活性NLRP3炎症盘的冷EM结构
Le Xiao1,2, Venkat Giri Magupalli1,2, Hao Wu3,4
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Nature
|November 28, 2022
概括
对于炎症至关重要的NLRP3炎症酶形成了一个活跃的盘结构. Cryo-EM揭示了NEK7结合如何触发这种转化,激活caspase-1进行免疫反应.
科学领域:
- 天生的免疫力
- 分子生物学
- 结构生物学
背景情况:
- 在检测危险信号时激活caspase-1的细胞复合体.
- 含有NACHT,LRR和PYD的蛋白3 (NLRP3) 炎症酶感知膜损伤并驱动炎症.
- 了解NLRP3激活机制对于控制炎症疾病至关重要.
研究的目的:
- 确定NLRP3炎症组合的结构基础.
- 阐明NEK7在NLRP3激活中的作用.
- 为了可视化NLRP3与ASC和caspase-1的相互作用.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来获得高分辨率结构.
- 分析了NLRP3与腺5'-O-3-三酸盐,NEK7和ASC的复合物.
- 进行了突变性研究,以评估已确定的相互作用的功能重要性.
主要成果:
- 化EM检测发现与ATP和NEK7结合的盘状活性NLRP3寡合体.
- NACHT域采用一个活跃的构造,由NACHT相关的域稳定.
- N-终端PYD形成一个吸收ASC的丝,而NEK7则打破了不活跃的NLRP3结构.
结论:
- 通过NEK7介导的形状变化揭示NLRP3炎症酶激活的机制.
- 有序的NACHT关联域和PYD线程对于主动的磁盘形成和信号发送至关重要.
- 这项研究提供了NEK7如何将非活跃的NLRP3转化为炎症信号平台的分子理解.
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