Structural basis for phage-mediated activation and repression of bacterial DSR2 anti-phage defense system

Jun-Tao Zhang, Xiao-Yu Liu, Zhuolin Li, Xin-Yang Wei, Xin-Yi Song, Ning Cui, Jirui Zhong, Hongchun Li and Ning Jia ()
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Jun-Tao Zhang: Southern University of Science and Technology
Xiao-Yu Liu: Southern University of Science and Technology
Zhuolin Li: Southern University of Science and Technology
Xin-Yang Wei: Southern University of Science and Technology
Xin-Yi Song: Southern University of Science and Technology
Ning Cui: Southern University of Science and Technology
Jirui Zhong: Chinese Academy of Sciences
Hongchun Li: Chinese Academy of Sciences
Ning Jia: Southern University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Silent information regulator 2 (Sir2) proteins typically catalyze NAD+-dependent protein deacetylation. The recently identified bacterial Sir2 domain-containing protein, defense-associated sirtuin 2 (DSR2), recognizes the phage tail tube and depletes NAD+ to abort phage propagation, which is counteracted by the phage-encoded DSR anti-defense 1 (DSAD1), but their molecular mechanisms remain unclear. Here, we determine cryo-EM structures of inactive DSR2 in its apo form, DSR2–DSAD1 and DSR2–DSAD1–NAD+, as well as active DSR2–tube and DSR2–tube–NAD+ complexes. DSR2 forms a tetramer with its C-terminal sensor domains (CTDs) in two distinct conformations: CTDclosed or CTDopen. Monomeric, rather than oligomeric, tail tube proteins preferentially bind to CTDclosed and activate Sir2 for NAD+ hydrolysis. DSAD1 binding to CTDopen allosterically inhibits tube binding and tube-mediated DSR2 activation. Our findings provide mechanistic insight into DSR2 assembly, tube-mediated DSR2 activation, and DSAD1-mediated inhibition and NAD+ substrate catalysis in bacterial DSR2 anti-phage defense systems.

Date: 2024
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DOI: 10.1038/s41467-024-47177-9

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