Activation of the bacterial defense-associated sirtuin system

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<sup>+</sup> pocket volume in SIR2, thus activates the NADase activity and leads to cellular NAD<sup>+</sup> depletion.

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Publication Details

Journal
Communications Biology
Published
2025-02-24
DOI
https://doi.org/10.1038/s42003-025-07743-3
Citations
1
Primary Topic
Biochemical and Molecular Research
Type
article
Field-Weighted Citation Impact
0.81
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article

Activation of the bacterial defense-associated sirtuin system

Jie Wang, Xia Yu, Weihe Zhang, Sheng Cui et al.
1 citations
Communications Biology
Biochemical and Molecular Research
0.81
article

Activation of the bacterial defense-associated sirtuin system

Jie Wang, Xia Yu, Weihe Zhang, Sheng Cui, Kun Shang, Linyue Wang, Xiaopan Gao, Kaixiang Zhu, Bo Qin, Hongtao Zhu, Lei Hua
article en
1 citations

Abstract

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<sup>+</sup> pocket volume in SIR2, thus activates the NADase activity and leads to cellular NAD<sup>+</sup> depletion.

Communications BiologyVol. 8(1)
Capital Medical University (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Yanan University Affiliated Hospital (CN), Beijing Chest Hospital (CN), Songshan Lake Materials Laboratory (CN), FZU ‒ Institute of Physics of the Academy of Sciences of the Czech Republic (CZ), Institute of Physics (CN), Center for Life Sciences (CN), National Laboratory for Superconductivity (CN), University of Chinese Academy of Sciences (CN), Tsinghua University (CN)
Openalex Percentile: Top 31%
Biochemical and Molecular Research
0.81
DOIOpen Access PDFOpenAlex
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