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Toxins
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Structure and Function of Bacterial ADP-Ribosylation Toxins
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Structure and Function of Bacterial ADP-Ribosylation Toxins

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 23743

Special Issue Editor

Prof. Rod Merrill

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Guest Editor
Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada
Interests: Enzyme reaction mechanism of the bacterial mono-ADP-ribosyltransferase family; Inhibition mechanisms and structural complexes of toxins with inhibitors; X-ray structures of protein-protein complexes involving toxins

Special Issue Information

Bacterial mono-ADP-ribosyltransferase toxins (mART toxins) belong to a family of toxins that catalyze the covalent transfer of an ADP-ribose moiety from NAD+ to a macromolecule (often protein or DNA) in a host cell, changing target activity and impairing the function and survival of the host cell. Many members are the principal causative agents in serious diseases, including cholera, whooping cough, traveler’s diarrhea, gastroenteritis, diphtheria, and secondary infections of immune-compromised individuals. Members of this family are steadily increasing and are classified into five groups based on domain organization and host target substrate: (i) the DT-group consisting of a single-chain polypeptide with an A-B dimer; (ii) the CT-group characterized by a hexameric AB5-domain; (iii) the C2-group which includes binary toxins from the Clostridium genus with AB-domain structure, but are separate polypeptides (usually); (iv) the C3-group of single-domain proteins that often modify GTP-binding proteins, RhoA, B and C at Asn-41, but also target other substrates like vimentin and Crk proteins; and finally, (v) the Pierisin-group of DNA/RNA-targeting mART toxins. Although effective inhibitors against these five classes of mART toxins have not been readily forthcoming, recently, some encouraging results pertaining to active-site competitive inhibitors that mimic the NAD+ substrate have been reported.

Bacterial mART toxins share a common structural fold composed of ~100 residues with low sequence homology formed by a core scaffold of two perpendicular β-sheets, flanked by variable helical sub-structures and exposed-loops that constitute a cleft for the binding of the NAD+ substrate. The SCOP2 database assigns mART toxins (SCOP2: 56400) to the α + β class of proteins (SCOP2: 53931) and the “unusual” ADP-ribosylation fold (SCOP2: 56398). This fold is shared with eukaryotic mART proteins, Ecto-ARTs (SCOP2: 82814), and with the C-terminal domain of poly (ADP-ribose) polymerases known as PARPs (SCOP2: 56398), among others ADP-ribosylation proteins.

The conserved mART catalytic core is amenable to new toxin discovery using bioinformatics-based techniques that exploit an expanding library of bacterial genome sequence data. This method initially featured position-specific iterative BLAST methods, followed by a comparative structural approach implementing secondary structure prediction algorithms. Presently, a bona fide structure-based approach entails comparative modeling of 3-D structures, including substrate-binding residues while using known mART toxin structures as templates.

Prof. Rod Merrill
Guest Editor

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Keywords

  • Bacterial toxins
  • ADP-ribosylation
  • bioinformatics
  • inhibitor development
  • structural biology

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Published Papers (7 papers)

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Research

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20 pages, 4041 KiB  
Article
Mapping the DNA-Binding Motif of Scabin Toxin, a Guanine Modifying Enzyme from Streptomyces scabies
by Maritza Vatta, Bronwyn Lyons, Kayla A. Heney, Taylor Lidster and A. Rod Merrill
Toxins 2021, 13(1), 55; https://doi.org/10.3390/toxins13010055 - 13 Jan 2021
Cited by 4 | Viewed by 3105
Abstract
Scabin is a mono-ADP-ribosyltransferase toxin/enzyme and possible virulence factor produced by the agriculture pathogen, Streptomyces scabies. Recently, molecular dynamic approaches and MD simulations revealed its interaction with both NAD+ and DNA substrates. An Essential Dynamics Analysis identified a crab-claw-like mechanism, including [...] Read more.
Scabin is a mono-ADP-ribosyltransferase toxin/enzyme and possible virulence factor produced by the agriculture pathogen, Streptomyces scabies. Recently, molecular dynamic approaches and MD simulations revealed its interaction with both NAD+ and DNA substrates. An Essential Dynamics Analysis identified a crab-claw-like mechanism, including coupled changes in the exposed motifs, and the Rβ1-RLa-NLc-STTβ2-WPN-WARTT-(QxE)ARTT sequence motif was proposed as a catalytic signature of the Pierisin family of DNA-acting toxins. A new fluorescence assay was devised to measure the kinetics for both RNA and DNA substrates. Several protein variants were prepared to probe the Scabin-NAD-DNA molecular model and to reveal the reaction mechanism for the transfer of ADP-ribose to the guanine base in the DNA substrate. The results revealed that there are several lysine and arginine residues in Scabin that are important for binding the DNA substrate; also, key residues such as Asn110 in the mechanism of ADP-ribose transfer to the guanine base were identified. The DNA-binding residues are shared with ScARP from Streptomyces coelicolor but are not conserved with Pierisin-1, suggesting that the modification of guanine bases by ADP-ribosyltransferases is divergent even in the Pierisin family. Full article
(This article belongs to the Special Issue Structure and Function of Bacterial ADP-Ribosylation Toxins)
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30 pages, 3184 KiB  
Article
Several New Putative Bacterial ADP-Ribosyltransferase Toxins Are Revealed from In Silico Data Mining, Including the Novel Toxin Vorin, Encoded by the Fire Blight Pathogen Erwinia amylovora
by Olivier Tremblay, Zachary Thow, Jennifer Geddes-McAlister and A. Rod Merrill
Toxins 2020, 12(12), 792; https://doi.org/10.3390/toxins12120792 - 11 Dec 2020
Cited by 4 | Viewed by 4344
Abstract
Mono-ADP-ribosyltransferase (mART) toxins are secreted by several pathogenic bacteria that disrupt vital host cell processes in deadly diseases like cholera and whooping cough. In the last two decades, the discovery of mART toxins has helped uncover the mechanisms of disease employed by pathogens [...] Read more.
Mono-ADP-ribosyltransferase (mART) toxins are secreted by several pathogenic bacteria that disrupt vital host cell processes in deadly diseases like cholera and whooping cough. In the last two decades, the discovery of mART toxins has helped uncover the mechanisms of disease employed by pathogens impacting agriculture, aquaculture, and human health. Due to the current abundance of mARTs in bacterial genomes, and an unprecedented availability of genomic sequence data, mART toxins are amenable to discovery using an in silico strategy involving a series of sequence pattern filters and structural predictions. In this work, a bioinformatics approach was used to discover six bacterial mART sequences, one of which was a functional mART toxin encoded by the plant pathogen, Erwinia amylovora, called Vorin. Using a yeast growth-deficiency assay, we show that wild-type Vorin inhibited yeast cell growth, while catalytic variants reversed the growth-defective phenotype. Quantitative mass spectrometry analysis revealed that Vorin may cause eukaryotic host cell death by suppressing the initiation of autophagic processes. The genomic neighbourhood of Vorin indicated that it is a Type-VI-secreted effector, and co-expression experiments showed that Vorin is neutralized by binding of a cognate immunity protein, VorinI. We demonstrate that Vorin may also act as an antibacterial effector, since bacterial expression of Vorin was not achieved in the absence of VorinI. Vorin is the newest member of the mART family; further characterization of the Vorin/VorinI complex may help refine inhibitor design for mART toxins from other deadly pathogens. Full article
(This article belongs to the Special Issue Structure and Function of Bacterial ADP-Ribosylation Toxins)
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Review

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16 pages, 2766 KiB  
Review
The Buzz about ADP-Ribosylation Toxins from Paenibacillus larvae, the Causative Agent of American Foulbrood in Honey Bees
by Julia Ebeling, Anne Fünfhaus and Elke Genersch
Toxins 2021, 13(2), 151; https://doi.org/10.3390/toxins13020151 - 16 Feb 2021
Cited by 8 | Viewed by 3223
Abstract
The Gram-positive, spore-forming bacterium Paenibacillus larvae is the etiological agent of American Foulbrood, a highly contagious and often fatal honey bee brood disease. The species P. larvae comprises five so-called ERIC-genotypes which differ in virulence and pathogenesis strategies. In the past two decades, [...] Read more.
The Gram-positive, spore-forming bacterium Paenibacillus larvae is the etiological agent of American Foulbrood, a highly contagious and often fatal honey bee brood disease. The species P. larvae comprises five so-called ERIC-genotypes which differ in virulence and pathogenesis strategies. In the past two decades, the identification and characterization of several P. larvae virulence factors have led to considerable progress in understanding the molecular basis of pathogen-host-interactions during P. larvae infections. Among these virulence factors are three ADP-ribosylating AB-toxins, Plx1, Plx2, and C3larvin. Plx1 is a phage-born toxin highly homologous to the pierisin-like AB-toxins expressed by the whites-and-yellows family Pieridae (Lepidoptera, Insecta) and to scabin expressed by the plant pathogen Streptomyces scabiei. These toxins ADP-ribosylate DNA and thus induce apoptosis. While the presumed cellular target of Plx1 still awaits final experimental proof, the classification of the A subunits of the binary AB-toxins Plx2 and C3larvin as typical C3-like toxins, which ADP-ribosylate Rho-proteins, has been confirmed experimentally. Normally, C3-exoenzymes do not occur together with a B subunit partner, but as single domain toxins. Interestingly, the B subunits of the two P. larvae C3-like toxins are homologous to the B-subunits of C2-like toxins with striking structural similarity to the PA-63 protomer of Bacillus anthracis. Full article
(This article belongs to the Special Issue Structure and Function of Bacterial ADP-Ribosylation Toxins)
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12 pages, 2589 KiB  
Review
Common Mechanism for Target Specificity of Protein- and DNA-Targeting ADP-Ribosyltransferases
by Toru Yoshida and Hideaki Tsuge
Toxins 2021, 13(1), 40; https://doi.org/10.3390/toxins13010040 - 7 Jan 2021
Cited by 9 | Viewed by 2678
Abstract
Many bacterial pathogens utilize ADP-ribosyltransferases (ARTs) as virulence factors. The critical aspect of ARTs is their target specificity. Each individual ART modifies a specific residue of its substrates, which could be proteins, DNA, or antibiotics. However, the mechanism underlying this specificity is poorly [...] Read more.
Many bacterial pathogens utilize ADP-ribosyltransferases (ARTs) as virulence factors. The critical aspect of ARTs is their target specificity. Each individual ART modifies a specific residue of its substrates, which could be proteins, DNA, or antibiotics. However, the mechanism underlying this specificity is poorly understood. Here, we review the substrate recognition mechanism and target residue specificity based on the available complex structures of ARTs and their substrates. We show that there are common mechanisms of target residue specificity among protein- and DNA-targeting ARTs. Full article
(This article belongs to the Special Issue Structure and Function of Bacterial ADP-Ribosylation Toxins)
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25 pages, 9070 KiB  
Review
Development of Anti-Virulence Therapeutics against Mono-ADP-Ribosyltransferase Toxins
by Miguel R. Lugo and Allan R. Merrill
Toxins 2021, 13(1), 16; https://doi.org/10.3390/toxins13010016 - 25 Dec 2020
Cited by 5 | Viewed by 2971
Abstract
Mono-ADP-ribosyltransferase toxins are often key virulence factors produced by pathogenic bacteria as tools to compromise the target host cell. These toxins are enzymes that use host cellular NAD+ as the substrate to modify a critical macromolecule target in the host cell machinery. [...] Read more.
Mono-ADP-ribosyltransferase toxins are often key virulence factors produced by pathogenic bacteria as tools to compromise the target host cell. These toxins are enzymes that use host cellular NAD+ as the substrate to modify a critical macromolecule target in the host cell machinery. This post-translational modification of the target macromolecule (usually protein or DNA) acts like a switch to turn the target activity on or off resulting in impairment of a critical process or pathway in the host. One approach to stymie bacterial pathogens is to curtail the toxic action of these factors by designing small molecules that bind tightly to the enzyme active site and prevent catalytic function. The inactivation of these toxins/enzymes is targeted for the site of action within the host cell and small molecule therapeutics can function as anti-virulence agents by disarming the pathogen. This represents an alternative strategy to antibiotic therapy with the potential as a paradigm shift that may circumvent multi-drug resistance in the offending microbe. In this review, work that has been accomplished during the past two decades on this approach to develop anti-virulence compounds against mono-ADP-ribosyltransferase toxins will be discussed. Full article
(This article belongs to the Special Issue Structure and Function of Bacterial ADP-Ribosylation Toxins)
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12 pages, 2407 KiB  
Review
Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae
by Kohei Ogura, Kinnosuke Yahiro and Joel Moss
Toxins 2021, 13(1), 12; https://doi.org/10.3390/toxins13010012 - 24 Dec 2020
Cited by 14 | Viewed by 4245
Abstract
Pathogenic microorganisms produce various virulence factors, e.g., enzymes, cytotoxins, effectors, which trigger development of pathologies in infectious diseases. Cholera toxin (CT) produced by O1 and O139 serotypes of Vibrio cholerae (V. cholerae) is a major cytotoxin causing severe diarrhea. Cholix cytotoxin [...] Read more.
Pathogenic microorganisms produce various virulence factors, e.g., enzymes, cytotoxins, effectors, which trigger development of pathologies in infectious diseases. Cholera toxin (CT) produced by O1 and O139 serotypes of Vibrio cholerae (V. cholerae) is a major cytotoxin causing severe diarrhea. Cholix cytotoxin (Cholix) was identified as a novel eukaryotic elongation factor 2 (eEF2) adenosine-diphosphate (ADP)-ribosyltransferase produced mainly in non-O1/non-O139 V. cholerae. The function and role of Cholix in infectious disease caused by V. cholerae remain unknown. The crystal structure of Cholix is similar to Pseudomonas exotoxin A (PEA) which is composed of an N-terminal receptor-recognition domain and a C-terminal ADP-ribosyltransferase domain. The endocytosed Cholix catalyzes ADP-ribosylation of eEF2 in host cells and inhibits protein synthesis, resulting in cell death. In a mouse model, Cholix caused lethality with severe liver damage. In this review, we describe the mechanism underlying Cholix-induced cytotoxicity. Cholix-induced apoptosis was regulated by mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways, which dramatically enhanced tumor necrosis factor-α (TNF-α) production in human liver, as well as the amount of epithelial-like HepG2 cancer cells. In contrast, Cholix induced apoptosis in hepatocytes through a mitochondrial-dependent pathway, which was not stimulated by TNF-α. These findings suggest that sensitivity to Cholix depends on the target cell. A substantial amount of information on PEA is provided in order to compare/contrast this well-characterized mono-ADP-ribosyltransferase (mART) with Cholix. Full article
(This article belongs to the Special Issue Structure and Function of Bacterial ADP-Ribosylation Toxins)
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Other

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1 pages, 187 KiB  
Erratum
Erratum: Tremblay, O., et al. Several New Putative Bacterial ADP-Ribosyltransferase Toxins Are Revealed from In Silico Data Mining, Including the Novel Toxin Vorin, Encoded by the Fire Blight Pathogen Erwinia amylovora. Toxins 2020, 12, 792
by Olivier Tremblay, Zachary Thow, Jennifer Geddes-McAlister and A. Rod Merrill
Toxins 2021, 13(3), 229; https://doi.org/10.3390/toxins13030229 - 22 Mar 2021
Viewed by 1600
Abstract
The authors wish to make the following corrections to this paper [...] Full article
(This article belongs to the Special Issue Structure and Function of Bacterial ADP-Ribosylation Toxins)
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