多个弱制动器协同作用,控制STIM1和储存的进入
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
概括
存储运行的入口依赖于STIM1和Orai1. 四个弱约束保持STIM1在休息细胞中不活跃,允许在储量耗尽时快速激活.
科学领域:
- 细胞生物学 细胞生物学
- 分子信号传输的方法
- 生物物理学的生物物理.
背景情况:
- 储存运行的入 (SOCE) 对于细胞信号传输至关重要,在ER耗尽时由STIM1和Orai1相互作用调节.
- 当ER充足时,STIM1必须保持不活跃,但在储量耗尽时迅速和可逆地激活,以防止病理.
- 规范STIM1双重监管要求的确切机制仍然不完全理解.
研究的目的:
- 阐明STIM1.1休息状态的结构基础和监管机制.
- 了解STIM1如何在休息状态下平衡不活动,并在ER储量耗尽时快速激活.
主要方法:
- 单分子Förster共振能量转移 (smFRET) 在脂质膜中测量全长二维STIM1.
- 利用AlphaFold2结构建模来分析STIM1.1的静止状态结构.
- 研究了个人结构限制在STIM1法规中的作用.
主要成果:
- 确定了四个关键的弱制约 ("车"),使STIM1在静止细胞中保持不活跃的形状.
- 这些制动包括Ca2+结合的EF-SAM域,域交换的疏水性相互作用,CC1α1-CC3对齐以及CC1α2/3域的相互作用.
- 任何单个抑制的破坏都会导致自发的STIM1激活,突出显示抑制的合作性.
结论:
- STIM1的静止状态是通过四个弱的,合作的约束网络来稳定.
- 这种多车系统确保休息细胞的自发活动最小,同时允许在ER储量耗尽时快速激活.
- 了解这些调节车,可以了解信号通路的微调.
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