Disruption of the X-loop turn of the prion protein linked to scrapie resistance.
Disruption of the X-loop turn of the prion protein linked to scrapie resistance.
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DOI：
10.1093/protein/gzs009
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发表时间：
2012-05
期刊：
影响因子：
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通讯作者：
Alexander D. Scouras;V. Daggett
中科院分区：
文献类型：
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作者：
Alexander D. Scouras;V. Daggett
PrP(C)是由PrP(C)错误折叠和聚集成具有毒性和感染性的寡聚体(PrP(SC))而引起的一类神经退行性疾病。这些低聚物对于理解和抗击这些疾病至关重要。PrP序列的差异可能通过将适应蛋白的耐受性转变为PrP(SC)构象和/或PrP(SC)和PrP(C)之间的识别事件来影响疾病易感性。我们选择了两组PrP(SC)抗性突变序列进行溶剂化原子分子动力学模拟，以研究抗性的结构基础。第一组涉及绵羊选择性繁殖导致的X-环(残基164-171)突变。第二组包括针对螺旋C的随机突变鉴定的8个小鼠突变，然后在细胞培养中进行筛选。在不同的pH条件下对14个不同的突变体和对照构建体进行了多次模拟，模拟时间总计为3.6μS。在两个物种的野生型PrP中，X环在中性pH下形成了一个稳定的转折。PRP(SC)抗性突变中断了这一转折，尽管只有一个突变体在X环中。X-环是紧凑的，埋在我们之前描述的PrP(Sc)样低聚物的螺旋模型中。基于本文提出的研究结果，在螺旋低聚物模型的背景下，我们提出X环的扩张破坏了原纤维堆积，为耐药性提供了结构基础。
The prion diseases are a class of neurodegenerative diseases caused by the misfolding and aggregation of the prion protein (PrP(C)) into toxic and infectious oligomers (PrP(Sc)). These oligomers are critical to understanding and combating these diseases. Differences in the sequence of PrP affect disease susceptibility, likely by shifting the tolerance of the protein for adaptation to PrP(Sc) conformations and/or the recognition event between PrP(Sc) and PrP(C) prior to conversion of the PrP(C). We selected two sets of PrP(Sc)-resistant mutant sequences for solvated atomistic molecular dynamics simulation to investigate the structural basis of resistance. The first group involved mutation in the X-loop (residues 164-171) resulting from selective breeding of sheep. The second group included eight mutants in mice identified by random mutagenesis targeting helix C followed by screening in cell cultures. Multiple simulations were performed of 14 different mutant and control constructs under different pH conditions for a total of 3.6 μs of simulation time. The X-loop formed a stable turn at neutral pH in wild-type PrP from both species. PrP(Sc)-resistant mutations disrupted this turn even though only one of the mutants is in the X-loop. The X-loop is compact and buried in our previously described spiral models of PrP(Sc)-like oligomers. On the basis of the findings presented here and in the context of the spiral oligomer model, we propose that expansion of the X-loop disrupts protofibril packing, providing a structural basis for resistance.