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20  structures 760  species 0  interactions 1081  sequences 3  architectures

Family: YafQ_toxin (PF15738)

Summary: Bacterial toxin of type II toxin-antitoxin system, YafQ

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This is the Wikipedia entry entitled "Toxin-antitoxin system". More...

Toxin-antitoxin system Edit Wikipedia article

(A) The vertical gene transfer of a toxin-antitoxin system. (B) Horizontal gene transfer of a toxin-antitoxin system. PSK stands for post-segregational killing and TA represents a locus encoding a toxin and an antitoxin.[1]

A toxin-antitoxin system is a set of two or more closely linked genes that together encode both a "toxin" protein and a corresponding "antitoxin". Toxin-antitoxin systems are widely distributed in prokaryotes, and organisms often have them in multiple copies.[2][3] When these systems are contained on plasmids â€“ transferable genetic elements â€“ 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 antitoxin is degraded and the stable toxic protein kills the new cell; this is known as 'post-segregational killing' (PSK).[4][5]

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 that binds the toxin mRNA. The toxic protein in a type II system is inhibited post-translationally by the binding of an antitoxin protein. Type III toxin-antitoxin systems consist of a small RNA that binds directly to the toxin protein and inhibits its activity.[6] There are also types IV-VI, which are less common.[7] Toxin-antitoxin genes are often inherited through horizontal gene transfer[8][9] and are associated with pathogenic bacteria, having been found on plasmids conferring antibiotic resistance and virulence.[1]

Chromosomal toxin-antitoxin systems also exist, some of which are thought to perform cell functions such as responding to stresses, causing cell cycle arrest and bringing about programmed cell death.[1][10] 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.[11] Toxin-antitoxin systems have several biotechnological applications, such as maintaining plasmids in cell lines, targets for antibiotics, and as positive selection vectors.[12]

Biological functions

Stabilization and fitness of mobile DNA

As stated above, toxin-antitoxin systems are well characterized as plasmid addiction modules. It was also proposed that toxin-antitoxin systems have evolved as plasmid exclusion modules. A cell that would carry two plasmids from the same incompatibility group will eventually generate two daughters cells carrying either plasmid. Should one of these plasmids encode for a TA system, its "displacement" by another TA-free plasmid system will prevent its inheritance and thus induce post-segregetational killing.[13] This theory was corroborated through computer modelling.[14] Toxin-antitoxin systems can also be found on other mobile genetic elements such as conjugative transposons and temperate bacteriophages and could be implicated in the maintenance and competition of these elements.[15]

Genome stabilization

A chromosome map of Sinorhizobium meliloti, with its 25 chromosomal toxin-antitoxin systems. Orange-labelled loci are confirmed TA systems[16] and green labels show putative systems.[17]

Toxin-antitoxin systems could prevent harmful large deletions in a bacterial genome, though arguably deletions of large coding regions are fatal to a daughter cell regardless.[11] In Vibrio cholerae, multiple type II toxin-antitoxin systems located in a super-integron were shown to prevent the loss of gene cassettes.[18]

Altruistic cell death

mazEF, a toxin-antitoxin locus found in E. coli and other bacteria, was proposed to induce programmed cell death in response to starvation, specifically a lack of amino acids.[19] This would release 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 would be an example of altruism and how bacterial colonies could resemble multicellular organisms.[14] However, the "mazEF-mediated PCD" has largely been refuted by several studies.[20][21][22]

Stress tolerance

Another theory states that chromosomal toxin-antitoxin systems are designed to be bacteriostatic rather than bactericidal.[23] RelE, for example, is a global inhibitor of translation, is induced during nutrient stress. By shutting down translation under stress, it could reduce the chance of starvation by lowering the cell's nutrient requirements.[24] However, it was shown that several toxin-antitoxin systems, including relBE, do not give any competitive advantage under any stress condition.[21]

Anti-addiction

It has been proposed that chromosomal homologues of plasmid toxin-antitoxin systems may serve as anti-addiction modules, which would allow progeny to lose a plasmid without suffering the effects of the toxin it encodes.[9] For example, a chromosomal copy of the ccdA antitoxin encoded in the chromosome of Erwinia chrysanthemi is able to neutralize the ccdB toxin encoded on the F plasmid and thus, prevent toxin activation when such a plasmid is lost.[25] Similarly, the ataR antitoxin encoded on the chromosome of E. coli O157:H7 is able neutralize the ataTP toxin encoded on plasmids found in other enterohemorragic E. coli.[26]

Phage protection

Type III toxin-antitoxin systems have been shown to protect bacteria from bacteriophages.[27][28] During an infection, bacteriophages hijack transcription and translation, which could prevent antitoxin replenishment and release toxin, triggering what is called an "abortive infection".[27][28] Similar protective effects have been observed with type I[29] and type II[30] toxin-antitoxin systems.

Antimicrobial persistence

When bacteria are challenged with antibiotics, a small and distinct subpopulation of cells is able to withstand the treatment by a phenomenon dubbed as "persistence" (not to be confused with resistance).[31] Due to their bacteriostatic properties, type II toxin-antitoxin systems have previously been thought to be responsible for persistence, by switching a fraction of the bacterial population to a dormant state.[32] However, this hypothesis has been widely invalidated.[33][34][35]

Selfish DNA

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.[1][36] Thus, chromosomal toxin-antitoxin systems would serve no purpose and could be treated as "junk DNA". For example, the ccdAB system encoded in the chromosome of E. coli O157:H7 has been shown to be under negative selection, albeit at a slow rate due to its addictive properties.[8]

System types

Type I

The hok/sok type I toxin-antitoxin system

Type I toxin-antitoxin systems rely on the base-pairing of complementary antitoxin RNA with the toxin 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 of the toxin mRNA. 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.[37]

Toxins of type I systems are small, hydrophobic proteins that confer toxicity by damaging cell membranes.[1] 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.[10]

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.[5] 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.[37]

Example systems

Toxin Antitoxin Notes Ref.
hok sok The original and best-understood type I toxin-antitoxin system (pictured), which stabilises plasmids in a number of gram-negative bacteria [37]
fst RNAII The first type I system to be identified in gram-positive bacteria [38]
tisB istR A chromosomal system induced in the SOS response [39]
ldrD rdlD A chromosomal system in Enterobacteriaceae [40]
flmA flmB A hok/sok homologue, which also stabilises the F plasmid [41]
ibs sib Discovered in E. coli intergenic regions, the antitoxin was originally named QUAD RNA [42]
txpA/brnT ratA Ensures the inheritance of the skin element during sporulation in Bacillus subtilis [43]
symE symR A chromosomal system induced in the SOS response [3]
XCV2162 ptaRNA1 A system identified in Xanthomonas campestris with erratic phylogenetic distribution. [44]
sprA1 sprA1as

Type II

The genetic context of a typical type II toxin-antitoxin locus, produced during a bioinformatics analysis[17]

Type II toxin-antitoxin systems are generally better-understood than type I.[37] In this system a labile proteic antitoxin tightly binds and inhibits the activity of a stable toxin.[10] The largest family of type II toxin-antitoxin systems is vapBC,[45] which has been found through bioinformatics searches to represent between 37 and 42% of all predicted type II loci.[16][17]Type II systems are organised in operons with the antitoxin protein typically being located upstream of the toxin, which helps to prevent expression of the toxin without the antitoxin.[46] The proteins are typically around 100 amino acids in length,[37] and exhibit toxicity in a number of ways: CcdB, for example, affects DNA replication by poisoning DNA gyrase[47] whereas the MazF and RelE toxins are endoribonuclease that cleaves cellular mRNAs at specific sequence motifs.[48][24] The most common toxic activity is the protein acting as an endonuclease, also known as an interferase.[49][50]

A third protein can sometimes be involved in type II toxin-antitoxin systems. in the case of the ω-ε-ζ (omega-epsilon-zeta) system, the omega protein is a DNA binding protein that negatively regulates the transcription of the whole system.[51] Similarly, the paaR2 protein regulates the expression of the paaR2-paaA2-parE2 toxin-antitoxin system.[52] Other toxin-antitoxin systems can be found with a chaperone as a third component.[53] This chaperone is essential for proper folding of the antitoxin, thus making the antitoxin addicted to its cognate chaperone.

Example systems

Toxin Antitoxin Notes Ref.
ccdB ccdA Found on the F plasmid of Escherichia coli [47]
parE parD Found in multiple copies in Caulobacter crescentus [54]
mazF mazE Found in E. coli and in chromosomes of other bacteria [29]
yafO yafN A system induced by the SOS response to DNA damage in E. coli [55]
hicA hicB Found in archaea and bacteria [56]
kid kis Stabilises the R1 plasmid and is related to the CcdB/A system [23]
ζ ε Found mostly in Gram-positive bacteria [51]
ataT ataR Found in enterohemorragic E. coli and Klebsiella spp. [57]

Type III

ToxN_toxin
Identifiers
SymbolToxN, type III toxin-antitoxin system
PfamPF13958

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.[6] 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).[27][58] 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.[59]

Type IV

Type IV toxin-antitoxin systems are similar to type II systems, because they consist of two proteins. Unlike type II systems, the antitoxin in type IV toxin-antitoxin systems counteracts the activity of the toxin, and the two proteins do not directly interact.[60][61]

Type V

ghoST is a type V toxin-antitoxin system, in which the antitoxin (GhoS) cleaves the ghoT mRNA. This system is regulated by a type II system, mqsRA.[62]

Type VI

socAB is a type VI toxin-antitoxin system that was discovered in Caulobacter crescentus. The antitoxin, SocA, promotes degradation of the toxin, SocB, by the protease ClpXP.[63]

Biotechnological applications

The biotechnological applications of toxin-antitoxin systems have begun to be realised by several biotechnology organisations.[12][23] 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.[64][65] 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.[12]

Additionally, toxin-antitoxin systems may be a future target for antibiotics. Inducing suicide modules against pathogens could help combat the growing problem of multi-drug resistance.[66]

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 the ccdB-encoded toxin, which has been incorporated into plasmid vectors.[67] 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.[12]

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.[67]

Genetically modified organisms must be contained in a pre-defined area during research.[66] 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.[23][68]

See also

References

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  49. ^ Christensen-Dalsgaard M, Overgaard M, Winther KS, Gerdes K (2008). RNA decay by messenger RNA interferases. Methods in Enzymology. 447. pp. 521–35. doi:10.1016/S0076-6879(08)02225-8. ISBN 978-0-12-374377-0. PMID 19161859.
  50. ^ Yamaguchi Y, Inouye M (2009). mRNA interferases, sequence-specific endoribonucleases from the toxin-antitoxin systems. Progress in Molecular Biology and Translational Science. 85. pp. 467–500. doi:10.1016/S0079-6603(08)00812-X. ISBN 978-0-12-374761-7. PMID 19215780.
  51. ^ a b 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 (12): 1183–94. doi:10.1007/s00109-011-0797-4. PMC 3218275. PMID 21822621.
  52. ^ Hallez R, Geeraerts D, Sterckx Y, Mine N, Loris R, Van Melderen L (May 2010). "New toxins homologous to ParE belonging to three-component toxin-antitoxin systems in Escherichia coli O157:H7". Molecular Microbiology. 76 (3): 719–32. doi:10.1111/j.1365-2958.2010.07129.x. PMID 20345661.
  53. ^ Bordes P, Cirinesi AM, Ummels R, Sala A, Sakr S, Bitter W, Genevaux P (May 2011). "SecB-like chaperone controls a toxin-antitoxin stress-responsive system in Mycobacterium tuberculosis". Proceedings of the National Academy of Sciences of the United States of America. 108 (20): 8438–43. doi:10.1073/pnas.1101189108. PMC 3100995. PMID 21536872.
  54. ^ 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". Molecular Microbiology. 77 (1): 236–51. doi:10.1111/j.1365-2958.2010.07207.x. PMC 2907451. PMID 20487277. (subscription required)
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External links

  • RASTA – Rapid Automated Scan for Toxins and Antitoxins in Bacteria

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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 toxin of type II toxin-antitoxin system, YafQ Provide feedback

YafQ is a family of bacterial toxin ribonucleases of type II toxin-antitoxin systems. The E.coli gene is expressed from the dinB operon [1,2]. The cognate antitoxin for the E. coli protein is DinJ, in family RelB_antitoxin, PF02604.

Literature references

  1. Motiejunaite R, Armalyte J, Markuckas A, Suziedeliene E;, FEMS Microbiol Lett. 2007;268:112-119.: Escherichia coli dinJ-yafQ genes act as a toxin-antitoxin module. PUBMED:17263853 EPMC:17263853

  2. Prysak MH, Mozdzierz CJ, Cook AM, Zhu L, Zhang Y, Inouye M, Woychik NA;, Mol Microbiol. 2009;71:1071-1087.: Bacterial toxin YafQ is an endoribonuclease that associates with the ribosome and blocks translation elongation through sequence-specific and frame-dependent mRNA cleavage. PUBMED:19210620 EPMC:19210620

  3. Kolodkin-Gal I, Verdiger R, Shlosberg-Fedida A, Engelberg-Kulka H;, PLoS One. 2009;4:e6785.: A differential effect of E. coli toxin-antitoxin systems on cell death in liquid media and biofilm formation. PUBMED:19707553 EPMC:19707553


Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR004386

YafQ is a ribosome-associated endoribonuclease that serves as part of a toxin-antitoxin system, for which DinJ is the antidote component [PUBMED:17263853]. It associates with the ribosome and blocks translation elongation through sequence-specific and frame-dependent mRNA cleavage [PUBMED:19210620].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Plasmid-antitox (CL0136), which has the following description:

The families in this clan are plasmid encoded anti-toxins involved in plasmid maintenance. The plasmid encodes both a toxin and an antitoxin. Upon loss of the plasmid the antitoxin is inactivated more rapidly than the toxin. This allows the toxin to interact with its target thus killing the cell or impeding growth.

The clan contains the following 15 members:

BrnT_toxin DUF2281 Gp49 HigB-like_toxin MqsR_toxin ParE-like_toxin ParE_toxin PHD_like PhdYeFM_antitox REGB_T4 RelE Toxin_YhaV TrmO_C YafQ_toxin YoeB_toxin

Alignments

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...

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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.

  Seed
(85)
Full
(1081)
Representative proteomes UniProt
(7764)
NCBI
(8841)
Meta
(47)
RP15
(58)
RP35
(209)
RP55
(430)
RP75
(907)
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PP/heatmap 1 View               

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(85)
Full
(1081)
Representative proteomes UniProt
(7764)
NCBI
(8841)
Meta
(47)
RP15
(58)
RP35
(209)
RP55
(430)
RP75
(907)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

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.

  Seed
(85)
Full
(1081)
Representative proteomes UniProt
(7764)
NCBI
(8841)
Meta
(47)
RP15
(58)
RP35
(209)
RP55
(430)
RP75
(907)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

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...

Trees

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.

Curation View help on the curation process

Seed source: Jackhmmer:Q47149
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Coggill P
Number in seed: 85
Number in full: 1081
Average length of the domain: 87.20 aa
Average identity of full alignment: 34 %
Average coverage of the sequence by the domain: 94.32 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 30.0 30.0
Trusted cut-off 30.0 30.0
Noise cut-off 29.8 29.9
Model length: 88
Family (HMM) version: 6
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Structures

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 YafQ_toxin domain has been found. There are 20 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 sequence.

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