Structures and activation mechanism of the Gabija anti-phage system

Jing Li; Rui Cheng; Zhiming Wang; Wuliu Yuan; Jun Xiao; Xinyuan Zhao; Xinran Du; Shiyu Xia; Lianrong Wang; Bin Zhu; Longfei Wang

doi:10.1038/s41586-024-07270-x

Structures and activation mechanism of the Gabija anti-phage system

Nature. 2024 Mar 12. doi: 10.1038/s41586-024-07270-x. Online ahead of print.

Authors

Jing Li^#^{1

2

3

4}, Rui Cheng^#⁵, Zhiming Wang^#^{1

2

3

4}, Wuliu Yuan^{1

2

3

4}, Jun Xiao^{1

2

3

4}, Xinyuan Zhao⁵, Xinran Du⁶, Shiyu Xia⁷, Lianrong Wang^{3

4

8}, Bin Zhu⁹, Longfei Wang^{10

11

12

13}

Affiliations

¹ Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
² Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, China.
³ Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
⁴ Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
⁵ Key Laboratory of Molecular Biophysics, the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
⁶ School of Electronic Information, Wuhan University, Wuhan, China.
⁷ Divison of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
⁸ Department of Gastroenterology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China.
⁹ Key Laboratory of Molecular Biophysics, the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China. bin_zhu@hust.edu.cn.
¹⁰ Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, China. wanglf@whu.edu.cn.
¹¹ Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, China. wanglf@whu.edu.cn.
¹² Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. wanglf@whu.edu.cn.
¹³ Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan, China. wanglf@whu.edu.cn.

^# Contributed equally.

PMID: 38471529
DOI: 10.1038/s41586-024-07270-x

Abstract

Prokaryotes have evolved intricate innate immune systems against phage infection^1-7. 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.