STING与TBK1结合和酸化的结构基础
Conggang Zhang1, Guijun Shang2, Xiang Gui1
1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|March 8, 2019
概括
细胞质DNA可以触发cGAS-STING通路. 这项研究揭示了cGAMP结合的STING如何激活TBK1激酶,这需要蛋白质寡合化来实现STING酸化和免疫反应.
科学领域:
- 免疫学
- 分子生物学
- 结构生物学
背景情况:
- 通过cGAS-STING通路激活宿主免疫.
- 循环GMP- AMP合成酶 (cGAS) 感知DNA,产生循环GMP- AMP (cGAMP) 来激活干扰素基因 (STING).
- 激活的STING会招募并激活TBK1激酶,从而导致IRF3酸化和I型干扰素诱导,但激活机制尚不清楚.
研究的目的:
- 阐明cGAMP结合的STING激活TBK1激酶的结构机制.
- 了解STING如何被TBK1化以启动下游免疫信号.
主要方法:
- 用冷电子显微镜 (cryo-EM) 确定与cGAMP结合的STING复合的人类TBK1的结构.
- 用于验证拟议的相互作用模型的突变分析.
主要成果:
- 化EM结构显示STING的C端尾插入TBK1二分体中的槽.
- 这种结合模式阻止了TBK1活性位点对STING的直接酸化,这表明需要寡合化.
- 突变数据支持cGAMP诱导STING和TBK1的寡合化,从而促进STING的酸化.
结论:
- 通过cGAMP结合诱导的TBK1的STING酸化取决于这两种蛋白质的寡合化.
- 这种结构洞察力澄清了cGAS-STING先天免疫信号通路的关键步骤.
- 这些发现为了解DNA触发的免疫激活提供了机制基础.
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