Chiti Fabrizio, Stefani Massimo, Taddei Niccolò, Ramponi Giampietro, Dobson Christopher M
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Nature. 2003 Aug 14;424(6950):805-8. doi: 10.1038/nature01891.
In order for any biological system to function effectively, it is essential to avoid the inherent tendency of proteins to aggregate and form potentially harmful deposits. In each of the various pathological conditions associated with protein deposition, such as Alzheimer's and Parkinson's diseases, a specific peptide or protein that is normally soluble is deposited as insoluble aggregates generally referred to as amyloid. It is clear that the aggregation process is generally initiated from partially or completely unfolded forms of the peptides and proteins associated with each disease. Here we show that the intrinsic effects of specific mutations on the rates of aggregation of unfolded polypeptide chains can be correlated to a remarkable extent with changes in simple physicochemical properties such as hydrophobicity, secondary structure propensity and charge. This approach allows the pathogenic effects of mutations associated with known familial forms of protein deposition diseases to be rationalized, and more generally enables prediction of the effects of mutations on the aggregation propensity of any polypeptide chain.
为使任何生物系统有效发挥功能，避免蛋白质固有的聚集倾向并形成潜在有害沉积物至关重要。在与蛋白质沉积相关的各种病理状况中，如阿尔茨海默病和帕金森病，通常可溶的特定肽或蛋白质会以不溶性聚集体形式沉积，这些聚集体一般被称为淀粉样蛋白。显然，聚集过程通常由与每种疾病相关的肽和蛋白质的部分或完全未折叠形式引发。在此我们表明，特定突变对未折叠多肽链聚集速率的内在影响在很大程度上可与诸如疏水性、二级结构倾向和电荷等简单物理化学性质的变化相关联。这种方法能够使与已知家族性蛋白质沉积疾病形式相关的突变的致病效应合理化，更广泛地说，能够预测突变对任何多肽链聚集倾向的影响。
