Summary: Bacterial antitoxin of ParD toxin-antitoxin type II system and RHH
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Toxin-antitoxin system Edit Wikipedia article
A toxin-antitoxin system is a set of two or more closely linked genes that together encode both a protein 'poison' and a corresponding 'antidote'. When these systems are contained on plasmids – transferable genetic elements – they ensure that only the daughter cells that inherit the plasmid survive after cell division. If the plasmid is absent in a daughter cell, the unstable anti-toxin is degraded and the stable toxic protein kills the new cell; this is known as 'post-segregational killing' (PSK). Toxin-antitoxin systems are widely distributed in prokaryotes, and organisms often have them in multiple copies.
Toxin-antitoxin systems are typically classified according to how the antitoxin neutralises the toxin. In a type I toxin-antitoxin system, the translation of messenger RNA (mRNA) that encodes the toxin is inhibited by the binding of a small non-coding RNA antitoxin to the mRNA. The protein toxin in a type II system is inhibited post-translationally by the binding of another protein antitoxin. A single example of a type III toxin-antitoxin system has been described whereby a protein toxin is bound directly by an RNA molecule. Toxin-antitoxin genes are often transferred through horizontal gene transfer and are associated with pathogenic bacteria, having been found on plasmids conferring antibiotic resistance and virulence.
Chromosomal toxin-antitoxin systems also exist, some of which perform cell functions such as responding to stresses, causing cell cycle arrest and bringing about programmed cell death. In evolutionary terms, toxin-antitoxin systems can be considered selfish DNA in that the purpose of the systems are to replicate, regardless of whether they benefit the host organism or not. Some have proposed adaptive theories to explain the evolution of toxin-antitoxin systems; for example, chromosomal toxin-antitoxin systems could have evolved to prevent the inheritance of large deletions of the host genome. Toxin-antitoxin systems have several biotechnological applications, such as a method of maintaining plasmids in cell lines, targets for antibiotics, and as positive selection vectors.
Plasmid stabilising toxin-antitoxin systems have been used as examples of selfish DNA as part of the gene centered view of evolution. It has been theorised that toxin-antitoxin loci serve only to maintain their own DNA, at the expense of the host organism. Other theories propose the systems have evolved to increase the fitness of plasmids in competition with other plasmids. Thus, the toxin-antitoxin system confers an advantage to the host DNA by eliminating competing plasmids in cell progeny. This theory was corroborated through computer modelling. This does not, however, explain the presence of toxin-antitoxin systems on chromosomes.
Chromosomal toxin-antitoxin systems have a number of adaptive theories explaining their success at natural selection. The simplest explanation of their existence on chromosomes is that they prevent harmful large deletions of the cell's genome, though arguably deletions of large coding regions are fatal to a daughter cell regardless. MazEF, a toxin-antitoxin locus found in E. coli and other bacteria, induces programmed cell death in response to starvation, specifically a lack of amino acids. This releases the cell's contents for absorption by neighbouring cells, potentially preventing the death of close relatives, and thereby increasing the inclusive fitness of the cell that perished. This is an example of altruism and how bacterial colonies resemble multicellular organisms.
Another theory states that chromosomal toxin-antitoxin systems are designed to be bacteriostatic rather than bactericidal. RelE, for example, is a global inhibitor of translation during nutrient stress, and its expression reduces the chance of starvation by lowering the cell's nutrient requirements. A homologue of mazF toxin called mazF-mx is essential for fruiting body formation in Myxococcus xanthus. When nutrients become limiting in this swarming bacteria, a group of 50,000 cells converge into a fruiting body structure. The maxF-mx toxin is a component of this nutrient-stress pathway; it enables a percentage of cells within the fruiting body to form myxospores. It has been suggested that M. xanthus has hijacked the toxin-antitoxin system, replacing the antitoxin with its own molecular control to regulate its development.
It has also been proposed that chromosomal copies of plasmid toxin-antitoxin systems may serve as anti-addiction modules – a method of omitting a plasmid from progeny without suffering the effects of the toxin. An example of this is an antitoxin on the Erwinia chrysanthemi genome that counteracts the toxic activity of an F plasmid toxin counterpart.
Nine possible functions of toxin-antitoxin systems have been proposed. These are:
- Junk – they have been acquired from plasmids and retained due to their addictive nature.
- Stabilisation of genomic parasites – chromosomal remnants from transposons and bacteriophages.
- Selfish alleles – non-addictive alleles are unable to replace addictive alleles during recombination but the opposite is able to occur.
- Gene regulation – some toxins act as a means of general repression of gene expression while others are more specific.
- Growth control – bacteriostatic toxins, as mentioned above, restrict growth rather than killing the host cell.
- Persisters – some bacterial populations contain a sub-population of 'persisters' controlled by toxin-antitoxin systems that are slow-growing, hardy individuals, which potentially insure the population against catastrophic loss.
- Programmed cell arrest and the preservation of the commons – the altruistic explanation as demonstrated by MazEF, detailed above.
- Programmed cell death – similar to the above function, although individuals must have variable stress survival level to prevent entire population destruction.
- Antiphage mechanism – when bacteriophage interrupt the host cell's transcription and translation, a toxin-antitoxin system may be activated that limits the phage's replication.
An experiment where five TA systems were deleted from a strain of E. coli found no evidence that the TA systems conferred an advantage to the host. This result casts doubt on the growth control and programmed cell death hypotheses.
Type I toxin-antitoxin systems rely on the base-pairing of complementary antitoxin RNA with the toxin's mRNA. Translation of the mRNA is then inhibited either by degradation via RNase III or by occluding the Shine-Dalgarno sequence or ribosome binding site. Often the toxin and antitoxin are encoded on opposite strands of DNA. The 5' or 3' overlapping region between the two genes is the area involved in complementary base-pairing, usually with between 19–23 contiguous base pairs.
Toxins of type I systems are small, hydrophobic proteins that confer toxicity by damaging cell membranes. Few intracellular targets of type I toxins have been identified, possibly due to the difficult nature of analysing proteins that are poisonous to their bacterial hosts.
Type I systems sometimes include a third component. In the case of the well-characterised hok/sok system, in addition to the hok toxin and sok antitoxin, there is a third gene, called mok. This open reading frame almost entirely overlaps that of the toxin, and the translation of the toxin is dependent on the translation of this third component. Thus the binding of antitoxin to toxin is sometimes a simplification, and the antitoxin in fact binds a third RNA, which then affects toxin translation.
|Hok||Sok||The original and best-understood type I toxin-antitoxin system (pictured), which stabilises plasmids in a number of gram-negative bacteria|||
|fst||RNAII||The first type I system to be identified in gram-positive bacteria|||
|TisB||IstR||Responds to DNA damage|||
|LdrD||RdlD||A chromosomal system in Enterobacteriaceae|||
|FlmA||FlmB||A hok/sok homologue, which also stabilises the F plasmid|||
|Ibs||Sib||Discovered in E. coli intergenic regions, the antitoxin was originally named QUAD RNA|||
|TxpA/BrnT||RatA||Ensures the inheritance of the skin element during sporulation in Bacillus subtilis|||
|SymE||SymR||A chromosomal system induced as an SOS response|||
|XCV2162||ptaRNA1||A system identified in Xanthomonas campestris with erratic phylogenetic distribution.|||
Type II toxin-antitoxin systems are generally better-understood than type I. In this system a labile protein antitoxin tightly binds and inhibits the activity of a stable toxin. The largest family of type II toxin-antitoxin systems is vapBC, which has been found through bioinformatics searches to represent between 37 and 42% of all predicted type II loci.
Type II systems are organised in operons with the antitoxin protein typically being located upstream of the toxin. The antitoxin inhibits the toxin by downregulating its expression. The proteins are typically around 100 amino acids in length, and exhibit toxicity in a number of ways: CcdB protein, for example, affects DNA gyrase by poisoning DNA topoisomerase II whereas MazF protein is a toxic endoribonuclease that cleaves cellular mRNAs at specific sequence motifs. The most common toxic activity is the protein acting as an endonuclease, also known as an interferase.
A third protein can sometimes be involved in type II toxin-antitoxin systems. In the case of the aforementioned MazEF addiction module, in addition to the toxin and antitoxin there is a regulatory protein involved called MazG. MazG protein interacts with E. coli's Era GTPase and is described as a 'nucleoside triphosphate pyrophosphohydrolase,' which hydrolyses nucleoside triphosphates to monophosphates. Later research showed that MazG is transcribed in the same polycistronic mRNA as MazE and MazF, and that MazG bound the MazF toxin to further inhibit its activity.
|CcdB||CcdA||Found on the F plasmid of Escherichia coli|||
|ParE||ParD||Found in multiple copies in Caulobacter crescentus|||
|MazF||MazE||Found in E. coli and in chromosomes of other bacteria|||
|yafO||yafN||A system induced by the SOS response to DNA damage in E. coli|||
|HicA||HicB||Found in archaea and bacteria|||
|Kid||Kis||Stabilises the R1 plasmid and is related to the CcdB/A system|||
|Zeta||Epsilon||Found mostly in Gram-positive bacteria|||
|Symbol||ToxN, type III toxin-antitoxin system|
Type III toxin-antitoxin systems rely on direct interaction between a toxic protein and an RNA antitoxin. The toxic effects of the protein are neutralised by the RNA gene. One example is the ToxIN system from the bacterial plant pathogen Erwinia carotovora. The toxic ToxN protein is approximately 170 amino acids long and has been shown to be toxic to E. coli. The toxic activity of ToxN is inhibited by ToxI RNA, an RNA with 5.5 direct repeats of a 36 nucleotide motif (AGGTGATTTGCTACCTTTAAGTGCAGCTAGAAATTC). Crystallographic analysis of ToxIN has found that ToxN inhibition requires the formation of a trimeric ToxIN complex, whereby three ToxI monomers bind three ToxN monomers; the complex is held together by extensive protein-RNA interactions.
The biotechnological applications of toxin-antitoxin systems have begun to be realised by several biotechnology organisations. A primary usage is in maintaining plasmids in a large bacterial cell culture. In an experiment examining the effectiveness of the hok/sok locus, it was found that segregational stability of an inserted plasmid expressing beta-galactosidase was increased by between 8 and 22 times compared to a control culture lacking a toxin-antitoxin system. In large-scale microorganism processes such as fermentation, progeny cells lacking the plasmid insert often have a higher fitness than those who inherit the plasmid and can outcompete the desirable microorganisms. A toxin-antitoxin system maintains the plasmid thereby maintaining the efficiency of the industrial process.
Ensuring a plasmid accepts an insert is a common problem of DNA cloning. Toxin-antitoxin systems can be used to positively select for only those cells that have taken up a plasmid containing the inserted gene of interest, screening out those that lack the inserted gene. An example of this application comes from CcdB-encoded toxin, which has been incorporated into plasmid vectors. The gene of interest is then targeted to recombine into the CcdB locus, inactivating the transcription of the toxic protein. Thus, cells containing the plasmid but not the insert perish due to the toxic effects of CcdB protein, and only those that incorporate the insert survive.
Another example application involves both the CcdB toxin and CcdA antitoxin. CcdB is found in recombinant bacterial genomes and an inactivated version of CcdA is inserted into a linearised plasmid vector. A short extra sequence is added to the gene of interest that activates the antitoxin when the insertion occurs. This method ensures orientation-specific gene insertion.
Genetically modified organisms must be contained in a pre-defined area during research. Toxin-antitoxin systems can cause cell suicide in certain conditions, such as a lack of a lab-specific growth medium they would not encounter outside of the controlled laboratory set-up.
- Van Melderen L, Saavedra De Bast M (March 2009). Rosenberg, Susan M., ed. "Bacterial Toxin–Antitoxin Systems: More Than Selfish Entities?". PLoS Genet. 5 (3): e1000437. doi:10.1371/journal.pgen.1000437. PMC 2654758. PMID 19325885. Retrieved 2010-08-13.
- Gerdes K (February 2000). "Toxin-Antitoxin Modules May Regulate Synthesis of Macromolecules during Nutritional Stress". J. Bacteriol. 182 (3): 561–72. doi:10.1128/JB.182.3.561-572.2000. PMC 94316. PMID 10633087. Retrieved 2010-08-11.
- Faridani OR, Nikravesh A, Pandey DP, Gerdes K, Good L (2006). "Competitive inhibition of natural antisense Sok-RNA interactions activates Hok-mediated cell killing in Escherichia coli". Nucleic Acids Res. 34 (20): 5915–22. doi:10.1093/nar/gkl750. PMC 1635323. PMID 17065468. Retrieved 2010-08-09.
- Fozo EM, Makarova KS, Shabalina SA, Yutin N, Koonin EV, Storz G (June 2010). "Abundance of type I toxin–antitoxin systems in bacteria: searches for new candidates and discovery of novel families". Nucleic Acids Res. 38 (11): 3743–59. doi:10.1093/nar/gkq054. PMC 2887945. PMID 20156992. Retrieved 2010-08-11.
- Gerdes K, Wagner EG (April 2007). "RNA antitoxins". Curr. Opin. Microbiol. 10 (2): 117–24. doi:10.1016/j.mib.2007.03.003. PMID 17376733. Retrieved 2010-08-10.
- Labrie SJ, Samson JE, Moineau S (May 2010). "Bacteriophage resistance mechanisms". Nat. Rev. Microbiol. 8 (5): 317–27. doi:10.1038/nrmicro2315. PMID 20348932.
- Mine N, Guglielmini J, Wilbaux M, Van Melderen L (April 2009). "The Decay of the Chromosomally Encoded ccdO157 Toxin–Antitoxin System in the Escherichia coli Species". Genetics 181 (4): 1557–66. doi:10.1534/genetics.108.095190. PMC 2666520. PMID 19189956. Retrieved 2010-08-13.
- Hayes F (September 2003). "Toxins-antitoxins: plasmid maintenance, programmed cell death, and cell cycle arrest". Science 301 (5639): 1496–9. doi:10.1126/science.1088157. PMID 12970556. Retrieved 2010-08-11.
- Rowe-Magnus DA, Guerout AM, Biskri L, Bouige P, Mazel D (March 2003). "Comparative Analysis of Superintegrons: Engineering Extensive Genetic Diversity in the Vibrionaceae". Genome Res. 13 (3): 428–42. doi:10.1101/gr.617103. PMC 430272. PMID 12618374. Retrieved 2010-08-13.
- Stieber D, Gabant P, Szpirer C (September 2008). "The art of selective killing: plasmid toxin/antitoxin systems and their technological applications". BioTechniques 45 (3): 344–6. doi:10.2144/000112955. PMID 18778262. Retrieved 2010-08-18.
- Cooper TF, Heinemann JA (November 2000). "Postsegregational killing does not increase plasmid stability but acts to mediate the exclusion of competing plasmids". Proc. Natl. Acad. Sci. U.S.A. 97 (23): 12643–8. doi:10.1073/pnas.220077897. PMC 18817. PMID 11058151. Retrieved 2010-08-13.
- Mochizuki A, Yahara K, Kobayashi I, Iwasa Y (February 2006). "Genetic Addiction: Selfish Gene's Strategy for Symbiosis in the Genome". Genetics 172 (2): 1309–23. doi:10.1534/genetics.105.042895. PMC 1456228. PMID 16299387. Retrieved 2010-08-13.
- Pandey DP, Gerdes K (2005). "Toxin–antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes". Nucleic Acids Res. 33 (3): 966–76. doi:10.1093/nar/gki201. PMC 549392. PMID 15718296. Retrieved 2010-08-11.
- Sevin EW, Barloy-Hubler F (2007). "RASTA-Bacteria: a web-based tool for identifying toxin-antitoxin loci in prokaryotes". Genome Biol. 8 (8): R155. doi:10.1186/gb-2007-8-8-r155. PMC 2374986. PMID 17678530. Retrieved 2010-08-24.
- Aizenman E, Engelberg-Kulka H, Glaser G (June 1996). "An Escherichia coli chromosomal "addiction module" regulated by guanosine corrected 3',5'-bispyrophosphate: a model for programmed bacterial cell death". Proc. Natl. Acad. Sci. U.S.A. 93 (12): 6059–63. doi:10.1073/pnas.93.12.6059. PMC 39188. PMID 8650219. Retrieved 2010-08-13.
- Diago-Navarro E, Hernandez-Arriaga AM, López-Villarejo J, et al. (August 2010). "parD toxin-antitoxin system of plasmid R1—basic contributions, biotechnological applications and relationships with closely-related toxin-antitoxin systems". FEBS J. 277 (15): 3097–117. doi:10.1111/j.1742-4658.2010.07722.x. PMID 20569269.
- Christensen SK, Mikkelsen M, Pedersen K, Gerdes K (December 2001). "RelE, a global inhibitor of translation, is activated during nutritional stress". Proc. Natl. Acad. Sci. U.S.A. 98 (25): 14328–33. doi:10.1073/pnas.251327898. PMC 64681. PMID 11717402. Retrieved 2010-08-13.
- Nariya H, Inouye M (January 2008). "MazF, an mRNA interferase, mediates programmed cell death during multicellular Myxococcus development". Cell 132 (1): 55–66. doi:10.1016/j.cell.2007.11.044. PMID 18191220. Retrieved 2010-08-13.
- Curtis PD, Taylor RG, Welch RD, Shimkets LJ (December 2007). "Spatial Organization of Myxococcus xanthus during Fruiting Body Formation". J. Bacteriol. 189 (24): 9126–30. doi:10.1128/JB.01008-07. PMC 2168639. PMID 17921303.
- Saavedra De Bast M, Mine N, Van Melderen L (July 2008). "Chromosomal Toxin-Antitoxin Systems May Act as Antiaddiction Modules". J. Bacteriol. 190 (13): 4603–9. doi:10.1128/JB.00357-08. PMC 2446810. PMID 18441063. Retrieved 2010-08-13.
- Magnuson RD (2007). "Hypothetical Functions of Toxin-Antitoxin Systems". J Bacteriol 189 (17): 6089–92. doi:10.1128/JB.00958-07. PMC 1951896. PMID 17616596.
- Engelberg-Kulka H, Amitai S, Kolodkin-Gal I, Hazan R (October 2006). "Bacterial Programmed Cell Death and Multicellular Behavior in Bacteria". PLoS Genet. 2 (10): e135. doi:10.1371/journal.pgen.0020135. PMC 1626106. PMID 17069462. Retrieved 2010-11-01.
- Pimentel B, Madine MA, de la Cueva-Méndez G (October 2005). "Kid cleaves specific mRNAs at UUACU sites to rescue the copy number of plasmid R1". EMBO J. 24 (19): 3459–69. doi:10.1038/sj.emboj.7600815. PMC 1276173. PMID 16163387.
- Kussell E, Kishony R, Balaban NQ, Leibler S (April 2005). "Bacterial Persistence: A Model of Survival in Changing Environments". Genetics 169 (4): 1807–14. doi:10.1534/genetics.104.035352. PMC 1449587. PMID 15687275. Retrieved 2010-11-01.
- Hazan R, Engelberg-Kulka H (September 2004). "Escherichia coli mazEF-mediated cell death as a defense mechanism that inhibits the spread of phage P1". Mol. Genet. Genomics 272 (2): 227–34. doi:10.1007/s00438-004-1048-y. PMID 15316771.
- Pecota DC, Wood TK (April 1996). "Exclusion of T4 phage by the hok/sok killer locus from plasmid R1". J. Bacteriol. 178 (7): 2044–50. PMC 177903. PMID 8606182. Retrieved 2010-11-01.
- Tsilibaris V, Maenhaut-Michel G, Mine N, Van Melderen L (2007). "What Is the Benefit to Escherichia coli of Having Multiple Toxin-Antitoxin Systems in Its Genome?". J. Bacteriol. 189 (17): 6101–8. doi:10.1128/JB.00527-07. PMC 1951899. PMID 17513477.
- Fozo EM, Hemm MR, Storz G (December 2008). "Small Toxic Proteins and the Antisense RNAs That Repress Them". Microbiol. Mol. Biol. Rev. 72 (4): 579–89, Table of Contents. doi:10.1128/MMBR.00025-08. PMC 2593563. PMID 19052321. Retrieved 2010-08-11.
- Greenfield TJ, Ehli E, Kirshenmann T, Franch T, Gerdes K, Weaver KE (August 2000). "The antisense RNA of the par locus of pAD1 regulates the expression of a 33-amino-acid toxic peptide by an unusual mechanism". Mol. Microbiol. 37 (3): 652–60. doi:10.1046/j.1365-2958.2000.02035.x. PMID 10931358. Retrieved 2010-09-20. (subscription required)
- Vogel J, Argaman L, Wagner EG, Altuvia S (December 2004). "The small RNA IstR inhibits synthesis of an SOS-induced toxic peptide". Curr. Biol. 14 (24): 2271–6. doi:10.1016/j.cub.2004.12.003. PMID 15620655. Retrieved 2010-08-11.
- Kawano M, Oshima T, Kasai H, Mori H (July 2002). "Molecular characterization of long direct repeat (LDR) sequences expressing a stable mRNA encoding for a 35-amino-acid cell-killing peptide and a cis-encoded small antisense RNA in Escherichia coli". Mol. Microbiol. 45 (2): 333–49. doi:10.1046/j.1365-2958.2002.03042.x. PMID 12123448. Retrieved 2010-08-16. (subscription required)
- Loh SM, Cram DS, Skurray RA (June 1988). "Nucleotide sequence and transcriptional analysis of a third function (Flm) involved in F-plasmid maintenance". Gene 66 (2): 259–68. doi:10.1016/0378-1119(88)90362-9. PMID 3049248.
- Fozo EM, Kawano M, Fontaine F, et al. (December 2008). "Repression of small toxic protein synthesis by the Sib and OhsC small RNAs". Mol. Microbiol. 70 (5): 1076–93. doi:10.1111/j.1365-2958.2008.06394.x. PMC 2597788. PMID 18710431. Retrieved 2010-08-11. (subscription required)
- Silvaggi JM, Perkins JB, Losick R (October 2005). "Small Untranslated RNA Antitoxin in Bacillus subtilis". J. Bacteriol. 187 (19): 6641–50. doi:10.1128/JB.187.19.6641-6650.2005. PMC 1251590. PMID 16166525. Retrieved 2010-09-16.
- Findeiss S, Schmidtke C, Stadler PF, Bonas U (March 2010). "A novel family of plasmid-transferred anti-sense ncRNAs". RNA Biol. 7 (2): 120–4. doi:10.4161/rna.7.2.11184. PMID 20220307. Retrieved 2010-08-24.
- 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.
- Bernard P, Couturier M (August 1992). "Cell killing by the F plasmid CcdB protein involves poisoning of DNA-topoisomerase II complexes". J. Mol. Biol. 226 (3): 735–45. doi:10.1016/0022-2836(92)90629-X. PMID 1324324. Retrieved 2010-08-11.
- Zhang Y, Zhang J, Hoeflich KP, Ikura M, Qing G, Inouye M (October 2003). "MazF cleaves cellular mRNAs specifically at ACA to block protein synthesis in Escherichia coli". Mol. Cell 12 (4): 913–23. doi:10.1016/S1097-2765(03)00402-7. PMID 14580342. Retrieved 2010-08-11.
- Christensen-Dalsgaard M, Overgaard M, Winther KS, Gerdes K (2008). "RNA decay by messenger RNA interferases". Meth. Enzymol. Methods in Enzymology 447: 521–35. doi:10.1016/S0076-6879(08)02225-8. ISBN 978-0-12-374377-0. PMID 19161859. Retrieved 2010-08-16.
- Yamaguchi Y, Inouye M (2009). "mRNA interferases, sequence-specific endoribonucleases from the toxin-antitoxin systems". Prog Mol Biol Transl Sci. Progress in Molecular Biology and Translational Science 85: 467–500. doi:10.1016/S0079-6603(08)00812-X. ISBN 978-0-12-374761-7. PMID 19215780. Retrieved 2010-08-16.
- Singletary LA, Gibson JL, Tanner EJ, et al. (December 2009). "An SOS-Regulated Type 2 Toxin-Antitoxin System". J. Bacteriol. 191 (24): 7456–65. doi:10.1128/JB.00963-09. PMC 2786605. PMID 19837801. Retrieved 2010-08-16.
- Zhang J, Inouye M (October 2002). "MazG, a Nucleoside Triphosphate Pyrophosphohydrolase, Interacts with Era, an Essential GTPase in Escherichia coli". J. Bacteriol. 184 (19): 5323–9. doi:10.1128/JB.184.19.5323-5329.2002. PMC 135369. PMID 12218018. Retrieved 2010-08-16.
- Gross M, Marianovsky I, Glaser G (January 2006). "MazG – a regulator of programmed cell death in Escherichia coli". Mol. Microbiol. 59 (2): 590–601. doi:10.1111/j.1365-2958.2005.04956.x. PMID 16390452. Retrieved 2010-08-16. (subscription required)
- Fiebig A, Castro Rojas CM, Siegal-Gaskins D, Crosson S (July 2010). "Interaction specificity, toxicity, and regulation of a paralogous set of ParE/RelE-family toxin-antitoxin systems". Mol. Microbiol. 77 (1): 236–51. doi:10.1111/j.1365-2958.2010.07207.x. PMC 2907451. PMID 20487277. Retrieved 2010-08-11. (subscription required)
- Jørgensen MG1, Pandey DP, Jaskolska M, Gerdes K. (December 2009). "HicA of Escherichia coli defines a novel family of translation-independent mRNA interferases in bacteria and archaea.". Journal of Bacteriology 191 (4): 1191–1199. doi:10.1128/JB.01013-08. PMC 2631989. PMID 19060138. Retrieved April 4, 2015.
- Mutschler H & Meinhart A (December 2011). "ε/ζ systems: their role in resistance, virulence, and their potential for antibiotic development.". Journal of Molecular Medicine 89 (2): 1183–1194. doi:10.1007/s00109-011-0797-4. PMC 3218275. PMID 21822621.
- Fineran PC, Blower TR, Foulds IJ, Humphreys DP, Lilley KS, Salmond GP (2009). "The phage abortive infection system, ToxIN, functions as a protein–RNA toxin–antitoxin pair". Proc Natl Acad Sci U S A 106 (3): 894–9. doi:10.1073/pnas.0808832106. PMC 2630095. PMID 19124776.
- Blower TR, Fineran PC, Johnson MJ, Toth IK, Humphreys DP, Salmond GP (2009). "Mutagenesis and Functional Characterization of the RNA and Protein Components of the toxIN Abortive Infection and Toxin-Antitoxin Locus of Erwinia". J Bacteriol 191 (19): 6029–39. doi:10.1128/JB.00720-09. PMC 2747886. PMID 19633081.
- Blower TR, Pei XY, Short FL, et al. (February 2011). "A processed noncoding RNA regulates an altruistic bacterial antiviral system". Nat. Struct. Mol. Biol. 18 (2): 185–90. doi:10.1038/nsmb.1981. PMID 21240270.
- Wu K, Jahng D, Wood TK (1994). "Temperature and growth rate effects on the hok/sok killer locus for enhanced plasmid stability". Biotechnol. Prog. 10 (6): 621–9. doi:10.1021/bp00030a600. PMID 7765697.
- Pecota DC, Kim CS, Wu K, Gerdes K, Wood TK (May 1997). "Combining the hok/sok, parDE, and pnd postsegregational killer loci to enhance plasmid stability". Appl. Environ. Microbiol. 63 (5): 1917–24. PMC 168483. PMID 9143123.
- Gerdes K, Christensen SK, Løbner-Olesen A (May 2005). "Prokaryotic toxin-antitoxin stress response loci". Nat. Rev. Microbiol. 3 (5): 371–82. doi:10.1038/nrmicro1147. PMID 15864262.
- Bernard P, Gabant P, Bahassi EM, Couturier M (October 1994). "Positive-selection vectors using the F plasmid ccdB killer gene". Gene 148 (1): 71–4. doi:10.1016/0378-1119(94)90235-6. PMID 7926841.
- Torres B, Jaenecke S, Timmis KN, García JL, Díaz E (December 2003). "A dual lethal system to enhance containment of recombinant micro-organisms". Microbiology (Reading, Engl.) 149 (Pt 12): 3595–601. doi:10.1099/mic.0.26618-0. PMID 14663091.
- Wen, J; Won, D; Fozo, EM (Feb 2014). "The ZorO-OrzO type I toxin-antitoxin locus: repression by the OrzO antitoxin.". Nucleic Acids Research 42 (3): 1930–46. doi:10.1093/nar/gkt1018. PMC 3919570. PMID 24203704.
- RASTA – Rapid Automated Scan for Toxins and Antitoxins in Bacteria
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Bacterial antitoxin of ParD toxin-antitoxin type II system and RHH Provide feedback
ParD is the antitoxin of a bacterial toxin-antitoxin gene pair. The cognate toxin is ParE in, PF05016. The family contains several related antitoxins from Cyanobacteria, Proteobacteria and Actinobacteria. Antitoxins of this class carry an N-terminal ribbon-helix-helix domain, RHH, that is highly conserved across all type II bacterial antitoxins, which dimerises with the RHH domain of a second VapB molecule. A hinge section follows the RHH, with an additional pair of flexible alpha helices at the C-terminus. This C-terminus is the toxin-binding region of the dimer, and so is specific to the cognate toxin, whereas the RHH domain has the specific function of lying across the RNA-binding groove of the toxin dimer and inactivating the active-site - a more general function of all type II antitoxins.
Fiebig A, Castro Rojas CM, Siegal-Gaskins D, Crosson S;, Mol Microbiol. 2010;77:236-251.: Interaction specificity, toxicity and regulation of a paralogous set of ParE/RelE-family toxin-antitoxin systems. PUBMED:20487277 EPMC:20487277
Internal database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR022789
ParD is the antitoxin of a bacterial toxin-antitoxin gene pair. The cognate toxin is ParE in (INTERPRO). The family contains several related antitoxins from Cyanobacteria, Proteobacteria and Actinobacteria. Antitoxins of this class carry an N-terminal ribbon-helix-helix domain, RHH, that is highly conserved across all type II bacterial antitoxins, which dimerises with the RHH domain of a second VapB molecule. A hinge section follows the RHH, with an additional pair of flexible alpha helices at the C terminus. This C terminus is the toxin-binding region of the dimer, and so is specific to the cognate toxin, whereas the RHH domain has the specific function of lying across the RNA-binding groove of the toxin dimer and inactivating the active-site - a more general function of all type II antitoxins [PUBMED:15718296, PUBMED:20487277, PUBMED:20143871].
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
This superfamily contains many antitoxin families, all of which carry a ribbon-helix-helix DNA-binding motif with the beta-ribbon located in and recognising the major groove of operator DNA .
The clan contains the following 31 members:Arc BrnA_antitoxin CcdA CopG_antitoxin DUF1778 DUF1902 DUF217 DUF2540 DUF2610 HicB HicB-like_2 HicB_lk_antitox MetJ Omega_Repress ParD ParD_antitoxin ParD_like ParG PSK_trans_fac REGB_T4 RelB RepB-RCR_reg RHH_1 RHH_3 RHH_4 RHH_5 RHH_7 SeqA_N TraY VapB_antitoxin VirC2
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||4|
|Number in full:||621|
|Average length of the domain:||75.50 aa|
|Average identity of full alignment:||25 %|
|Average coverage of the sequence by the domain:||85.39 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||12|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the ParD_antitoxin domain has been found. There are 4 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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