The structural basis of the activation and inhibition of DSR2 NADase by phage proteins

Ruiwen Wang, Qi Xu, Zhuoxi Wu, Jialu Li, Hao Guo, Tianzhui Liao, Yuan Shi, Ling Yuan, Haishan Gao, Rong Yang (), Zhubing Shi () and Faxiang Li ()
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Ruiwen Wang: Central South University
Qi Xu: Westlake University
Zhuoxi Wu: Central South University
Jialu Li: Westlake University
Hao Guo: Central South University
Tianzhui Liao: Central South University
Yuan Shi: Westlake University
Ling Yuan: Central South University
Haishan Gao: Westlake University
Rong Yang: Hunan Normal University
Zhubing Shi: Westlake University
Faxiang Li: Central South University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract DSR2, a Sir2 domain-containing protein, protects bacteria from phage infection by hydrolyzing NAD+. The enzymatic activity of DSR2 is triggered by the SPR phage tail tube protein (TTP), while suppressed by the SPbeta phage-encoded DSAD1 protein, enabling phages to evade the host defense. However, the molecular mechanisms of activation and inhibition of DSR2 remain elusive. Here, we report the cryo-EM structures of apo DSR2, DSR2-TTP-NAD+ and DSR2-DSAD1 complexes. DSR2 assembles into a head-to-head tetramer mediated by its Sir2 domain. The C-terminal helical regions of DSR2 constitute four partner-binding cavities with opened and closed conformation. Two TTP molecules bind to two of the four C-terminal cavities, inducing conformational change of Sir2 domain to activate DSR2. Furthermore, DSAD1 competes with the activator for binding to the C-terminal cavity of DSR2, effectively suppressing its enzymatic activity. Our results provide the mechanistic insights into the DSR2-mediated anti-phage defense system and DSAD1-dependent phage immune evasion.

Date: 2024
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DOI: 10.1038/s41467-024-50410-0

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