Huang Z, Gabriel J M, Baldwin M A, Fletterick R J, Prusiner S B, Cohen F E
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7139-43. doi: 10.1073/pnas.91.15.7139.
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.
朊病毒疾病是一组发生在人类和动物身上的神经退行性疾病，似乎是由朊病毒蛋白（PrP）的构象变化引起的。利用圆二色性和红外光谱获得的数据，计算研究预测了PrP细胞形式（PrPc）的三维结构。一种由二级结构预测和二级结构元件堆积评估组成的启发式方法被用于寻找合理的三级结构。在应用了一系列实验和理论限制后，出现了四个四螺旋束的结构模型。四个预测螺旋内的一组氨基酸被确定为对螺旋之间的三级相互作用很重要。这些氨基酸可能对维持PrPc的稳定三级结构至关重要。在PrPc的四个合理结构模型中，X束模型似乎与11个已知点突变中的5个最相关，这些点突变与遗传性朊病毒疾病相关。这5个突变聚集在X束结构的一个中心疏水核心周围。此外，这些突变发生在预计对螺旋-螺旋相互作用很重要的那些氨基酸处或附近。这里提出的PrPc三维结构不仅可以为遗传性朊病毒疾病中PrP基因突变的合理化提供基础，还可以指导用于进一步实验研究的基因工程PrP分子的设计。
