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Mechanistic basis for the allosteric activation of NADase activity in the Sir2-HerA antiphage defense system

Author

Listed:
  • Xiangkai Zhen

    (Fujian Normal University)

  • Biao Zhou

    (Guangzhou Medical University
    Chinese Academy of Sciences
    Guangzhou National Laboratory)

  • Zihe Liu

    (Fujian Normal University)

  • Xurong Wang

    (Fujian Normal University)

  • Heyu Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Shuxian Wu

    (Fujian Normal University)

  • Zekai Li

    (Fujian Normal University)

  • Jiamin liang

    (Fujian Normal University)

  • Wanyue Zhang

    (Fujian Normal University)

  • Qingjian Zhu

    (Fujian Normal University)

  • Jun He

    (Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Xiaoli Xiong

    (Chinese Academy of Sciences)

  • Songying Ouyang

    (Fujian Normal University)

Abstract

Sir2-HerA is a widely distributed antiphage system composed of a RecA-like ATPase (HerA) and an effector with potential NADase activity (Sir2). Sir2-HerA is believed to provide defense against phage infection in Sir2-dependent NAD+ depletion to arrest the growth of infected cells. However, the detailed mechanism underlying its antiphage activity remains largely unknown. Here, we report functional investigations of Sir2-HerA from Staphylococcus aureus (SaSir2-HerA), unveiling that the NADase function of SaSir2 can be allosterically activated by the binding of SaHerA, which then assembles into a supramolecular complex with NADase activity. By combining the cryo-EM structure of SaSir2-HerA in complex with the NAD+ cleavage product, it is surprisingly observed that Sir2 protomers that interact with HerA are in the activated state, which is due to the opening of the α15-helix covering the active site, allowing NAD+ to access the catalytic pocket for hydrolysis. In brief, our study provides a comprehensive view of an allosteric activation mechanism for Sir2 NADase activity in the Sir2-HerA immune system.

Suggested Citation

  • Xiangkai Zhen & Biao Zhou & Zihe Liu & Xurong Wang & Heyu Zhao & Shuxian Wu & Zekai Li & Jiamin liang & Wanyue Zhang & Qingjian Zhu & Jun He & Xiaoli Xiong & Songying Ouyang, 2024. "Mechanistic basis for the allosteric activation of NADase activity in the Sir2-HerA antiphage defense system," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53614-6
    DOI: 10.1038/s41467-024-53614-6
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