Structural Basis for Toxin Inhibition in the VapXD Toxin-Antitoxin System

Bertelsen, Marie B.; Senissar, Mériem; Nielsen, Maja; Bisiak, Francesco; Cunha, Marta V.; Molinaro, Ashley L; Daines, Dayle A.; Brodersen, D.E.

doi:10.1016/j.str.2020.10.002

Cited by 15 publications

(18 citation statements)

References 43 publications

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“…The structures of HipBA modules from E. coli (HipBA Ec ) and Shewanella onesidensis (HipBA So ) reveal that both TA modules form a HipA 2 –HipB 2 heterotetramer in which HipB binds far from the kinase catalytic center of HipA 12 . Such neutralization strategy differs from most of other type II TA systems, where antitoxins binding usually occludes the active site 13 or mediate allosteric regulation of the toxin 14 – 16 .…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of toxin neutralization in the HipBST toxin-antitoxin system of Legionella pneumophila

Zhen

et al. 2022

Nat Commun

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Toxin-antitoxin (TA) systems are ubiquitous genetic modules in bacteria and archaea. Here, we perform structural and biochemical characterization of the Legionella pneumophila effector Lpg2370, demonstrating that it is a Ser/Thr kinase. Together with two upstream genes, lpg2370 constitutes the tripartite HipBST TA. Notably, the toxin Lpg2370 (HipTLp) and the antitoxin Lpg2369 (HipSLp) correspond to the C-terminus and N-terminus of HipA from HipBA TA, respectively. By determining crystal structures of autophosphorylated HipTLp, its complex with AMP-PNP, and the structure of HipTLp-HipSLp complex, we identify residues in HipTLp critical for ATP binding and those contributing to its interactions with HipSLp. Structural analysis reveals that HipSLp binding induces a loop-to-helix shift in the P-loop of HipTLp, leading to the blockage of ATP binding and inhibition of the kinase activity. These findings establish the L. pneumophila effector Lpg2370 as the HipBST TA toxin and elucidate the molecular basis for HipT neutralization in HipBST TA.

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Section: Introductionmentioning

confidence: 99%

Molecular mechanism of toxin neutralization in the HipBST toxin-antitoxin system of Legionella pneumophila

Zhen

et al. 2022

Nat Commun

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“…This has been described multiple times for VapBC complexes, which are frequently hetero‐octamers (for a review see Bendtsen and Brodersen, 2017) 42 . Higher order association of toxin–antitoxin complexes outside the context of transcription regulation has since then been reported for hicAB , vapXD , and parDE 28,30,31,38,43 . In the case of hicAB , these higher order complexes differ between different species with heterotetramers, heterohexamers as well as hetero‐octamers being observed 28,30,31 .…”

Section: Regulation Of Toxin Activity By the Antitoxinmentioning

confidence: 90%

“…VapD toxins form a conserved dimer with their catalytic site located in a deep cleft near the dimer interface. 37,38 Haemophilus influenzae VapD is inhibited by VapX via the formation of a pseudo-symmetric VapD 2 -VapX heterotrimer (Figure 1g). 38 In this arrangement, the active sites of both VapD monomers interact with the single VapX.…”

Section: Stoichiometry Of Toxin Neutralizationmentioning

confidence: 99%

“…37,38 Haemophilus influenzae VapD is inhibited by VapX via the formation of a pseudo-symmetric VapD 2 -VapX heterotrimer (Figure 1g). 38 In this arrangement, the active sites of both VapD monomers interact with the single VapX. The ataRT and related kacAT modules equally require the formation of a dimer for activity.…”

Section: Stoichiometry Of Toxin Neutralizationmentioning

confidence: 99%

“…42 Higher order association of toxin-antitoxin complexes outside the context of transcription regulation has since then been reported for hicAB, vapXD, and parDE. 28,30,31,38,43 In the case of hicAB, these higher order complexes differ between different species with heterotetramers, heterohexamers as well as hetero-octamers being observed. 28,30,31 It is tempting to speculate that such higher order structures carry some functionality, for example, further harnessing the activity of the toxin, as was recently suggested.…”

Section: Stoichiometry Of Toxin Neutralizationmentioning

confidence: 99%

See 2 more Smart Citations

Prokaryote toxin–antitoxin modules: Complex regulation of an unclear function

2021

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Toxin-antitoxin (TA) modules are small operons in bacteria and archaea that encode a metabolic inhibitor (toxin) and a matching regulatory protein (antitoxin). While their biochemical activities are often well defined, their biological functions remain unclear. In Type II TA modules, the most common class, both toxin and antitoxin are proteins, and the antitoxin inhibits the biochemical activity of the toxin via complex formation with the toxin. The different TA modules vary significantly regarding structure and biochemical activity. Both regulation of protein activity by the antitoxin and regulation of transcription can be highly complex and sometimes show striking parallels between otherwise unrelated TA modules. Interplay between the multiple levels of regulation in the broader context of the cell as a whole is most likely required for optimum fine-tuning of these systems. Thus, TA modules can go through great lengths to prevent activation and to reverse accidental activation, in agreement with recent in vivo data. These complex mechanisms seem at odds with the lack of a clear biological function.

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Structural Variations and Rearrangements in Bacterial Type II Toxin-Antitoxin Systems

Nielsen,

Brodersen

2024

Subcellular Biochemistry

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Structural Basis for Toxin Inhibition in the VapXD Toxin-Antitoxin System

Cited by 15 publications

References 43 publications

Molecular mechanism of toxin neutralization in the HipBST toxin-antitoxin system of Legionella pneumophila

Molecular mechanism of toxin neutralization in the HipBST toxin-antitoxin system of Legionella pneumophila

Prokaryote toxin–antitoxin modules: Complex regulation of an unclear function

Structural Variations and Rearrangements in Bacterial Type II Toxin-Antitoxin Systems

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