Cyclic ADP ribose isomers: Production, chemical structures, and immune signaling

• DOI: 10.1126/science.adc8969
• Publication Date: 2022-09-01T18:00:13Z
• Authors: Mohammad K. Manik; Yun Shi; Sulin Li; Mark A. Zaydman; Neha Damaraju; Samuel Eastman; Thomas G. Smith; Weixi Gu; Veronika Masic; Tamim Mosaiab; James S. Weagley; Steven J. Hancock; Eduardo Vasquez; Lauren Hartley-Ta...; Nestoras Kargios; Natsumi Maruta; Bryan Y. J. Lim; Hayden Burdett; Michael J. Landsberg; Mark A. Schembri; Ivan Prokes; Lijiang Song; Murray Grant; Aaron DiAntonio; Jeffrey D. Nanson; Ming Guo; Jeffrey Milbrandt; Thomas Ve; Bostjan Kobe
• Keywords: Ribose; Cyclic ADP-Ribose

Cyclic adenosine diphosphate (ADP)–ribose (cADPR) isomers are signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via nicotinamide adenine dinucleotide (oxidized form) (NAD + ) hydrolysis. We show that v-cADPR (2′cADPR) v2-cADPR (3′cADPR) cyclized O-glycosidic bond formation between the ribose moieties in ADPR. Structures of 2′cADPR-producing TIR reveal conformational changes lead to an active assembly resembles those Toll-like adaptor domains. Mutagenesis reveals a conserved tryptophan is essential for cyclization. 3′cADPR activator ThsA effector proteins from antiphage defense system termed Thoeris suppressor immunity when HopAM1. Collectively, our results molecular basis cADPR isomer production establish bacteria as antiviral immunity–suppressing molecule.