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Cryo-EM structure of human DNA-PK holoenzyme 期刊论文

编号：

47600587-0062-4d2b-86fc-6ace8fa3f049
作者：

Yin, Xiaotong^[1,2,3];Liu, Mengjie^[1,2,3];Tian, Yuan^[1,2,3];Wang, Jiawei^[4];Xu, Yanhui(徐彦辉)*^[1,2,3,5]
语种：

English
期刊：

CELL RESEARCH ISSN：1001-0602 2017 年 27 卷 11 期 (1341 - 1350) ; NOV
收录：
关键词：

Cryo-EM structure DNA-PK DNA-PKcs activation NHEJ
摘要：

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase complex composed of a catalytic subunit (DNA-PKcs) and KU70/80 heterodimer bound to DNA. DNA-PK holoenzyme plays a critical role in non-homologous end joining (NHEJ), the major DNA repair pathway. Here, we determined cryo-electron microscopy structure of human DNA-PK holoenzyme at 6.6 angstrom resolution. In the complex structure, DNA-PKcs, KU70, KU80 and DNA duplex form a 650-kDa heterotetramer with 1:1:1:1 stoichiometry. The N-terminal a-solenoid (similar to 2 800 residues) of DNA-PKcs adopts a double-ring fold and connects the catalytic core domain of DNA-PKcs and KU70/80-DNA. DNA-PKcs and KU70/80 together form a DNA-binding tunnel, which cradles similar to 30-bp DNA and prevents sliding inward of DNA-PKcs along with DNA duplex, suggesting a mechanism by which the broken DNA end is protected from unnecessary processing. Structural and biochemical analyses indicate that KU70/80 and DNA coordinately induce conformational changes of DNA-PKcs and allosterically stimulate its kinase activity. We propose a model for activation of DNA-PKcs in which allosteric signals are generated upon DNA-PK holoenzyme formation and transmitted to the kinase domain through N-terminal HEAT repeats and FAT domain of DNA-PKcs. Our studies suggest a mechanism for recognition and protection of broken DNA ends and provide a structural basis for understanding the activation of DNA-PKcs and DNA-PK-mediated NHEJ pathway.
推荐引用方式
GB/T 7714：

Yin Xiaotong,Liu Mengjie,Tian Yuan, et al. Cryo-EM structure of human DNA-PK holoenzyme [J].CELL RESEARCH,2017,27(11):1341-1350.
APA：

Yin Xiaotong,Liu Mengjie,Tian Yuan,Wang Jiawei,&Xu Yanhui.(2017).Cryo-EM structure of human DNA-PK holoenzyme .CELL RESEARCH,27(11):1341-1350.
MLA：

Yin Xiaotong, et al. "Cryo-EM structure of human DNA-PK holoenzyme" .CELL RESEARCH 27,11(2017):1341-1350.

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