PROPOSED 3-DIMENSIONAL STRUCTURE FOR THE CELLULAR PRION PROTEIN
PROPOSED 3-DIMENSIONAL STRUCTURE FOR THE CELLULAR PRION PROTEIN
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DOI：
10.1073/pnas.91.15.7139
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发表时间：
1994-07-19
影响因子：
11.1
通讯作者：
COHEN, FE
中科院分区：
文献类型：
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作者：
HUANG, ZW;GABRIEL, JM;COHEN, FE
朊病毒病是一组人类和动物的神经退行性疾病，似乎是由朊病毒蛋白（PrP）的构象变化引起的。利用圆二色谱和红外光谱获得的数据，计算研究预测的三维结构的细胞形式的PrP（PrPc）。一个启发式的方法，包括二级结构的预测和评价的包装的二级元素被用来寻找合理的三级结构。在应用了一系列实验和理论约束后，出现了四种四螺旋束的结构模型。一组氨基酸内的四个预测的螺旋被确定为重要的三级螺旋之间的相互作用。这些氨基酸可能是维持PrPc三级结构稳定所必需的。在PrPc的四种合理的结构模型中，X束模型似乎与11个已知的与遗传性朊病毒疾病分离的点突变中的5个最相关。这5个突变聚集在X束结构中的中央疏水核心周围。此外，这些突变发生在或接近那些氨基酸，预计是重要的螺旋-螺旋相互作用。PrPc的三维结构不仅为PrP基因在遗传性朊病毒疾病中的突变提供了理论依据，而且为进一步的实验研究提供了设计PrP基因工程分子的指导。
Prion diseases are a group of neurodegenerative disorders in humans and animals that seem to result from a conformational change in the prion protein (PrP). Utilizing data obtained by circular dichroism and infrared spectroscopy, computational studies predicted the three-dimensional structure of the cellular form of PrP (PrPc). A heuristic approach consisting of the prediction of secondary structures and of an evaluation of the packing of secondary elements was used to search for plausible tertiary structures. After a series of experimental and theoretical constraints were applied, four structural models of four-helix bundles emerged. A group of amino acids within the four predicted helices were identified as important for tertiary interactions between helices. These amino acids could be essential for maintaining a stable tertiary structure of PrPc. Among four plausible structural models for PrPc, the X-bundle model seemed to correlate best with 5 of 11 known point mutations that segregate with the inherited prion diseases. These 5 mutations cluster around a central hydrophobic core in the X-bundle structure. Furthermore, these mutations occur at or near those amino acids which are predicted to be important for helix-helix interactions. The three dimensional structure of PrPc proposed here may not only provide a basis for rationalizing mutations of the PrP gene in the inherited prion diseases but also guide design of genetically engineered PrP molecules for further experimental studies.