Mechanism of regulation and neutralization of the AtaR–AtaT toxin–antitoxin system

Jurėnas, Dukas; Melderen, Laurence Van; García-Pino, Abel

doi:10.1038/s41589-018-0216-z

Cited by 35 publications

(45 citation statements)

References 44 publications

(36 reference statements)

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“…f Time courses of the acetylation of Met-tRNAf Met variants with mutations in the bottom half of the three consecutive G-C pairs in a. g Quantification of the acetylation efficiencies in f, as in e. The bars in the graph are SD of three independent (n = 3) experiments, and the data are presented as mean values ± SD. respectively 20,21 . The loop between α3 and β4 in AtaTb and α1 in AtaTa form the path for the 3′-end of tRNA to enter the catalytic site and interact with the 3′-single-stranded region of tRNAf Met (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The crystal belongs to the space group P2 1 2 1 2 and contains eight AtaT molecules and two Ac-Met-tRNAf Met molecules in the asymmetric unit. The initial phase was determined by the molecular replacement method, using the AtaT homodimer (PDB: 6GTP) 20 and tRNAf Met structures in the structure of the complex of Met-tRNAf Met formyltransferase and formyl-Met-tRNAf Met (PDB: 2FMT) 24 as search models. The structure was model-built and refined to an R factor of 28.6% (R free = 34.1%) at 3.8 Å resolution.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, the crystal structures of AtaT and its complex with the cognate antitoxin AtaR have been reported 20,21 . The structural and biochemical studies revealed that the homodimerization of AtaT is required for both the enzymatic activity and the toxicity.…”

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confidence: 99%

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Mechanism of aminoacyl-tRNA acetylation by an aminoacyl-tRNA acetyltransferase AtaT from enterohemorrhagic E. coli

et al. 2020

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Toxin-antitoxin systems in bacteria contribute to stress adaptation, dormancy, and persistence. AtaT, a type-II toxin in enterohemorrhagic E. coli, reportedly acetylates the α-amino group of the aminoacyl-moiety of initiator Met-tRNAfMet, thus inhibiting translation initiation. Here, we show that AtaT has a broader specificity for aminoacyl-tRNAs than initially claimed. AtaT efficiently acetylates Gly-tRNAGly, Trp-tRNATrp, Tyr-tRNATyr and Phe-tRNAPhe isoacceptors, in addition to Met-tRNAfMet, and inhibits global translation. AtaT interacts with the acceptor stem of tRNAfMet, and the consecutive G-C pairs in the bottom-half of the acceptor stem are required for acetylation. Consistently, tRNAGly, tRNATrp, tRNATyr and tRNAPhe also possess consecutive G-C base-pairs in the bottom halves of their acceptor stems. Furthermore, misaminoacylated valyl-tRNAfMet and isoleucyl-tRNAfMet are not acetylated by AtaT. Therefore, the substrate selection by AtaT is governed by the specific acceptor stem sequence and the properties of the aminoacyl-moiety of aminoacyl-tRNAs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Mechanism of aminoacyl-tRNA acetylation by an aminoacyl-tRNA acetyltransferase AtaT from enterohemorrhagic E. coli

et al. 2020

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“…Structures are colored in rainbow from N-terminus (blue) to C-terminus (red), in cases of dimers the second monomer is in gray. Structures were visualized using ChimeraX, PDB codes were following: E. coli MazF:3nfc; E. coli HicAB:6hpb (Manav et al, 2019); S. oneidensis SO_3166-SO3165 (HEPN): 5yep (Jia et al, 2018); H. pylori HP0315 (VapD): 3ui3 (Kwon et al, 2012); S. flexneri VapC D7A : 5ecw (Xu et al, 2016); E. coli RelE R81A,R83A : 2kc9 (Li et al, 2009); E. coli HipA S150A : 3tpb (Schumacher et al, 2012); E. coli AtaT Y 144F : 6gtp (Jurenas et al, 2019); prophage P1 Phd-Doc: 3k33 (Garcia-Pino et al, 2010). In the cases of structures in complexes with antitoxin, the coordinates of antitoxin were deleted.…”

Section: Mazf Toxinsmentioning

confidence: 99%

The Variety in the Common Theme of Translation Inhibition by Type II Toxin–Antitoxin Systems

Jurėnas

Melderen

2020

Front. Genet.

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Type II Toxin-antitoxin (TA) modules are bacterial operons that encode a toxic protein and its antidote, which form a self-regulating genetic system. Antitoxins put a halter on toxins in many ways that distinguish different types of TA modules. In type II TA modules, toxin and antitoxin are proteins that form a complex which physically sequesters the toxin, thereby preventing its toxic activity. Type II toxins inhibit various cellular processes, however, the translation process appears to be their favorite target and nearly every step of this complex process is inhibited by type II toxins. The structural features, enzymatic activities and target specificities of the different toxin families are discussed. Finally, this review emphasizes that the structural folds presented by these toxins are not restricted to type II TA toxins or to one particular cellular target, and discusses why so many of them evolved to target translation as well as the recent developments regarding the role(s) of these systems in bacterial physiology and evolution.

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“…This leaves the toxins to exert their toxic effects, which leads to growth arrest and dormancy.” [ 4 ] Hence, it is common to assume a protease degrading antitoxin bound to toxin is the means to activate toxins. [ 70–72 ] We suggest that the current model of reactivation of toxins in this manner is unlikely and unsupported in that to the best of our knowledge, there are no reports showing the degradation of antitoxins bound to toxins in vitro or in vivo. Hence, it seems this paradigm has been established, like cell killing, without experimental evidence.…”

Section: Reviewmentioning

confidence: 96%

Toxin/Antitoxin System Paradigms: Toxins Bound to Antitoxins Are Not Likely Activated by Preferential Antitoxin Degradation

Song

Wood

2020

Adv. Biosys.

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Periodically, a scientific field should examine its early premises. For ubiquitous toxin/antitoxin (TA) systems, several initial paradigms require adjustment based on accumulated data. For example, it is now clear that under physiological conditions, there is little evidence that toxins of TA systems cause cell death and little evidence that TA systems cause persistence. Instead, TA systems are utilized to reduce metabolism during stress, inhibit phages, stabilize genetic elements, and influence biofilm formation (bacterial cells attached via an extracellular matrix). In this essay, it is argued that toxins bound to antitoxins are not likely to become activated by preferential antitoxin degradation but instead, de novo toxin synthesis in the absence of stoichiometric amounts of antitoxin activates toxins.

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Mechanism of regulation and neutralization of the AtaR–AtaT toxin–antitoxin system

Cited by 35 publications

References 44 publications

Mechanism of aminoacyl-tRNA acetylation by an aminoacyl-tRNA acetyltransferase AtaT from enterohemorrhagic E. coli

Mechanism of aminoacyl-tRNA acetylation by an aminoacyl-tRNA acetyltransferase AtaT from enterohemorrhagic E. coli

The Variety in the Common Theme of Translation Inhibition by Type II Toxin–Antitoxin Systems

Toxin/Antitoxin System Paradigms: Toxins Bound to Antitoxins Are Not Likely Activated by Preferential Antitoxin Degradation

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