Nicking mechanism underlying the DNA phosphorothioate-sensing antiphage defense by SspE

Haiyan Gao, Xinqi Gong, Jinchuan Zhou, Yubing Zhang, Jinsong Duan, Yue Wei, Liuqing Chen, Zixin Deng, Jiawei Wang, Shi Chen (), Geng Wu () and Lianrong Wang ()
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Haiyan Gao: Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University
Xinqi Gong: Renmin University of China
Jinchuan Zhou: Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University
Yubing Zhang: Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University
Jinsong Duan: Tsinghua University
Yue Wei: Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University
Liuqing Chen: Shanghai Jiao Tong University
Zixin Deng: Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University
Jiawei Wang: Tsinghua University
Shi Chen: Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University
Geng Wu: Shanghai Jiao Tong University
Lianrong Wang: Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract DNA phosphorothioate (PT) modification, with a nonbridging phosphate oxygen substituted by sulfur, represents a widespread epigenetic marker in prokaryotes and provides protection against genetic parasites. In the PT-based defense system Ssp, SspABCD confers a single-stranded PT modification of host DNA in the 5′-CPSCA-3′ motif and SspE impedes phage propagation. SspE relies on PT modification in host DNA to exert antiphage activity. Here, structural and biochemical analyses reveal that SspE is preferentially recruited to PT sites mediated by the joint action of its N-terminal domain (NTD) hydrophobic cavity and C-terminal domain (CTD) DNA binding region. PT recognition enlarges the GTP-binding pocket, thereby increasing GTP hydrolysis activity, which subsequently triggers a conformational switch of SspE from a closed to an open state. The closed-to-open transition promotes the dissociation of SspE from self PT-DNA and turns on the DNA nicking nuclease activity of CTD, enabling SspE to accomplish self-nonself discrimination and limit phage predation, even when only a small fraction of modifiable consensus sequences is PT-protected in a bacterial genome.

Date: 2022
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DOI: 10.1038/s41467-022-34505-0

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