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Crystallographic tertiary structure of a VapC toxin PIN domain.

VapBC (virulence associated proteins B and C) is the largest family of type II toxin-antitoxin system genetic loci in prokaryotes.[1] VapBC operons consist of two genes: VapC encodes a toxic PilT N-terminus (PIN) domain, and VapB encodes a matching antitoxin.[2] The toxins in this family are thought to perform RNA cleavage, which is inhibited by the co-expression of the antitoxin, in a manner analogous to a poison and antidote.

First discovered in 1992, vapBC loci are now thought make up around 37–42% of all type II toxin-antitoxin systems.[3][4]


Following the discoveries of two other type II toxin-antitoxin systems,[5][6] the first vapBC system to be characterised was found in Salmonella dublin strain G19 in 1992.[7] It was characterised as a system for ensuring that all daughter cells contained a copy of the plasmid encoding the vapBC locus. The two components of this plasmidic system were originally named vagC and vagD (virulence-associated gene) for the toxin and antitoxin genes respectively. VagC was predicted to encode a 12kDa polypeptide, while vagD encoded a smaller 10kDa protein.[7] Their open reading frames were found to overlap by a single nucleotide; suggesting they were translated together, and at a constant molar ratio.[8]


VapBC operons have been found in distantly related prokaryotes, including the pathogens Leptospira interrogans,[9] Mycobacterium tuberculosis[10] and Piscirickettsia salmonis.[11] The loci have been described as "surprisingly abundant, especially in Archaea"[12]—vapBC family members made up 37% of all TA families identified by one bioinformatics search[3] and 42% of those found by another.[4]

Bioinformatics searches have discovered vapBC homologues on both chromosomes and plasmids, and often in high copy number per cell. They are less common, however, in firmicutes and cyanobacteria.[3] Genomes with high numbers of vapBC loci include: M. tuberculosis with 45 predicted loci;[10] S.tokodaii with 25;[4] S.solfataricus with 23[4] and Sinorhizobium meliloti with 21.[10]


A proposed consensus secondary structure and primary sequence for the targets of the vapC toxin.[13]

VapC toxins, specifically the PIN domains, act as ribonucleases in cleaving RNA molecules, thereby reducing the rate of translation.[10][14] In the bacteria Shigella flexneri and Salmonella enterica, VapC toxins have been shown to perform specific cleavage of a tRNA, but in other bacteria the RNA cleavage may be less specific.[15] The specificity of VapC-mediated RNase activity is thought to be influenced by both the primary sequence of the target and secondary structural motifs .[16]

VapC is strongly inhibited by direct protein interaction with VapB, its cognate antitoxin. The toxin-antitoxin complex is thought to autoregulate its own operon, repressing transcription of both components through a DNA-binding domain in VapB.[17]

In some organisms, vapBC loci have been assigned other potential functions. In the hyperthermophilic archaean Sulfolobus solfataricus, for example, a vapBC gene cassette is though to regulate heat shock response.[2]

See also[edit]


  1. ^ Robson, Jennifer; McKenzie, Joanna L.; Cursons, Ray; Cook, Gregory M.; Arcus, Vickery L. (17 July 2009). "The vapBC Operon from Mycobacterium smegmatis Is An Autoregulated Toxin–Antitoxin Module That Controls Growth via Inhibition of Translation". Journal of Molecular Biology 390 (3): 353–367. doi:10.1016/j.jmb.2009.05.006. PMID 19445953. 
  2. ^ a b Cooper, CR; Daugherty, AJ; Tachdjian, S; Blum, PH; Kelly, RM (Feb 2009). "Role of vapBC toxin-antitoxin loci in the thermal stress response of Sulfolobus solfataricus". Biochemical Society transactions 37 (Pt 1): 123–6. doi:10.1042/BST0370123. PMC 2919284. PMID 19143615. Retrieved 11 May 2011. 
  3. ^ a b c Sevin, Emeric W; Barloy-Hubler, Frédérique (1 January 2007). "RASTA-Bacteria: a web-based tool for identifying toxin-antitoxin loci in prokaryotes". Genome Biology 8 (8): R155. doi:10.1186/gb-2007-8-8-r155. PMC 2374986. PMID 17678530. Retrieved 11 May 2011. 
  4. ^ a b c d Pandey, D. P.; Gerdes, K (18 February 2005). "Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes". Nucleic Acids Research 33 (3): 966–976. doi:10.1093/nar/gki201. PMC 549392. PMID 15718296. Retrieved 13 May 2011. 
  5. ^ Ogura, T; Hiraga, S (Aug 1983). "Mini-F plasmid genes that couple host cell division to plasmid proliferation". Proceedings of the National Academy of Sciences of the United States of America 80 (15): 4784–8. doi:10.1073/pnas.80.15.4784. PMC 384129. PMID 6308648. Retrieved 13 May 2011. 
  6. ^ Bravo, A; de Torrontegui, G; Díaz, R (Nov 1987). "Identification of components of a new stability system of plasmid R1, ParD, that is close to the origin of replication of this plasmid". Molecular & general genetics : MGG 210 (1): 101–10. doi:10.1007/bf00337764. PMID 3323833. 
  7. ^ a b Pullinger, GD; Lax, AJ (Jun 1992). "A Salmonella dublin virulence plasmid locus that affects bacterial growth under nutrient-limited conditions". Molecular microbiology 6 (12): 1631–43. doi:10.1111/j.1365-2958.1992.tb00888.x. PMID 1495391. 
  8. ^ Das, A; Yanofsky, C (1989-11-25). "Restoration of a translational stop-start overlap reinstates translational coupling in a mutant trpB'-trpA gene pair of the Escherichia coli tryptophan operon". Nucleic Acids Research 17 (22): 9333–40. doi:10.1093/nar/17.22.9333. PMC 335135. PMID 2685759. Retrieved 13 May 2011. 
  9. ^ Zhang, YX; Li, J; Guo, XK; Wu, C; Bi, B; Ren, SX; Wu, CF; Zhao, GP (Jun 2004). "Characterization of a novel toxin-antitoxin module, VapBC, encoded by Leptospira interrogans chromosome". Cell research 14 (3): 208–16. doi:10.1038/ PMID 15225414. 
  10. ^ a b c d Arcus, V. L.; McKenzie, J. L.; Robson, J.; Cook, G. M. (29 October 2010). "The PIN-domain ribonucleases and the prokaryotic VapBC toxin-antitoxin array". Protein Engineering Design and Selection 24 (1–2): 33–40. doi:10.1093/protein/gzq081. PMID 21036780. 
  11. ^ Gómez, FA; Cárdenas, C; Henríquez, V; Marshall, SH (Apr 2011). "Characterization of a functional toxin-antitoxin module in the genome of the fish pathogen Piscirickettsia salmonis". FEMS microbiology letters 317 (1): 83–92. doi:10.1111/j.1574-6968.2011.02218.x. PMID 21241361. 
  12. ^ Gerdes, K; Christensen, SK; Løbner-Olesen, A (May 2005). "Prokaryotic toxin-antitoxin stress response loci". Nature reviews. Microbiology 3 (5): 371–82. doi:10.1038/nrmicro1147. PMID 15864262. 
  13. ^ McKenzie, JL; Robson, J; Berney, M; Smith, TC; Ruthe, A; Gardner, PP; Arcus, VL; Cook, GM (May 2012). "A VapBC toxin-antitoxin module is a posttranscriptional regulator of metabolic flux in mycobacteria.". Journal of bacteriology 194 (9): 2189–204. doi:10.1128/jb.06790-11. PMID 22366418. 
  14. ^ Van Melderen, Laurence (1 December 2010). "Toxin–antitoxin systems: why so many, what for?". Current Opinion in Microbiology 13 (6): 781–785. doi:10.1016/j.mib.2010.10.006. PMID 21041110. 
  15. ^ Winther, K. S.; Gerdes, K. (18 April 2011). "Enteric virulence associated protein VapC inhibits translation by cleavage of initiator tRNA". Proceedings of the National Academy of Sciences 108 (18): 7403–7407. doi:10.1073/pnas.1019587108. 
  16. ^ Sharrock, A.V. (2013) Characterisation of VapBC Toxin-Antitoxins from Mycobacterium tuberculosis. Unpublished Masters Thesis, University of Waikato, Hamilton, New Zealand
  17. ^ Miallau, L.; Faller, M.; Chiang, J.; Arbing, M.; Guo, F.; Cascio, D.; Eisenberg, D. (4 November 2008). "Structure and Proposed Activity of a Member of the VapBC Family of Toxin-Antitoxin Systems: VapBC-5 from Mycobacterium tuberculosis". Journal of Biological Chemistry 284 (1): 276–283. doi:10.1074/jbc.M805061200. PMC 2610494. PMID 18952600. Retrieved 13 May 2011. 

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