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PMID:22847002
| Citation |
Oda, M, Kabura, M, Takagishi, T, Suzue, A, Tominaga, K, Urano, S, Nagahama, M, Kobayashi, K, Furukawa, K, Furukawa, K and Sakurai, J (2012) Clostridium perfringens alpha-toxin recognizes the GM1a-TrkA complex. J. Biol. Chem. 287:33070-9 |
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| Abstract |
Clostridium perfringens alpha-toxin is the major virulence factor in the pathogenesis of gas gangrene. Alpha-toxin is a 43-kDa protein with two structural domains; the N-domain contains the catalytic site and coordinates the divalent metal ions, and the C-domain is a membrane-binding site. The role of the exposed loop region (72-93 residues) in the N-domain, however, has been unclear. Here we show that this loop contains a ganglioside binding motif (H … SXWY … G) that is the same motif seen in botulinum neurotoxin and directly binds to a specific conformation of the ganglioside Neu5Acα2-3(Galβ1-3GalNAcβ1-4)Galβ1-4Glcβ1Cer (GM1a) through a carbohydrate moiety. Confocal microscopy analysis using fluorescently labeled BODIPY-GM1a revealed that the toxin colocalized with GM1a and induced clustering of GM1a on the cell membranes. Alpha-toxin was only slightly toxic in β1,4-N-acetylgalactosaminyltransferase knock-out mice, which lack the a-series gangliosides that contain GM1a, but was highly toxic in α2,8-sialyltransferase knock-out mice, which lack both b-series and c-series gangliosides, similar to the control mice. Moreover, experiments with site-directed mutants indicated that Trp-84 and Tyr-85 in the exposed alpha-toxin loop play an important role in the interaction with GM1a and subsequent activation of TrkA. These results suggest that binding of alpha-toxin to GM1a facilitates the activation of the TrkA receptor and induces a signal transduction cascade that promotes the release of chemokines. Therefore, we conclude that GM1a is the primary cellular receptor for alpha-toxin, which can be a potential target for drug developed against this pathogen. |
| Links |
PubMed PMC3463319 Online version:10.1074/jbc.M112.393801 |
| Keywords |
Amino Acid Motifs; Amino Acid Substitution; Animals; Bacterial Toxins; Calcium-Binding Proteins; Cell Line; Chemokines/genetics; Chemokines/secretion; Clostridium perfringens; G(M1) Ganglioside/analogs & derivatives; G(M1) Ganglioside/genetics; G(M1) Ganglioside/metabolism; Macrophages, Peritoneal/metabolism; Mice; Mice, Knockout; Mutagenesis, Site-Directed; N-Acetylgalactosaminyltransferases/genetics; N-Acetylgalactosaminyltransferases/metabolism; Protein Structure, Tertiary; Receptor, trkA/genetics; Receptor, trkA/metabolism; Sialyltransferases/genetics; Sialyltransferases/metabolism; Type C Phospholipases |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0044507: positive regulation of receptor activity in other organism |
ECO:0000314: |
P |
Using direct flourescent binding array, the Clostridium perfringens alpha toxin binds very tightly with ganglioside GM1a because of its lack of sailic acid. The alpha toxin was also shown to induce IL-8 by binding to A549 cells. This was demonstrated by various concentrations of alpha toxin to 549 cells and measuring the amount of IL-8. |
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Notes
See also
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