All-Atom Simulations Reveal How Single-Point Mutations Promote Serpin Misfolding.
All-Atom Simulations Reveal How Single-Point Mutations Promote Serpin Misfolding.
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DOI：
10.1016/j.bpj.2018.03.027
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发表时间：
2017-07
影响因子：
3.4
通讯作者：
Fang Wang;S. Orioli;A. Ianeselli;G. Spagnolli;S. a Beccara;A. Gershenson;P. Faccioli;P. Wintrode
中科院分区：
文献类型：
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作者：
Fang Wang;S. Orioli;A. Ianeselli;G. Spagnolli;S. a Beccara;A. Gershenson;P. Faccioli;P. Wintrode
蛋白质错误折叠与许多疾病有关，包括血清病。对于经典的抑制性丝氨酸α1-抗胰蛋白酶，突变会导致蛋白质缺乏导致肺部疾病，错误折叠的突变会在肝细胞中积累，导致肝脏疾病。利用基于最新发展的偏向泛函算法的全原子模拟，我们阐明了野生型α1-抗胰蛋白酶是如何折叠的，以及与疾病相关的S(Glu264Val)和Z(Glu342Lys)突变是如何导致错误折叠的。有害的Z突变会在早期破坏折叠，而相对良性的S突变会在后期表现出轻微的错误折叠。一些抑制子突变可以改善Z突变的影响，对这些突变的模拟有助于阐明空间碰撞和静电相互作用在Z错误折叠中的相对作用。这些结果证明了原子性事件与疾病严重性之间的显着相关性，并揭示了驱动链偏离正确折叠路线的机制。
Protein misfolding is implicated in many diseases, including serpinopathies. For the canonical inhibitory serpinα1-antitrypsin, mutations can result in protein deficiencies leading to lung disease, and misfolded mutants can accumulate in hepatocytes, leading to liver disease. Using all-atom simulations based on the recently developed bias functional algorithm, we elucidate how wild-typeα1-antitrypsin folds and how the disease-associated S (Glu264Val) and Z (Glu342Lys) mutations lead to misfolding. The deleterious Z mutation disrupts folding at an early stage, whereas the relatively benign S mutant shows late-stage minor misfolding. A number of suppressor mutations ameliorate the effects of the Z mutation, and simulations on these mutants help to elucidate the relative roles of steric clashes and electrostatic interactions in Z misfolding. These results demonstrate a striking correlation between atomistic events and disease severity and shine light on the mechanisms driving chains away from their correct folding routes.