核酶对cGAS抑制的结构机制
Ganesh R Pathare1,2, Alexiane Decout3, Selene Glück3
1Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
Nature
|September 10, 2020
概括
染色体结合通过将其锁定在单体状态中来抑制循环GMP- AMP合成酶 (cGAS),防止基因组DNA的虚假激活. 这种结构洞察力揭示了cGAS如何区分自我与非自我DNA.
科学领域:
- 免疫学
- 结构生物学
- 分子生物学
背景情况:
- 循环GMP-AMP合成酶 (cGAS) 是一个DNA传感器,对天生的免疫力至关重要,对感染,压力和癌症作出反应.
- 在检测双链DNA时,细胞质cGAS会产生2' 3' cGMP- AMP,从而诱导炎症性细胞因子和I型干扰素.
- 核cGAS活动受到染色素的限制,但这种抑制的结构基础尚不清楚.
研究的目的:
- 阐明人体cGAS的染色质介导抑制的结构基础.
- 了解cGAS区分自我 (基因组) 和非自我DNA的机制.
主要方法:
- 电子显微镜测定与核细胞结合的人体cGAS的结构.
- 生物化学分析以调查cGAS与核素相互作用.
- 使用突变cGAS进行基于细胞的测试以评估功能后果.
主要成果:
- 该结构显示了cGAS,基因组H2A-H2B酸性补丁和核细胞DNA之间的广泛接触.
- cGAS与第二个核体结合,采用单体状态,以阻碍激活.
- 在cGAS- 酸性补丁接口的突变消除了体外核酶抑制,并允许细胞中的基因组DNA激活cGAS.
结论:
- 这项研究揭示了cGAS与色素相互作用的结构基础.
- 核酶结合将cGAS锁定为不活跃的单体,防止基因组DNA的虚假激活.
- 这种机制使cGAS能够区分自我与非自我DNA,这对于免疫监测至关重要.
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