Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases
Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases
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DOI：
10.1073/pnas.212527999
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发表时间：
2002-12-10
影响因子：
11.1
通讯作者：
Dobson, CM
中科院分区：
文献类型：
--
作者：
Chiti, F;Calamai, M;Dobson, CM
蛋白质聚集和高度不溶性淀粉样结构的形成与一系列使人衰弱的病症相关，所述病症包括阿尔茨海默病、帕金森病和克雅氏病。肌肉酰基磷酸酶（AcP）已经为调节淀粉样蛋白形成的突变变化提供了重要的见解。在本文中，我们已经使用了这个系统来研究的影响，修改蛋白质的电荷状态的突变，而不影响显着的疏水性或二级结构的多肽链的倾向。发现在变性条件下蛋白变体的聚集速率与其总体净电荷之间存在高度显著的负相关。这一结果表明，聚集通常受到使蛋白质的净电荷更接近中性的突变的青睐。根据这一发现，我们分析了与家族性淀粉样蛋白疾病相关的自然突变，这些突变涉及与疾病相关的蛋白质或蛋白质片段的净电荷的改变。已经鉴定了16种突变，其导致病理状况的作用机制尚不清楚或尚未完全理解。值得注意的是，这16个突变中的14个导致相应的肽或蛋白质的净电荷减少，这些肽或蛋白质转化为淀粉样蛋白沉积物。这一结果表明，电荷一直是分子进化中确保避免蛋白质聚集的关键参数，并确定净电荷的减少是至少某些形式的蛋白质沉积疾病的重要决定因素。
Protein aggregation and the formation of highly insoluble amyloid structures is associated with a range of debilitating human conditions, which include Alzheimer's disease, Parkinson's disease, and the Creutzfeldt-Jakob disease. Muscle acylphosphatase (AcP) has already provided significant insights into mutational changes that modulate amyloid formation. In the present paper, we have used this system to investigate the effects of mutations that modify the charge state of a protein without affecting significantly the hydrophobicity or secondary structural propensities of the polypeptide chain. A highly significant inverse correlation was found to exist between the rates of aggregation of the protein variants under denaturing conditions and their overall net charge. This result indicates that aggregation is generally favored by mutations that bring the net charge of the protein closer to neutrality. In light of this finding, we have analyzed natural mutations associated with familial forms of amyloid diseases that involve alteration of the net charge of the proteins or protein fragments associated with the diseases. Sixteen mutations have been identified for which the mechanism of action that causes the pathological condition is not yet known or fully understood. Remarkably, 14 of these 16 mutations cause the net charge of the corresponding peptide or protein that converts into amyloid deposits to be reduced. This result suggests that charge has been a key parameter in molecular evolution to ensure the avoidance of protein aggregation and identifies reduction of the net charge as an important determinant in at least some forms of protein deposition diseases.