质子激活化通道的结构和pH感应机制
Zheng Ruan1, James Osei-Owusu2, Juan Du1
1Department of Structural Biology, Van Andel Institute, Grand Rapids, MI, USA.
Nature
|November 5, 2020
概括
质子激活的化物通道 (PAC) 对于酸诱导的细胞损伤至关重要. 新结构揭示了pH值变化如何导致PAC关闭,并提供了对其激活机制的见解.
科学领域:
- 分子生物学
- 细胞生理学
- 结构生物学
背景情况:
- 在哺乳动物细胞中存在质子激活化物通道 (PAC).
- 在酸诱导的细胞死亡和组织损伤中发挥作用.
- 它代表了一种新型的,在进化过程中保存的蛋白质家族.
研究的目的:
- 阐明了以质子为依赖的PAC激活的结构基础.
- 在不同的pH条件下呈现人体PAC的冷电子显微镜结构.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定结构.
- 在高pH (休息封闭) 和低pH (与质子结合的非导电) 状态下分析人体PAC.
主要成果:
- 获得了人类PAC的两个结构:高pH封闭状态和低pH开放状态.
- 酸性化导致细胞外和膜外的结构变化.
- 确定了关键残留物 (His98,Lys319) 和螺旋运动 (TM1旋转),影响了通道封闭和离子选择性.
结论:
- 这项研究提供了PAC组合和质子依赖激活的分子细节.
- 结构性见解为了解PAC在生理和病理过程中的作用铺平了道路.
- 确定关键的残留物为治疗目标提供了潜力.
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