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<p>The NADase activity of the defense-associated sirtuins (DSRs) is activated by the phage tail tube protein (TTP). Herein, we report cryo-EM structures of a free-state <i>Bacillus subtilis</i> DSR2 tetramer and a fragment of the tetramer, a phage SPR tail tube, and two DSR2-TTP complexes. DSR2 contains an N-terminal SIR2 domain, a middle domain (MID) and a C-terminal domain (CTD). The DSR2 CTD harbors the α-solenoid tandem-repeats like the HEAT-repeat proteins. DSR2 assembles into a tetramer with four SIR2 clustered at the center, and two intertwined MID-CTD chains flank the SIR2 core. SPR TTPs self-assemble into a tube-like complex. Upon DSR2 binding, the D1 domain of SPR TTP is captured between the HEAT-repeats domains of DSR2, which conflicts with TTPs self-assembly. Binding of TTPs induces conformational changes in DSR2 tetramer, resulting in increase of the NAD<sup>+</sup> pocket volume in SIR2, thus activates the NADase activity and leads to cellular NAD<sup>+</sup> depletion.</p>

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Activation of the bacterial defense-associated sirtuin system

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月24日

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  • Kaixiang Zhu,
  • Kun Shang,
  • Linyue Wang,
  • Xia Yu,
  • Lei Hua,
  • Weihe Zhang,
  • Bo Qin,
  • Jia Wang,
  • Xiaopan Gao,
  • Hongtao Zhu,
  • Sheng Cui

摘要

The NADase activity of the defense-associated sirtuins (DSRs) is activated by the phage tail tube protein (TTP). Herein, we report cryo-EM structures of a free-state Bacillus subtilis DSR2 tetramer and a fragment of the tetramer, a phage SPR tail tube, and two DSR2-TTP complexes. DSR2 contains an N-terminal SIR2 domain, a middle domain (MID) and a C-terminal domain (CTD). The DSR2 CTD harbors the α-solenoid tandem-repeats like the HEAT-repeat proteins. DSR2 assembles into a tetramer with four SIR2 clustered at the center, and two intertwined MID-CTD chains flank the SIR2 core. SPR TTPs self-assemble into a tube-like complex. Upon DSR2 binding, the D1 domain of SPR TTP is captured between the HEAT-repeats domains of DSR2, which conflicts with TTPs self-assembly. Binding of TTPs induces conformational changes in DSR2 tetramer, resulting in increase of the NAD+ pocket volume in SIR2, thus activates the NADase activity and leads to cellular NAD+ depletion.