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

Xiangkai Zhen, Xiaolong Xu, Le Ye, Song Xie, Zhijie Huang, Sheng Yang, Yanhui Wang, Jinyu Li (), Feng Long () and Songying Ouyang ()
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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

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44660-7

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