseases in many mammals. Conversion can be triggered by low pH, and in vivo this appears to take place in an endocytic pathway and/or caveolae-like domains. It has thus far been impossible to characterize the conformational change at high resolution by experimental methods. Therefore, to investigate the effect of acidic pH on PrP conformation, we have performed 10-ns molecular dynamics simulations of PrP(C) in water at neutral and low pH. The core of the protein is well maintained at neutral pH. At low pH, however, the protein is more dynamic, and the sheet-like structure increases both by lengthening of the native beta-sheet and by addition of a portion of the N terminus to widen the sheet by another two strands. The side chain of Met-129, a polymorphic codon in humans associated with variant Creutzfeldt-Jakob disease, pulls the N terminus into the sheet. Neutralization of Asp-178 at low pH removes interactions that inhibit conversion, which is consistent with the Asp-178-Asn mutation causing human prion diseases.
在某些条件下，朊病毒蛋白（PrP）会发生构象变化，从正常的细胞异构体PrP（C）转变为PrP（Sc），后者是一种传染性异构体，能够在许多哺乳动物中引发神经退行性疾病。低pH值可触发这种转变，在体内，这种转变似乎发生在内吞途径和/或小窝样结构域中。到目前为止，通过实验方法在高分辨率下表征这种构象变化是不可能的。因此，为了研究酸性pH对PrP构象的影响，我们对处于中性和低pH水环境中的PrP（C）进行了10纳秒的分子动力学模拟。在中性pH值下，蛋白质的核心结构保持良好。然而，在低pH值下，蛋白质的动态性更强，通过延长天然β折叠以及添加N端的一部分使β折叠再增加两条链，片状结构增加。Met-129的侧链是人类中与变异型克雅氏病相关的多态密码子，它将N端拉进β折叠中。在低pH值下将Asp-178中和会消除抑制转变的相互作用，这与Asp-178-Asn突变导致人类朊病毒疾病的情况一致。
