7T28

Structure of phage Bsp38 anti-Pycsar nuclease Apyc1 in apo state

Summary for 7T28

• Entry DOI: 10.2210/pdb7t28/pdb
• Descriptor: Putative metal-dependent hydrolase, ZINC ION (3 entities in total)
• Functional Keywords: anti-pycsar, nuclease, immune evasion, viral protein
• Biological source: Bacillus phage BSP38
• Total number of polymer chains: 1
• Total formula weight: 29300.55

Authors

Hobbs, S.J.,Wein, T.,Lu, A.,Morehouse, B.R.,Schnabel, J.,Sorek, R.,Kranzusch, P.J. (deposition date: 2021-12-03, release date: 2022-04-20, Last modification date: 2024-04-03)

Primary citation

Hobbs, S.J.,Wein, T.,Lu, A.,Morehouse, B.R.,Schnabel, J.,Leavitt, A.,Yirmiya, E.,Sorek, R.,Kranzusch, P.J.
Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity.
Nature, 605:522-526, 2022

PubMed Abstract: The cyclic oligonucleotide-based antiphage signalling system (CBASS) and the pyrimidine cyclase system for antiphage resistance (Pycsar) are antiphage defence systems in diverse bacteria that use cyclic nucleotide signals to induce cell death and prevent viral propagation. Phages use several strategies to defeat host CRISPR and restriction-modification systems, but no mechanisms are known to evade CBASS and Pycsar immunity. Here we show that phages encode anti-CBASS (Acb) and anti-Pycsar (Apyc) proteins that counteract defence by specifically degrading cyclic nucleotide signals that activate host immunity. Using a biochemical screen of 57 phages in Escherichia coli and Bacillus subtilis, we discover Acb1 from phage T4 and Apyc1 from phage SBSphiJ as founding members of distinct families of immune evasion proteins. Crystal structures of Acb1 in complex with 3'3'-cyclic GMP-AMP define a mechanism of metal-independent hydrolysis 3' of adenosine bases, enabling broad recognition and degradation of cyclic dinucleotide and trinucleotide CBASS signals. Structures of Apyc1 reveal a metal-dependent cyclic NMP phosphodiesterase that uses relaxed specificity to target Pycsar cyclic pyrimidine mononucleotide signals. We show that Acb1 and Apyc1 block downstream effector activation and protect from CBASS and Pycsar defence in vivo. Active Acb1 and Apyc1 enzymes are conserved in phylogenetically diverse phages, demonstrating that cleavage of host cyclic nucleotide signals is a key strategy of immune evasion in phage biology.

PubMed: 35395152
DOI: 10.1038/s41586-022-04716-y

Experimental method

X-RAY DIFFRACTION (2.68 Å)