Journal Article

PUBDB-2024-01566

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Activation of Thoeris antiviral system via SIR2 effector filament assembly

Tamulaitiene, G. (Corresponding author) ; Sabonis, D. ; Sasnauskas, G. ; Ruksenaite, A. ; Silanskas, A. ; Avraham, C. ; Ofir, G. ; Sorek, R. ; Zaremba, M. (Corresponding author) ; Siksnys, V. (Corresponding author)

2024
Nature Publ. Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41586-024-07092-x

Abstract: To survive bacteriophage (phage) infections, bacteria developed numerous anti-phage defence systems1,2,3,4,5,6,7. Some of them (for example, type III CRISPR–Cas, CBASS, Pycsar and Thoeris) consist of two modules: a sensor responsible for infection recognition and an effector that stops viral replication by destroying key cellular components8,9,10,11,12. In the Thoeris system, a Toll/interleukin-1 receptor (TIR)-domain protein, ThsB, acts as a sensor that synthesizes an isomer of cyclic ADP ribose, 1′′−3′ glycocyclic ADP ribose (gcADPR), which is bound in the Smf/DprA-LOG (SLOG) domain of the ThsA effector and activates the silent information regulator 2 (SIR2)-domain-mediated hydrolysis of a key cell metabolite, NAD+ (refs. 12,13,14). Although the structure of ThsA has been solved15, the ThsA activation mechanism remained incompletely understood. Here we show that 1′′−3′ gcADPR, synthesized in vitro by the dimeric ThsB′ protein, binds to the ThsA SLOG domain, thereby activating ThsA by triggering helical filament assembly of ThsA tetramers. The cryogenic electron microscopy (cryo-EM) structure of activated ThsA revealed that filament assembly stabilizes the active conformation of the ThsA SIR2 domain, enabling rapid NAD+ depletion. Furthermore, we demonstrate that filament formation enables a switch-like response of ThsA to the 1′′−3′ gcADPR signal.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. iNEXT-Discovery - Infrastructure for transnational access and discovery in structural biology (871037) (871037)

Experiment(s):

1. PETRA Beamline P14 (PETRA III)

Appears in the scientific report 2024

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