Enterotoxin of Clostridiumperfringens type a forms ion-permeable channels in a lipid bilayer membrane

Sugimoto, Nakaba; Takagi, Masayuki; Ozutsumi, Kunihiro; Harada, S.; Matsuda, Morihiro

doi:10.1016/s0006-291x(88)80877-5

Cited by 22 publications

(11 citation statements)

References 12 publications

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“…Oligomerization of some ␤-PFTs involves N-terminal sequences that serve as a "latch" domain, linking two neighboring monomers (e.g., Staphylococcus aureus alpha-hemolysin and LukF hemolysin [30,36,[38][39][40]). CPE also has a high ␤-sheet composition (7,32) and a ␤-PFT-like ability to induce membrane permeability changes in sensitive cells (24) and forms pores or channels in artificial membranes (15,37). Our present data appear consistent with the possibility that the CPE N-terminal core sequence identified in this study acts as an N-terminal latch that mediates the protein-protein interactions needed for membrane permeability alterations.…”

Section: Discussionsupporting

confidence: 86%

“…The N-terminal 45-53 region of CPE under examination in this study is required (19) for the plasma membrane permeability alterations responsible for CPE-induced killing of mammalian cells (15,23,24,26,37). Therefore, the ability of each alanine-substituted rCPE variant to induce plasma membrane permeability changes in CaCo-2 cells was assessed in a 86 Rb release assay.…”

Section: Vol 72 2004 Site-directed Mutagenesis Of Cpe's Cytotoxicitmentioning

confidence: 99%

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Fine Mapping of the N-Terminal Cytotoxicity Region of Clostridium perfringens Enterotoxin by Site-Directed Mutagenesis

Smedley

McClane

2004

Infect Immun

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Clostridium perfringens enterotoxin (CPE) has a unique mechanism of action that results in the formation of large, sodium dodecyl sulfate-resistant complexes involving tight junction proteins; those complexes then induce plasma membrane permeability alterations in host intestinal epithelial cells, leading to cell death and epithelial desquamation. Previous deletion and point mutational studies mapped CPE receptor binding activity to the toxin's extreme C terminus. Those earlier analyses also determined that an N-terminal CPE region between residues D45 and G53 is required for large complex formation and cytotoxicity. To more finely map this N-terminal cytotoxicity region, site-directed mutagenesis was performed with recombinant CPE (rCPE). Alanine-scanning mutagenesis produced one rCPE variant, D48A, that failed to form large complexes or induce cytotoxicity, despite having normal ability to bind and form the small complex. Two saturation variants, D48E and D48N, also had a phenotype resembling that of the D48A variant, indicating that both size and charge are important at CPE residue 48. Another alanine substitution rCPE variant, I51A, was highly attenuated for large complex formation and cytotoxicity, but rCPE saturation variants I51L and I51V displayed a normal large complex formation and cytotoxicity phenotype. Collectively, these mutagenesis results identify a core CPE sequence extending from residues G47 to I51 that directly participates in large complex formation and cytotoxicity.

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Section: Discussionsupporting

confidence: 86%

Section: Vol 72 2004 Site-directed Mutagenesis Of Cpe's Cytotoxicitmentioning

confidence: 99%

Fine Mapping of the N-Terminal Cytotoxicity Region of Clostridium perfringens Enterotoxin by Site-Directed Mutagenesis

Smedley

McClane

2004

Infect Immun

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“…Ultimately, CPE is lethal to eukaryotic cells. Interestingly, CPE creates a high-conductance, linear, ion-permeable channel in lipid bilayers, consistent with a direct membrane insertion step (518). However, recent data indicate that CPE is not amphipathic in the absence of eukaryotic membrane proteins, suggesting that pore formation in the experimentally artificial lipid bilayer system is not physiologically relevant for this toxin (349).…”

Section: Clostridium Perfringens Type Amentioning

confidence: 66%

Enteric bacterial toxins: mechanisms of action and linkage to intestinal secretion.

Sears¹,

Kaper²

1996

Microbiological Reviews

318

145

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“…Whole-cell patch clamping of CaCo-2 cells demonstrated increased cationic permeability of those cells after CPE treatment (Hardy et al 1999). The enterotoxin was also shown to form pores, similar to those observed during CaCo-2 cell patch clamping, in artificial phospholipid bilayer systems lacking any proteins (Hardy et al 2001;Sugimoto et al 1988). While artificial membrane studies support the ability of CPE to interact directly with lipid bilayers, it might be noted that these studies used either CPE sonicated into membranes or exceptionally high enterotoxin concentrations, i.e., under pathophysiologic conditions, CPE binding to protein receptors remains essential.…”

Section: The Intestinal Action Of Cpementioning

confidence: 89%

The enteric toxins of Clostridium perfringens

Smedley

Fisher

Sayeed

et al. 2004

Reviews of Physiology, Biochemistry and Pharmacology

179

118

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The Gram-positive pathogen Clostridium perfringens is a major cause of human and veterinary enteric disease largely because this bacterium can produce several toxins when present inside the gastrointestinal tract. The enteric toxins of C. perfringens share two common features: (1) they are all single polypeptides of modest (approximately 25-35 kDa) size, although lacking in sequence homology, and (2) they generally act by forming pores or channels in plasma membranes of host cells. These enteric toxins include C. perfringens enterotoxin (CPE), which is responsible for the symptoms of a common human food poisoning and acts by forming pores after interacting with intestinal tight junction proteins. Two other C. perfringens enteric toxins, epsilon-toxin (a bioterrorism select agent) and beta-toxin, cause veterinary enterotoxemias when absorbed from the intestines; beta- and epsilon-toxins then apparently act by forming oligomeric pores in intestinal or extra-intestinal target tissues. The action of a newly discovered C. perfringens enteric toxin, beta2 toxin, has not yet been defined but precedent suggests it might also be a pore-former. Experience with other clostridial toxins certainly warrants continued research on these C. perfringens enteric toxins to develop their potential as therapeutic agents and tools for cellular biology.

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Enterotoxin of Clostridiumperfringens type a forms ion-permeable channels in a lipid bilayer membrane

Cited by 22 publications

References 12 publications

Fine Mapping of the N-Terminal Cytotoxicity Region of Clostridium perfringens Enterotoxin by Site-Directed Mutagenesis

Fine Mapping of the N-Terminal Cytotoxicity Region of Clostridium perfringens Enterotoxin by Site-Directed Mutagenesis

Enteric bacterial toxins: mechanisms of action and linkage to intestinal secretion.

The enteric toxins of Clostridium perfringens

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