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Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system

Author

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  • Xiangkai Zhen

    (Fujian Normal University)

  • Xiaolong Xu

    (China Wuhan University)

  • Le Ye

    (Fujian Normal University)

  • Song Xie

    (Fuzhou University)

  • Zhijie Huang

    (Fujian Normal University)

  • Sheng Yang

    (Fujian Normal University)

  • Yanhui Wang

    (China Wuhan University)

  • Jinyu Li

    (Fuzhou University)

  • Feng Long

    (China Wuhan University)

  • Songying Ouyang

    (Fujian Normal University)

Abstract

Argonaute (Ago) proteins are ubiquitous across all kingdoms of life. Eukaryotic Agos (eAgos) use small RNAs to recognize transcripts for RNA silencing in eukaryotes. In contrast, the functions of prokaryotic counterparts (pAgo) are less well known. Recently, short pAgos in conjunction with the associated TIR or Sir2 (SPARTA or SPARSA) were found to serve as antiviral systems to combat phage infections. Herein, we present the cryo-EM structures of nicotinamide adenine dinucleotide (NAD+)-bound SPARSA with and without nucleic acids at resolutions of 3.1 Å and 3.6 Å, respectively. Our results reveal that the APAZ (Analogue of PAZ) domain and the short pAgo form a featured architecture similar to the long pAgo to accommodate nucleic acids. We further identified the key residues for NAD+ binding and elucidated the structural basis for guide RNA and target DNA recognition. Using structural comparisons, molecular dynamics simulations, and biochemical experiments, we proposed a putative mechanism for NAD+ hydrolysis in which an H186 loop mediates nucleophilic attack by catalytic water molecules. Overall, our study provides mechanistic insight into the antiphage role of the SPARSA system.

Suggested Citation

  • Xiangkai Zhen & Xiaolong Xu & Le Ye & Song Xie & Zhijie Huang & Sheng Yang & Yanhui Wang & Jinyu Li & Feng Long & Songying Ouyang, 2024. "Structural basis of antiphage immunity generated by a prokaryotic Argonaute-associated SPARSA system," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44660-7
    DOI: 10.1038/s41467-023-44660-7
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    1. Ning Cui & Jun-Tao Zhang & Zhuolin Li & Xin-Yang Wei & Jie Wang & Ning Jia, 2024. "Tetramerization-dependent activation of the Sir2-associated short prokaryotic Argonaute immune system," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. 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.

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