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

Author

Listed:
  • Haiyan Gao

    (Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University
    Shanghai Jiao Tong 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
    Shanghai Jiao Tong University)

  • Jinsong Duan

    (Tsinghua University)

  • Yue Wei

    (Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University
    the First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital)

  • 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
    the First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital)

  • Geng Wu

    (Shanghai Jiao Tong University)

  • Lianrong Wang

    (Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University)

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.

Suggested Citation

  • Haiyan Gao & Xinqi Gong & Jinchuan Zhou & Yubing Zhang & Jinsong Duan & Yue Wei & Liuqing Chen & Zixin Deng & Jiawei Wang & Shi Chen & Geng Wu & Lianrong Wang, 2022. "Nicking mechanism underlying the DNA phosphorothioate-sensing antiphage defense by SspE," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34505-0
    DOI: 10.1038/s41467-022-34505-0
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    References listed on IDEAS

    as
    1. Xuan Zou & Xiaohong Xiao & Ziran Mo & Yashi Ge & Xing Jiang & Ruolin Huang & Mengxue Li & Zixin Deng & Shi Chen & Lianrong Wang & Sang Yup Lee, 2022. "Systematic strategies for developing phage resistant Escherichia coli strains," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Guang Liu & Wencheng Fu & Zhenyi Zhang & Yao He & Hao Yu & Yuli Wang & Xiaolei Wang & Yi-Lei Zhao & Zixin Deng & Geng Wu & Xinyi He, 2018. "Structural basis for the recognition of sulfur in phosphorothioated DNA," Nature Communications, Nature, vol. 9(1), pages 1-12, December.
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