ArticleProceedings of the National Academy of Sciences of the United States of America2014
Translocation domain mutations affecting cellular toxicity identify the Clostridium difficile toxin B pore.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 66 citations in OpenAlex.
- Article
- Mouse monoclonal antibodies againstInfection and immunity · 2025Article
- MappingmBio · 2025Article
- A sequence invariable region in TcdB2 is required for toxin escape fromJournal of bacteriology · 2024Article
- Structure and activation mechanism of the Makes caterpillars floppy 1 toxin.Nature communications · 2023Article
- Unconventional structure and mechanisms for membrane interaction and translocation of the NF-κB-targeting toxin AIP56.Nature communications · 2023Article
- Development and characterization of phage display-derived anti-toxin antibodies neutralizing TcdA and TcdB ofMicrobiology spectrum · 2023Article
- Nanobodies against C. difficile TcdA and TcdB reveal unexpected neutralizing epitopes and provide a toolkit for toxin quantitation in vivo.PLoS pathogens · 2023Article
- Review
- Small Molecule Inhibition of an Exopolysaccharide Modification Enzyme is a Viable Strategy To Block Pseudomonas aeruginosa Pel Biofilm Formation.Microbiology spectrum · 2023Article
- Review
- Structure and conformational dynamics ofLife science alliance · 2022Article
- Structure of the glucosyltransferase domain of TcdA in complex with RhoA provides insights into substrate recognition.Scientific reports · 2022Article
- Clostridioides difficile toxins: mechanisms of action and antitoxin therapeutics.Nature reviews. Microbiology · 2022Review
- Structural dynamics of receptor recognition and pH-induced dissociation of full-length Clostridioides difficile Toxin B.PLoS biology · 2022Article
- High-resolution structure of native toxin A from Clostridioides difficile.EMBO reports · 2022Article
- Neutralizing epitopes onFrontiers in immunology · 2022Article
- Novel structural insights for a pair of monoclonal antibodies recognizing non-overlapping epitopes of the glucosyltransferase domain ofCurrent research in structural biology · 2022Article
- Structural basis for selective modification of Rho and Ras GTPases byScience advances · 2021Article
- Large Clostridial Toxins: Mechanisms and Roles in Disease.Microbiology and molecular biology reviews : MMBR · 2021Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Disease associated with Clostridium difficile infection is caused by the actions of the homologous toxins TcdA and TcdB on colonic epithelial cells. Binding to target cells triggers toxin internalization into acidified vesicles, whereupon cryptic segments from within the 1,050-aa translocation domain unfurl and insert into the bounding membrane, creating a transmembrane passageway to the cytosol. Our current understanding of the mechanisms underlying pore formation and the subsequent translocation of the upstream cytotoxic domain to the cytosol is limited by the lack of information available regarding the identity and architecture of the transmembrane pore. Here, through systematic perturbation of conserved sites within predicted membrane-insertion elements of the translocation domain, we uncovered highly sensitive residues--clustered between amino acids 1,035 and 1,107--that when individually mutated, reduced cellular toxicity by as much as >1,000-fold. We demonstrate that defective variants are defined by impaired pore formation in planar lipid bilayers and biological membranes, resulting in an inability to intoxicate cells through either apoptotic or necrotic pathways. These findings along with the unexpected similarities uncovered between the pore-forming "hotspots" of TcdB and the well-characterized α-helical diphtheria toxin translocation domain provide insights into the structure and mechanism of formation of the translocation pore for this important class of pathogenic toxins.
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