Structures and activation mechanism of the Gabija anti-phage system

• 成果类型: Article
• 署名作者: Li, Jing; Cheng, Rui; Wang, Zhiming; Yuan, Wuliu; Xiao, Jun; Zhao, Xinyuan; Du, Xinran; Xia, Shiyu; Wang, Lianrong; Zhu, Bin; Wang, Longfei
• 署名单位: Wuhan University; Wuhan University; Wuhan University; Wuhan University; Wuhan University; Huazhong University of Science & Technology; Wuhan University; California Institute of Technology; Wuhan University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4426
• DOI: 10.1038/s41586-024-07270-x
• 发表日期: 2024-05-09
• 关键词: old family nucleases; toprim domain; arms-race; dna; bacteriophages; topoisomerases; enumeration; resistance; proteins; bacteria

摘要

Prokaryotes have evolved intricate innate immune systems against phage infection1-7. Gabija is a highly widespread prokaryotic defence system that consists of two components, GajA and GajB8. GajA functions as a DNA endonuclease that is inactive in the presence of ATP9. Here, to explore how the Gabija system is activated for anti-phage defence, we report its cryo-electron microscopy structures in five states, including apo GajA, GajA in complex with DNA, GajA bound by ATP, apo GajA-GajB, and GajA-GajB in complex with ATP and Mg2+. GajA is a rhombus-shaped tetramer with its ATPase domain clustered at the centre and the topoisomerase-primase (Toprim) domain located peripherally. ATP binding at the ATPase domain stabilizes the insertion region within the ATPase domain, keeping the Toprim domain in a closed state. Upon ATP depletion by phages, the Toprim domain opens to bind and cleave the DNA substrate. GajB, which docks on GajA, is activated by the cleaved DNA, ultimately leading to prokaryotic cell death. Our study presents a mechanistic landscape of Gabija activation. Structures of complexes containing GajA and GajB proteins of the prokaryotic Gabija anti-phage defence system reveal the mechanism of its activation after DNA cleavage upon ATP depletion.