STING聚合物结构揭示了激活,过度激活和抑制的机制
Sabrina L Ergun1, Daniel Fernandez2, Thomas M Weiss3
1Department of Biochemistry, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA.
Cell
|June 25, 2019
概括
干扰基因 (STING) 蛋白的ST刺激器
科学领域:
- 天生的免疫力
- 分子生物学
- 结构生物学
背景情况:
- 干扰基因刺激器 (STING) 激活的精确机制尚未完全理解.
- STING是先天免疫系统中的一个核心蛋白质,对于检测细胞核DNA和启动抗病毒和抗瘤反应至关重要.
研究的目的:
- 阐明由不同的配体激活STING的结构和生化机制.
- 了解STING突变如何导致过度活化和自身免疫性疾病.
- 探索循环二核酸对STING的差异激活.
主要方法:
- 用X射线结晶学和冷电子显微镜进行结构测定.
- 生物化学试验用于研究蛋白质 - 配体相互作用和聚合.
- 针对位点的突变发生,以调查特定残留物和突变的作用.
主要成果:
- 结合2'3'-cGAMP会诱导STING同质体的关闭,释放C端尾部并暴露聚合接口.
- 在囊148的二硫化键形成对STING的聚合和激活至关重要.
- 与疾病相关的突变聚集在C148或C-终端尾部结合部位周围,导致构成性激活.
- 细菌循环-di-GMP诱导另一个STING构造,合作激活,并部分对抗2'3'-cGAMP信号.
结论:
- 这项研究揭示了STING激活的详细机制,包括联体诱导的形状变化,C端尾部释放和聚合.
- 了解STING激活途径和特定突变的作用为了解自身免疫综合征提供了基础.
- 循环二核酸的差异激活表明复杂的调节机制控制先天免疫反应,并提供治疗途径.
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