8BTP

Helical structure of BcThsA in complex with 1''-3'gc(etheno)ADPR

Summary for 8BTP

• Entry DOI: 10.2210/pdb8btp/pdb
• Related: 8BTN 8BTO
• EMDB information: 16233 16234
• Descriptor: NAD(+) hydrolase ThsA, (1S,3S,4R,5R,7R,15R,16S,17R)-5-imidazo[2,1-f]purin-3-yl-10,12-bis(oxidanyl)-10,12-bis(oxidanylidene)-2,6,9,11,13,18-hexaoxa-10$l^{5},12$l^{5}-diphosphatricyclo[13.2.1.0^{3,7}]octadecane-4,16,17-triol, ETHENO-NAD (3 entities in total)
• Functional Keywords: thoeris, sir2 domain, slog domain, 3'cadpr, hydrolase
• Biological source: Bacillus cereus MSX-D12
• Total number of polymer chains: 12
• Total formula weight: 680046.18

Authors

Tamulaitiene, G.,Sasnauskas, G.,Sabonis, D. (deposition date: 2022-11-29, release date: 2024-02-21, Last modification date: 2024-04-03)

Primary citation

Tamulaitiene, G.,Sabonis, D.,Sasnauskas, G.,Ruksenaite, A.,Silanskas, A.,Avraham, C.,Ofir, G.,Sorek, R.,Zaremba, M.,Siksnys, V.
Activation of Thoeris antiviral system via SIR2 effector filament assembly.
Nature, 627:431-436, 2024

PubMed Abstract: To survive bacteriophage (phage) infections, bacteria developed numerous anti-phage defence systems. 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 components. 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. ). Although the structure of ThsA has been solved, 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.

PubMed: 38383786
DOI: 10.1038/s41586-024-07092-x

Experimental method

ELECTRON MICROSCOPY (2.75 Å)