ArticleThe Journal of biological chemistry2012
Mechanism of Clostridium perfringens enterotoxin interaction with claudin-3/-4 protein suggests structural modifications of the toxin to target specific claudins.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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49 citing papers in PubMed, 91 citations in OpenAlex.
- Structures of a synthetic antibody selected against and bound to the C-terminal domain of Clostridium perfringens enterotoxin.Protein science : a publication of the Protein Society · 2025Article
- Plateau Environment, Gut Microbiota, and Depression: A Possible Concealed Connection?Current issues in molecular biology · 2025Review
- Article
- Cryo-EM structures of Clostridium perfringens enterotoxin bound to its human receptor, claudin-4.Structure (London, England : 1993) · 2024Article
- Structural and biophysical insights into targeting of claudin-4 by a synthetic antibody fragment.Communications biology · 2024Article
- Upregulation of occludin by cytolethal distending toxin facilitatesInfection and immunity · 2023Article
- Storming the gate: New approaches for targeting the dynamic tight junction for improved drug delivery.Advanced drug delivery reviews · 2023Review
- cCPE Fusion Proteins as Molecular Probes to Detect Claudins and Tight Junction Dysregulation in Gastrointestinal Cell Lines, Tissue Explants and Patient-Derived Organoids.Pharmaceutics · 2023Article
- Computational study of ion permeation through claudin-4 paracellular channels.Annals of the New York Academy of Sciences · 2022Article
- The interaction among gut microbes, the intestinal barrier and short chain fatty acids.Animal nutrition (Zhongguo xu mu shou yi xue hui) · 2022Review
- Review
- Ablation of Red Stable Transfected Claudin Expressing Canine Prostate Adenocarcinoma and Transitional Cell Carcinoma Cell Lines by C-CPE Gold-Nanoparticle-Mediated Laser Intervention.International journal of molecular sciences · 2021Article
- Review
- Brain endothelial tricellular junctions as novel sites for T cell diapedesis across the blood-brain barrier.Journal of cell science · 2021Article
- Structural basis forProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Radiolabeled cCPE Peptides for SPECT Imaging of Claudin-4 Overexpression in Pancreatic Cancer.Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2020Article
- Targeting claudin-overexpressing thyroid and lung cancer by modified Clostridium perfringens enterotoxin.Molecular oncology · 2020Article
- Use of ModifiedInternational journal of molecular sciences · 2019Article
- Claudin-9 structures reveal mechanism for toxin-induced gut barrier breakdown.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Potential for Tight Junction Protein-Directed Drug Development Using Claudin Binders and Angubindin-1.International journal of molecular sciences · 2019Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Claudins (Cld) are essential constituents of tight junctions. Domain I of Clostridium perfringens enterotoxin (cCPE) binds to the second extracellular loop (ECL2) of a subset of claudins, e.g. Cld3/4 and influences tight junction formation. We aimed to identify interacting interfaces and to alter claudin specificity of cCPE. Mutagenesis, binding assays, and molecular modeling were performed. Mutation-guided ECL2 docking of Cld3/4 onto the crystal structure of cCPE revealed a common orientation of the proposed ECL2 helix-turn-helix motif in the binding cavity of cCPE: residues Leu(150)/Leu(151) of Cld3/4 bind similarly to a hydrophobic pit formed by Tyr(306), Tyr(310), and Tyr(312) of cCPE, and Pro(152)/Ala(153) of Cld3/4 is proposed to bind to a second pit close to Leu(223), Leu(254), and Leu(315). However, sequence variation in ECL2 of these claudins is likely responsible for slightly different conformation in the turn region, which is in line with different cCPE interaction modes of Cld3 and Cld4. Substitutions of other so far not characterized cCPE residues lining the pocket revealed two spatially separated groups of residues (Leu(223), Asp(225), and Arg(227) and Leu(254), lle(258), and Asp(284)), which are involved in binding to Cld3 and Cld4, albeit differently. Involvement of Asn(148) of Cld3 in cCPE binding was confirmed, whereas no evidence for involvement of Lys(156) or Arg(157) was found. We show structure-based alteration of cCPE generating claudin binders, which interact subtype-specific preferentially either with Cld3 or with Cld4. The obtained mutants and mechanistic insights will advance the design of cCPE-based modulators to target specific claudin subtypes related either to paracellular barriers that impede drug delivery or to tumors.
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