Biology subjects

Mosaiab, T.

Publications and source records attributed to Mosaiab, T..

2 recordsLinked to original sources

bioRxiv2026

Filament formation is a conserved mechanism of Thoeris SIR2 effector activation

Thoeris defence systems protect bacteria from phages via abortive infection. In type I Thoeris systems, ThsA effectors containing silent information regulator 2 (SIR2) and SMF/DprA-LOG (SLOG) domains are activated by the cyclic ADP-ribose (ADPR) isomer 3'cADPR, triggering abortive infection via nicotinamide adenine dinucleotide (NAD+) depletion. 3'cADPR activates the NADase activity of Bacillus subtilis ThsA tetramers via filament formation of its SIR2 domains, but the molecular details of how 3'cADPR triggers this process remain incompletely understood. Here, we demonstrate that ThsA activation by 3'cADPR-induced SIR2 filament formation is conserved in type I Thoeris systems from Streptococcus equi and Entercoccus facium. We present cryo-electron microscopy structures of the S. equi ThsA filament bound to 3'cADPR and the non-cleavable NAD+ analog carba-NAD+, and of the S. equi ThsA tetramer bound to 3'cADPR. These structures reveal that SIR2 filament formation is required to stabilise an active site conformation that can bind and hydrolyse NAD+. The structures also show that 3'cADPR induces quaternary alterations in the SLOG dimers and consequently the SIR2 tetramer to enable ThsA filament formation. Collectively, our study provides a comprehensive understanding of 3'cADPR-induced activation of type I Thoeris effectors.

microbiology↗

bioRxiv2022

Chemical structures of cyclic ADP ribose (cADPR) isomers and the molecular basis of their production and signaling

Cyclic ADP ribose (cADPR) isomers are important signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via NAD+ hydrolysis, yet their chemical structures are unknown. We show that v-cADPR (2cADPR) and v2-cADPR (3cADPR) isomers are cyclized by O-glycosidic bond formation between the ribose moieties in ADPR. Structures of v-cADPR (2cADPR)-producing TIR domains reveal that conformational changes are required for the formation of the active assembly that resembles those of Toll-like receptor adaptor TIR domains, and mutagenesis data demonstrate that a conserved tryptophan is essential for cyclization. We show that v2-cADPR (3cADPR) is a potent activator of ThsA effector proteins from Thoeris anti-phage defence systems and is responsible for suppression of plant immunity by the effector HopAM1. Collectively, our results define new enzymatic activities of TIR domains, reveal the molecular basis of cADPR isomer production, and establish v2-cADPR (3cADPR) as an antiviral signaling molecule and an effector-mediated signaling molecule for plant immunity suppression. One-Sentence SummaryThe chemical structures of two O-glycosidic bond-containing cyclic ADP ribose isomers, the molecular basis of their production, and their function in antiviral and plant immunity suppression by bacteria are reported.

biochemistry↗