Type II Toxin-Antitoxin Loci: The fic Family

  • Arnaud Goepfert
  • Alexander Harms
  • Tilman Schirmer
  • Christoph DehioEmail author


FIC domain containing proteins (Fic proteins) are present in all domains of life but particularly widespread among prokaryotes. FIC domains with a fully conserved HxFx[D/E]GNGRxxR active site motif catalyze adenylylation (also known as AMPylation), the transfer of an adenosine 5′-monophosphate moiety onto target proteins. Adenylylation activity is tightly controlled by an inhibitory α-helix (α inh) that can either be part of the Fic protein (intramolecular inhibition) or encoded on a different polypeptide chain (intermolecular inhibition), the latter constituting a novel class of type II toxin-antitoxin (TA) modules represented by VbhT-VbhA of Bartonella schoenbuchensis and FicT-FicA of Escherichia coli. The helix α inh harbors a [S/T]xxxE[G/N] motif with the conserved glutamate partially obstructing the ATP-binding site and forcing ATP to bind in a catalytically incompetent conformation. Release of inhibition by removal of the antitoxin component or by mutation of the conserved glutamate in α inh converts Fic proteins into toxins that severely impair bacterial growth.


Xanthomonas Campestris Active Site Motif Secretion Effector Protein Active Site Location Intermolecular Salt Bridge 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Arbing, M.A., et al. (2010). Crystal structures of Phd-Doc, HigA, and YeeU establish multiple evolutionary links between microbial growth-regulating toxin-antitoxin systems. Structure 18, 8, 996–1010.Google Scholar
  2. Das, D. (2009). Crystal structure of the Fic (Filamentation induced by cAMP) family protein SO4266 (gi|24375750) from Shewanella oneidensis MR-1 at 1.6 A resolution. Proteins, 75(1), 264–271.PubMedCrossRefGoogle Scholar
  3. Desveaux, D., Singer, A. U., Wu, A. J., McNulty, B. C., Musselwhite, L., Nimchuk, Z., et al. (2007). Type III effector activation via nucleotide binding, phosphorylation, and host target interaction. PLoS Pathogens, 3(3), e48.PubMedCrossRefGoogle Scholar
  4. Engel, P., Goepfert, A., Stanger, F. V., Harms, A., Schmidt, A., Schirmer, T., et al. (2012). Adenylylation control by intra- or intermolecular active-site obstruction in Fic proteins. Nature, 482(7383), 107–110.PubMedCrossRefGoogle Scholar
  5. Feng, F., Yang, F., Rong, W., Wu, X., Zhang, J., Chen, S., et al. (2012). A Xanthomonas uridine 5′-monophosphate transferase inhibits plant immune kinases. Nature, 485(7396), 114–118.PubMedCrossRefGoogle Scholar
  6. Hu, P., et al. (2009). Global functional atlas of Escherichia coli encompassing previously uncharacterized proteins. PLoS Biology, 7(4), e96.PubMedCrossRefGoogle Scholar
  7. Kawamukai, M., Matsuda, H., Fujii, W., Nishida, T., Izumoto, Y., Himeno, M., et al. (1988). Cloning of the fic-1 gene involved in cell filamentation induced by cyclic AMP and construction of a Δfic Escherichia coli strain. Journal of Bacteriology, 170(9), 3864–3869.PubMedGoogle Scholar
  8. Kawamukai, M., Matsuda, H., Fujii, W., Utsumi, R., & Komano, T. (1989). Nucleotide sequences of fic and fic-1 genes involved in cell filamentation induced by cyclic AMP in Escherichia coli. Journal of Bacteriology, 171(8), 4525–4529.PubMedGoogle Scholar
  9. Kinch, L. N., Yarbrough, M. L., Orth, K., & Grishin, N. V. (2009). Fido, a novel AMPylation domain common to fic, doc, and AvrB. PloS one, 4(6), e5818.PubMedCrossRefGoogle Scholar
  10. Lehnherr, H., Maguin, E., Jafri, S., & Yarmolinsky, M. B. (1993). Plasmid addiction genes of bacteriophage P1: Doc, which causes cell death on curing of prophage, and phd, which prevents host death when prophage is retained. Journal of Molecular Biology, 233(3), 414–428.PubMedCrossRefGoogle Scholar
  11. Liu, M., Zhang, Y., Inouye, M., & Woychik, N. A. (2008). Bacterial addiction module toxin Doc inhibits translation elongation through its association with the 30S ribosomal subunit. Proceedings of the National academy of Sciences of the United States of America, 105(15), 5885–5890.PubMedCrossRefGoogle Scholar
  12. Luong, P., Kinch, L. N., Brautigam, C. A., Grishin, N. V., Tomchick, D. R., & Orth, K. (2010). Kinetic and structural insights into the mechanism of AMPylation by VopS Fic domain. The Journal of Biological Chemistry, 285(26), 20155–20163.PubMedCrossRefGoogle Scholar
  13. Magnuson, R., & Yarmolinsky, M. B. (1998). Corepression of the P1 addiction operon by Phd and Doc. Journal of Bacteriology, 180(23), 6342–6351.PubMedGoogle Scholar
  14. Makarova, K. S., Wolf, Y. I., & Koonin, E. V. (2009). Comprehensive comparative-genomic analysis of type 2 toxin-antitoxin systems and related mobile stress response systems in prokaryotes. Biology Direct, 4, 19.PubMedCrossRefGoogle Scholar
  15. Mattoo, S., Durrant, E., Chen, M. J., Xiao, J., Lazar, C. S., Manning, G., et al. (2011). Comparative analysis of Histophilus somni immunoglobulin-binding protein A (IbpA) with other fic domain-containing enzymes reveals differences in substrate and nucleotide specificities. The Journal of Biological Chemistry, 286(37), 32834–32842.PubMedCrossRefGoogle Scholar
  16. Miller, W. G., Pearson, B. M., Wells, J. M., Parker, C. T., Kapitonov, V. V., & Mandrell, R. E. (2005). Diversity within the Campylobacter jejuni type I restriction-modification loci. Microbiology, 151(Pt 2), 337–351.PubMedCrossRefGoogle Scholar
  17. Mukherjee, S., Liu, X., Arasaki, K., McDonough, J., Galan, J. E., & Roy, C. R. (2011). Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature, 477(7362), 103–106.PubMedCrossRefGoogle Scholar
  18. Palanivelu, D. V., Goepfert, A., Meury, M., Guye, P., Dehio, C., & Schirmer, T. (2011). Fic domain-catalyzed adenylylation: Insight provided by the structural analysis of the type IV secretion system effector BepA. Protein science : a publication of the Protein Society, 20(3), 492–499.CrossRefGoogle Scholar
  19. Punta, M. et al. (2012). The Pfam protein families database. Nucleic acids research 40 (Database issue):D290–301.Google Scholar
  20. Utsumi, R., Nakamoto, Y., Kawamukai, M., Himeno, M., & Komano, T. (1982). Involvement of cyclic AMP and its receptor protein in filamentation of an Escherichia coli fic mutant. Journal of Bacteriology, 151(2), 807–812.PubMedGoogle Scholar
  21. Watson, J. D., & Milner-White, E. J. (2002). A novel main-chain anion-binding site in proteins: The nest. A particular combination of phi, psi values in successive residues gives rise to anion-binding sites that occur commonly and are found often at functionally important regions. Journal of Molecular Biology, 315(2), 171–182.PubMedCrossRefGoogle Scholar
  22. Worby, C. A., Mattoo, S., Kruger, R. P., Corbeil, L. B., Koller, A., Mendez, J. C., et al. (2009). The fic domain: Regulation of cell signaling by adenylylation. Molecular Cell, 34(1), 93–103.PubMedCrossRefGoogle Scholar
  23. Xiao, J., Worby, C. A., Mattoo, S., Sankaran, B., & Dixon, J. E. (2010). Structural basis of Fic-mediated adenylylation. Nature Structural & Molecular Biology, 17(8), 1004–1010.CrossRefGoogle Scholar
  24. Yamaguchi, Y., Park, J. H., & Inouye, M. (2011). Toxin-antitoxin systems in bacteria and archaea. Annual Review of Genetics, 45, 61–79.PubMedCrossRefGoogle Scholar
  25. Yarbrough, M. L., Li, Y., Kinch, L. N., Grishin, N. V., Ball, H. L., & Orth, K. (2009). AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling. Science, 323(5911), 269–272.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Arnaud Goepfert
    • 1
    • 2
  • Alexander Harms
    • 1
  • Tilman Schirmer
    • 2
  • Christoph Dehio
    • 1
    Email author
  1. 1.Focal Area Infection Biology, BiozentrumUniversity of BaselBaselSwitzerland
  2. 2.Focal Area Structural Biology and Biophysics, BiozentrumUniversity of BaselBaselSwitzerland

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