Identification of a diphtheria toxin‐like gene family beyond the <i>Corynebacterium</i> genus

Mansfield, Michael J.; Sugiman-Marangos, Seiji; Melnyk, Roman A.; Doxey, Andrew C.

doi:10.1002/1873-3468.13208

Cited by 17 publications

(15 citation statements)

References 52 publications

(56 reference statements)

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“…A query with Pfam PF01742 (botulinum neurotoxin protease) reveals a taxonomic distribution outside of Clostridium including the lineages Weissella and Chryseobacterium , consistent with earlier analyses (31,32) (Supplementary Figure S2). Similarly, a search with the diphtheria toxin domains (PF02763 or PF02764) reveals homologs in related genera Streptomyces and Austwickia , again reproducing recent analyses (33) almost instantaneously (Supplementary Figure S3). These examples illustrate the use of AnnoTree as a hypothesis-generating tool by revealing distributions of gene families that may be new or unexpected to users.…”

Section: Resultssupporting

confidence: 82%

AnnoTree: visualization and exploration of a functionally annotated microbial tree of life

Mendler

Chen

Parks

et al. 2019

Nucleic Acids Research

239

265

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Bacterial genomics has revolutionized our understanding of the microbial tree of life; however, mapping and visualizing the distribution of functional traits across bacteria remains a challenge. Here, we introduce AnnoTree—an interactive, functionally annotated bacterial tree of life that integrates taxonomic, phylogenetic and functional annotation data from over 27 000 bacterial and 1500 archaeal genomes. AnnoTree enables visualization of millions of precomputed genome annotations across the bacterial and archaeal phylogenies, thereby allowing users to explore gene distributions as well as patterns of gene gain and loss in prokaryotes. Using AnnoTree, we examined the phylogenomic distributions of 28 311 gene/protein families, and measured their phylogenetic conservation, patchiness, and lineage-specificity within bacteria. Our analyses revealed widespread phylogenetic patchiness among bacterial gene families, reflecting the dynamic evolution of prokaryotic genomes. Genes involved in phage infection/defense, mobile elements, and antibiotic resistance dominated the list of most patchy traits, as well as numerous intriguing metabolic enzymes that appear to have undergone frequent horizontal transfer. We anticipate that AnnoTree will be a valuable resource for exploring prokaryotic gene histories, and will act as a catalyst for biological and evolutionary hypothesis generation. AnnoTree is freely available at http://annotree.uwaterloo.ca

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Section: Resultssupporting

confidence: 82%

AnnoTree: visualization and exploration of a functionally annotated microbial tree of life

Mendler

Chen

Parks

et al. 2019

Nucleic Acids Research

239

265

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“…1a). Group I includes a large family of ADP-ribosyltransferase toxins, including diphtheria toxin-like sequences 31 and putative ADP-ribosyltransferase toxins (ADPRTs) from entomopathogenic fungi (Table S1). These sequences possess partial similarity only to the BoNT translocation domain (17.3% maximum sequence identity, PSI-BLAST E -value = 7 × 10 −40 ).…”

Section: Resultsmentioning

confidence: 99%

Bioinformatic discovery of a toxin family in Chryseobacterium piperi with sequence similarity to botulinum neurotoxins

Mansfield

Wentz

Zhang

et al. 2019

Sci Rep

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Clostridial neurotoxins (CNTs), which include botulinum neurotoxins (BoNTs) and tetanus neurotoxin (TeNT), are the most potent toxins known to science and are the causative agents of botulism and tetanus, respectively. The evolutionary origins of CNTs and their relationships to other proteins remains an intriguing question. Here we present a large-scale bioinformatic screen for putative toxin genes in all currently available genomes. We detect a total of 311 protein sequences displaying at least partial homology to BoNTs, including 161 predicted toxin sequences that have never been characterized. We focus on a novel toxin family from Chryseobacterium piperi with homology to BoNTs. We resequenced the genome of C. piperi to confirm and further analyze the genomic context of these toxins, and also examined their potential toxicity by expression of the protease domain of one C. piperi toxin in human cells. Our analysis suggests that these C. piperi sequences encode a novel family of metalloprotease toxins that are distantly related to BoNTs with similar domain architecture. These toxins target a yet unknown class of substrates, potentially reflecting divergence in substrate specificity between the metalloprotease domains of these toxins and the related metalloprotease domain of clostridial neurotoxins.

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“…Of the seven homologs we identified previously [6], AT and PT were the only two lacking the canonical 'RXXR' furin cleavage motif in the loop joining the putative catalytic fragments with the downstream putative translocation and receptor binding fragments (Figure 3A). Of note, however, AT and PT contain both Cys residues (C217/C231 and C239/C251, respectively) that bound this region, and the crystal structures confirm formation of the inter-fragment disulfide bonds (Figure 3A).…”

Section: At and Pt Lack The Canonical Protease Activation Site Of Dtmentioning

confidence: 99%

Structure-function analysis of distant diphtheria toxin homologs reveals insights into host adaptation

Sugiman-Marangos

Gill

Mansfield

et al. 2021

Preprint

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Diphtheria toxin (DT) is the archetype of bacterial exotoxins implicated in human diseases and has played a central role in defining the field of toxinology since its discovery in 1888. Despite being one of the most extensively characterized bacterial toxins, the origins and molecular evolution of DT host specialization remain unknown. Here, we determined high-resolution structures of two recently discovered distant homologs of DT. These DT-like proteins from non-human associated Streptomyces albireticuli (17% identity to DT) and Seinonella peptonophila (20% identity to DT) display remarkable structural similarity to DT enabling a comparative investigation into DT's unique toxicity toward mammalian cells. We find that the individual domains of DT-like toxins retain two critical features of DT's activity: full catalytic function and ability to translocate across mammalian cell membranes. However, we show that receptor-binding, pH-dependent pore-formation and proteolytic release of the cytotoxic enzyme into the cytosol are not optimized for human cell physiology and thus unable to efficiently deliver the cytotoxic cargo into human hosts. Our work provides structural insights into DT's evolutionary history, and implies key transitions required for the emergence of human-specificity of a major bacterial exotoxin with an important history in human disease.

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Identification of a diphtheria toxin‐like gene family beyond the Corynebacterium genus

Cited by 17 publications

References 52 publications

AnnoTree: visualization and exploration of a functionally annotated microbial tree of life

AnnoTree: visualization and exploration of a functionally annotated microbial tree of life

Bioinformatic discovery of a toxin family in Chryseobacterium piperi with sequence similarity to botulinum neurotoxins

Structure-function analysis of distant diphtheria toxin homologs reveals insights into host adaptation

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