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Avs2 drives non-canonical tetrameric assembly of trypsin-like domain for anti-phage defense

Guo, L.; Huang, P.; Liu, W.; Liu, J.; Xu, D.; Yu, S.; Wang, Z.; Zhang, L.; Li, Z.; Cao, X.; Yang, Q.; Cheng, M.; Wu, N.; Lu, M.; Qi, L.-W.; Xiao, Y.; Chen, M.

2026-08-26 microbiology
10.64898/2026.08.25.746987 bioRxiv
Show abstract

Bacteria have evolved diverse anti-phage defense systems, with the antiviral STAND family (Avs) representing one of the most diverse and widespread, encompassing at least 90 distinct families, yet only Avs3, Avs4, Avs5 and Avs7 have been well characterized. Here, we elucidated the molecular mechanism of Avs2-trypsin-MBL system, where phage terminase recognition by Avs2 triggers coupled activation of the protease and nuclease activities of trypsin-MBL. Cryo-EM structure of Avs2-trypsin-terminase and biochemical analysis reveal that the binding of terminase ATPase domain triggers the assembly of Avs2 into tetramer, with two unique ATP molecules bridging ATPase active-site recognition by TPR domain. This tetramerization drives the fused trypsin into an active C4-symmetric assembly, an architecture distinct from the conventional non-defense trypsin. Our study unravels the activation mechanism of Avs2-trypsin-MBL system, expanding our understanding on commonality and diversity of widespread Avs-mediated anti-phage immunity, alongside the structural and functional adaption of trypsin.

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