Rationalization of the effects of mutations on peptide and protein aggregation rates
Rationalization of the effects of mutations on peptide and protein aggregation rates
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DOI：
10.1038/nature01891
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发表时间：
2003-08-14
期刊：
影响因子：
64.8
通讯作者：
Dobson, CM
中科院分区：
文献类型：
--
作者：
Chiti, F;Stefani, M;Dobson, CM
为了使任何生物系统有效运作，必须避免蛋白质聚集并形成潜在有害沉积物的固有倾向(1-4)。在与蛋白质沉积有关的各种病理情况中，如阿尔茨海默氏症和帕金森氏病，通常可溶的特定多肽或蛋白质以不可溶聚集体的形式沉积，通常称为淀粉样蛋白(2，3)。很明显，聚集过程通常是由与每种疾病相关的部分或完全展开的多肽和蛋白质形式启动的。在这里，我们证明了特定突变对未折叠多肽链聚集速率的内在影响可以在很大程度上与简单物理化学性质的变化相关联，如疏水性、二级结构倾向和电荷。这种方法使与已知蛋白质沉积疾病的家族形式相关的突变的致病效应合理化，并且更一般地能够预测突变对任何多肽链的聚集倾向的影响。
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(1-4). 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(2,3). 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.