C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeability
The pore-forming Clostridium perfringens enterotoxin (CPE), a common cause of foodborne diseases, facilitates Ca2+ influx in enterocytes, leading to cell damage. Upon binding to certain claudins (e.g., claudin-4), CPE forms oligomeric pores in the cell membrane. While the mechanism of CPE-claudin in...
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Elsevier
2025-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037024004203 |
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| author | Santhosh Kumar Nagarajan Joy Weber Daniel Roderer Jörg Piontek |
| author_facet | Santhosh Kumar Nagarajan Joy Weber Daniel Roderer Jörg Piontek |
| author_sort | Santhosh Kumar Nagarajan |
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| description | The pore-forming Clostridium perfringens enterotoxin (CPE), a common cause of foodborne diseases, facilitates Ca2+ influx in enterocytes, leading to cell damage. Upon binding to certain claudins (e.g., claudin-4), CPE forms oligomeric pores in the cell membrane. While the mechanism of CPE-claudin interaction is well understood, the structure and assembly of the pore complex remain elusive. Here, we used AlphaFold2 complex prediction, structure alignment, and molecular dynamics simulations to generate models of prepore and pore states of the CPE/claudin-4 complex. We sequentially addressed CPE-claudin, CPE-CPE, and claudin-claudin interactions, along with CPE conformational changes. The CPE pore is a hexameric variant of the typical heptameric pore stem and cap architecture of aerolysin-like β-barrel pore-forming toxins (β-PFT). The pore is lined with three hexa-glutamate rings, which differ from other β-PFTs and confer CPE-specific cation selectivity. Additionally, the pore center is indicated to be anchored by a dodecameric claudin ring formed by a cis-interaction variant of an interface found in claudin-based tight junction strands. Mutation of an interface residue inhibited CPE-mediated cell damage in vitro. We propose that this claudin ring constitutes an anchor for a twisting mechanism that drives extension and membrane insertion of the CPE β-hairpins. Our pore model agrees with previous key experimental data and provides insights into the structural mechanisms of CPE-mediated cytotoxic cation influx. |
| format | Article |
| id | doaj-art-41dfbc32bc74437ca84938c55a1c1e9c |
| institution | Kabale University |
| issn | 2001-0370 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Computational and Structural Biotechnology Journal |
| spelling | doaj-art-41dfbc32bc74437ca84938c55a1c1e9c2025-01-11T06:41:08ZengElsevierComputational and Structural Biotechnology Journal2001-03702025-01-0127287306C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeabilitySanthosh Kumar Nagarajan0Joy Weber1Daniel Roderer2Jörg Piontek3Clinical Physiology/Nutritional Medicine, Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, GermanyClinical Physiology/Nutritional Medicine, Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, GermanyLeibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Straße 10, 13125 Berlin, Germany; Corresponding authors.Clinical Physiology/Nutritional Medicine, Department of Gastroenterology, Rheumatology and Infectious Diseases, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; Corresponding authors.The pore-forming Clostridium perfringens enterotoxin (CPE), a common cause of foodborne diseases, facilitates Ca2+ influx in enterocytes, leading to cell damage. Upon binding to certain claudins (e.g., claudin-4), CPE forms oligomeric pores in the cell membrane. While the mechanism of CPE-claudin interaction is well understood, the structure and assembly of the pore complex remain elusive. Here, we used AlphaFold2 complex prediction, structure alignment, and molecular dynamics simulations to generate models of prepore and pore states of the CPE/claudin-4 complex. We sequentially addressed CPE-claudin, CPE-CPE, and claudin-claudin interactions, along with CPE conformational changes. The CPE pore is a hexameric variant of the typical heptameric pore stem and cap architecture of aerolysin-like β-barrel pore-forming toxins (β-PFT). The pore is lined with three hexa-glutamate rings, which differ from other β-PFTs and confer CPE-specific cation selectivity. Additionally, the pore center is indicated to be anchored by a dodecameric claudin ring formed by a cis-interaction variant of an interface found in claudin-based tight junction strands. Mutation of an interface residue inhibited CPE-mediated cell damage in vitro. We propose that this claudin ring constitutes an anchor for a twisting mechanism that drives extension and membrane insertion of the CPE β-hairpins. Our pore model agrees with previous key experimental data and provides insights into the structural mechanisms of CPE-mediated cytotoxic cation influx.http://www.sciencedirect.com/science/article/pii/S2001037024004203Clostridium perfringens enterotoxinClaudinPore-forming toxinsMolecular dynamics simulationsProtein complex modeling |
| spellingShingle | Santhosh Kumar Nagarajan Joy Weber Daniel Roderer Jörg Piontek C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeability Computational and Structural Biotechnology Journal Clostridium perfringens enterotoxin Claudin Pore-forming toxins Molecular dynamics simulations Protein complex modeling |
| title | C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeability |
| title_full | C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeability |
| title_fullStr | C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeability |
| title_full_unstemmed | C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeability |
| title_short | C. perfringens enterotoxin-claudin pore complex: Models for structure, mechanism of pore assembly and cation permeability |
| title_sort | c perfringens enterotoxin claudin pore complex models for structure mechanism of pore assembly and cation permeability |
| topic | Clostridium perfringens enterotoxin Claudin Pore-forming toxins Molecular dynamics simulations Protein complex modeling |
| url | http://www.sciencedirect.com/science/article/pii/S2001037024004203 |
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