ArticleProceedings of the National Academy of Sciences of the United States of America2011
Structure, function and latency regulation of a bacterial enterotoxin potentially derived from a mammalian adamalysin/ADAM xenolog.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 75 citations in OpenAlex.
- The protease code of the bacterial gut microbiota: ecological regulation, barrier disruption, and rewiring host defense and signaling.Gut microbes · 2026Review
- Orally available designed miniproteins inhibit enterotoxigenicbioRxiv : the preprint server for biology · 2026Article
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- The "Direct Structural Disruption" Hypothesis:Toxins · 2026Review
- Repurposing Drugs as Bacteroides fragilis BFT-3 Inhibitors in the Animal Infection Model Galleria mellonella.Annals of the New York Academy of Sciences · 2026Article
- Biological Mechanisms of EnterotoxigenicToxins · 2025Review
- Dissecting Cytophagalysin: Structural and Biochemical Studies of a Bacterial Pappalysin-Family Metallopeptidase.Biomolecules · 2024Article
- Targeting microbial pathogenic mechanisms as a novel therapeutic strategy in IBD.Molecular medicine (Cambridge, Mass.) · 2024Review
- Overview of Bacterial Protein Toxins from Pathogenic Bacteria: Mode of Action and Insights into Evolution.Toxins · 2024Review
- Bacteroides fragilis toxin expression enables lamina propria niche acquisition in the developing mouse gut.Nature microbiology · 2024Article
- Promotion of Colitis in B Cell-Deficient C57BL/6 Mice Infected with EnterotoxigenicInternational journal of molecular sciences · 2023Article
- A comprehensive review on human disease-causing bacterial proteases and their impeding agents.Archives of microbiology · 2023Review
- Classification of domains in predicted structures of the human proteome.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Screening and epitope characterization of diagnostic nanobody against total and activatedFrontiers in immunology · 2023Article
- Zymogenic latency in an ∼250-million-year-old astacin metallopeptidase.Acta crystallographica. Section D, Structural biology · 2022Article
- Repositioning small molecule drugs as allosteric inhibitors of the BFT-3 toxin from enterotoxigenic Bacteroides fragilis.Protein science : a publication of the Protein Society · 2022Article
- An Introduction to Bacterial Biofilms and Their Proteases, and Their Roles in Host Infection and Immune Evasion.Biomolecules · 2022Review
- Structural and evolutionary insights into astacin metallopeptidases.Frontiers in molecular biosciences · 2022Article
- A clostripain-like protease plays a major role in generating the secretome of enterotoxigenic Bacteroides fragilis.Molecular microbiology · 2021Article
- Reversible autoinhibitory regulation ofProceedings of the National Academy of Sciences of the United States of America · 2020Article
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Enterotoxigenic Bacteroides fragilis is the most frequent disease-causing anaerobe in the intestinal tract of humans and livestock and its specific virulence factor is fragilysin, also known as B. fragilis toxin. This is a 21-kDa zinc-dependent metallopeptidase existing in three closely related isoforms that hydrolyze E-cadherin and contribute to secretory diarrhea, and possibly to inflammatory bowel disease and colorectal cancer. Here we studied the function and zymogenic structure of fragilysin-3 and found that its activity is repressed by a ∼170-residue prodomain, which is the largest hitherto structurally characterized for a metallopeptidase. This prodomain plays a role in both the latency and folding stability of the catalytic domain and it has no significant sequence similarity to any known protein. The prodomain adopts a novel fold and inhibits the protease domain via an aspartate-switch mechanism. The catalytic fragilysin-3 moiety is active against several protein substrates and its structure reveals a new family prototype within the metzincin clan of metallopeptidases. It shows high structural similarity despite negligible sequence identity to adamalysins/ADAMs, which have only been described in eukaryotes. Because no similar protein has been found outside enterotoxigenic B. fragilis, our findings support that fragilysins derived from a mammalian adamalysin/ADAM xenolog that was co-opted by B. fragilis through a rare case of horizontal gene transfer from a eukaryotic cell to a bacterial cell. Subsequently, this co-opted peptidase was provided with a unique chaperone and latency maintainer in the time course of evolution to render a robust and dedicated toxin to compromise the intestinal epithelium of mammalian hosts.
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