Mutational analysis of the propensity for amyloid formation by a globular protein
Mutational analysis of the propensity for amyloid formation by a globular protein
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DOI：
10.1093/emboj/19.7.1441
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发表时间：
2000-04-03
期刊：
影响因子：
11.4
通讯作者：
Dobson, CM
中科院分区：
文献类型：
--
作者：
Chiti, F;Taddei, N;Dobson, CM
在体外，通过添加三氟乙醇（TFE），酰基磷酸酶可以转化为在一系列人类疾病中观察到的淀粉样蛋白原纤维。通过监测导致聚集的TFE浓度范围，研究了一系列酰基磷酸酶突变体形成原纤维的倾向。我们发现，在不同的突变体中，聚集的趋势与蛋白质的天然状态的构象稳定性成反比。与此一致的是，最不稳定的酰基磷酸酶变体在没有TFE的水溶液中形成淀粉样蛋白原纤维。这些结果表明，导致淀粉样蛋白沉积的聚集过程是在非共价相互作用仍然有利的条件下从变性构象的集合中发生的。这些结果支持了一种假设，即球形蛋白天然状态的稳定性是在非病理条件下阻止天然蛋白在体内转化为淀粉样原纤维的主要因素。他们还认为，稳定淀粉样蛋白的天然状态有助于预防淀粉样疾病。
Acylphosphatase can be converted in vitro, by addition of trifluoroethanol (TFE), into amyloid fibrils of the type observed in a range of human diseases. The propensity to form fibrils has been investigated for a series of mutants of acylphosphatase by monitoring the range of TFE concentrations that result in aggregation. We have found that the tendency to aggregate correlates inversely with the conformational stability of the native state of the protein in the different mutants. In accord with this, the most strongly destabilized acylphosphatase variant forms amyloid fibrils in aqueous solution in the absence of TFE, These results show that the aggregation process that leads to amyloid deposition takes place from an ensemble of denatured conformations under conditions in which non-covalent interactions are still favoured. These results support the hypothesis that the stability of the native state of globular proteins is a major factor preventing the in vivo conversion of natural proteins into amyloid fibrils under non-pathological conditions. They also suggest that stabilizing the native states of amyloidogenic proteins could aid prevention of amyloidotic diseases.