ATP诱导导致ALS的C71G-hPFN1和新生的hSOD1的折叠
Jian Kang1, Liangzhong Lim1, Jianxing Song2
1Department of Biological Sciences, Faculty of Science, National University of Singapore, 10 Kent Ridge Crescent, Singapore, 119260, Singapore.
Communications chemistry
|September 5, 2023
概括
腺三酸盐 (ATP) 和三酸盐可以诱导蛋白质折叠,可能解释家族ALS和神经退行性疾病风险. 这项研究揭示了ATP的存在.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 神经科学是一个神经科学.
背景情况:
- 导致肌缩性侧面硬化症 (ALS) 的蛋白质突变,如C71G-人体蛋白1 (hPFN1) 和新生的人体超氧化物失突酶1 (hSOD1) 与疾病有关,但它们的机制尚不清楚.
- 了解蛋白质折叠和错误折叠对于破译神经退行性疾病病原体至关重要.
研究的目的:
- 阐明ATP及其衍生物影响ALS相关蛋白质,特别是C71G-hPFN1和新兴hSOD1.1的构造状态的机制.
- 研究三酸盐在蛋白质折叠和聚合中的作用.
主要方法:
- 核磁共振 (NMR) 谱学被用来分析由ATP及其类似物在C71G-hPFN1和hSOD1.1中诱导的构造变化.
- 在不同条件下对蛋白质构造和动态进行比较分析 (ATP诱导的折叠与Zn2+诱导的折叠).
主要成果:
- ATP完全将C71G-hPFN1折叠成一个稳定的形状,比例为1:2.
- ATP诱导新生的hSOD1在1: 8的比例下进入两个不同的并存状态.
- 诱导折叠的能力主要归因于三酸盐组;自由的三酸盐触发了聚合,其能力排名:ATP = ATPP = PPP > ADP = AMP-PNP = AMP-PCP = PP.
结论:
- ATP和三酸盐增强了在氨基酸序列中编码的内在蛋白质折叠能力.
- 这些发现为多酸盐在单细胞生物中作为原始伴侣的作用提供了潜在的机制.
- 这项研究揭示了与年龄相关的家族性ALS发病率和神经退行性疾病风险增加.
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