"静电循环"中的突变/金属缺乏在apo/holo SOD1变体中增强聚合过程:对ALS疾病的影响
Faezeh Ashkaran1, Bagher Seyedalipour2, Payam Baziyar1
1Department of Molecular and Cell Biology, Faculty of Basic Science, University of Mazandaran, Babolsar, Iran.
BMC chemistry
|September 19, 2024
概括
超氧化物脱酶 (SOD1) 中的突变和金属缺乏导致蛋白质错误折叠和聚合,导致粉样蛋白的形成. 这有助于神经退行性疾病,如ALS.
科学领域:
- 生物化学 生物化学
- 神经科学是一个神经科学.
- 结构生物学 结构生物学
背景情况:
- 蛋白质错误折叠和聚合成粉样纤维素与各种疾病有关.
- 超氧化物失调酶 (SOD1) 金属离子恒温的突变或破坏与肌肉增生侧面硬化症 (ALS) 有关.
- 这些因素在SOD1错折和聚合中的确切作用尚不清楚.
研究的目的:
- 调查突变和金属缺乏对SOD1结构性质和聚合倾向的影响.
- 在神经退行性疾病的背景下阐明SOD1错折背后的机制.
主要方法:
- 分子动力学 (MD) 模拟以建模形状变化.
- 福里埃变换红外光谱 (FTIR) 和蛋白质二次结构词典 (DSSP) 用于结构分析.
- 使用瓜尼尼化 (GdnHCl) 的热力学研究.
- 提奥夫拉T (ThT) 和8-anilinonaphthalene-1-sulfonic acid (ANS) 的光测试. 这两种光测试的结果是:
- 传输电子显微镜 (TEM) 用于集成可视化.
主要成果:
- MD模拟表明,突变/金属缺乏会改变SOD1的形状.
- 在apo/holo SOD1变体中增加的β-sheet结构表明聚合趋势,FTIR和DSSP证实了这一点.
- 热力学研究表明,金属缺乏,突变和S-S键的减少对于SOD1错折至关重要.
- 在破坏稳定的条件下,以apo/holo SOD1变体形成的氨基酸聚合物,通过光和TEM进行验证.
结论:
- 在SOD1的静电循环中的突变诱导结构异常,包括改变的疏水性和减少的二硫化键.
- 这些结构变化增加了SOD1的变性和随后的粉样/无形聚合物形成的倾向.
- 这些发现支持神经退行性疾病 (如ALS) 中的蛋白质聚合假设.
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