循环[G(2',5') pA(3',5') p]是由DNA激活的循环GMP-AMP合成酶产生的甲基动物的第二信使
Pu Gao1, Manuel Ascano, Yang Wu
1Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Cell
|May 8, 2013
概括
循环GMP-AMP (cGAMP) 是一种由cGAMP合成酶 (cGAS) 合成的甲基动物的第二信使. 这项研究揭示了cGAMP.
科学领域:
- 分子生物学分子生物学
- 免疫学 免疫学 免疫学
- 生物化学 生物化学
背景情况:
- 循环GMP-AMP (cGAMP) 作为metazoans中的第二信使,启动干扰素反应.
- cGAMP是由细胞质dDNA传感器,cGAMP合成酶 (cGAS) 从GTP和ATP产生.
研究的目的:
- 阐明甲状动物第二信使cGAMP的精确化学结构和合成机制.
- 研究cGAS激活和核酸结合的结构和催化机制.
- 与细菌的3',5'-结合类同类相比,表征metazoan 2',5'-结合的循环二核酸的独特性质.
主要方法:
- 结构生物学 (X射线结晶学,冷EM)
- 化学合成和化学分析
- 生物化学试验 (酶动力学,结合性研究)
- 细胞检测 (干扰素反应,免疫信号)
主要成果:
- 甲基动物的第二信使被确定为G(2',5') pA和A(3',5') p的基结,称为c[G(2',5') pA(3',5') p].
- 在dsDNA结合时,cGAS经历了结构变化,为cGAMP合成创造了一个活性核酸结合口袋.
- 循环发生阶段性,在最终c[G]产物之前形成5'-pppG(2',5') pA.
- 在cGAS dsDNA结合或催化部位的突变损害了它的活性.
- c[G(2',5')pA(3',5')p]代表了一种新型类型的2',5'-链接循环异种核酸第二信使在metazoans.
结论:
- 该研究定义了cGAMP的结构及其通过cGAS的合成途径.
- cGAMP是一种独特的甲基动物的第二信使,与细菌的循环二核化物不同.
- 这项工作确立了c[G(2',5') pA(3',5') p]作为循环二核酸第二信使的新家族的第一个成员.
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