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

Manik, M. K.; Shi, Y.; Li, S.; Zaydman, M. A.; Damaraju, N.; Eastman, S.; Smith, T.; Gu, W.; Masic, V.; Mosaiab, T.; Weagley, J. S.; Hancock, S. J.; Vasquez, E.; Hartley-Tassell, L.; Maruta, N.; Lim, B. Y.; Burdett, H.; Lansdberg, M. J.; Schembri, M. A.; Prokes, I.; Song, L.; Grant, M.; DiAntonio, A.; Nanson, J. D.; Guo, M.; Milbrandt, J.; Ve, T.; Kobe, B.

doi:10.1101/2022.05.07.491051

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bioRxiv · 10.1101/2022.05.07.491051

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

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Abstract

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.

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Manik, M. K., Shi, Y., Li, S., Zaydman, M. A., Damaraju, N., Eastman, S., Smith, T., Gu, W., Masic, V., Mosaiab, T., Weagley, J. S., Hancock, S. J., Vasquez, E., Hartley-Tassell, L., Maruta, N., Lim, B. Y., Burdett, H., Lansdberg, M. J., Schembri, M. A., Prokes, I., Song, L., Grant, M., DiAntonio, A., Nanson, J. D., Guo, M., Milbrandt, J., Ve, T., Kobe, B.. 2022-05-08. Chemical structures of cyclic ADP ribose (cADPR) isomers and the molecular basis of their production and signaling. https://doi.org/10.1101/2022.05.07.491051

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