| First Author | Oda M | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 39 | Pages | 33070-9 |
| PubMed ID | 22847002 | Mgi Jnum | J:190399 |
| Mgi Id | MGI:5448790 | Doi | 10.1074/jbc.M112.393801 |
| Citation | Oda M, et al. (2012) Clostridium perfringens alpha-toxin recognizes the GM1a-TrkA complex. J Biol Chem 287(39):33070-9 |
| abstractText | 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 Neu5Acalpha2-3(Galbeta1-3GalNAcbeta1-4)Galbeta1-4Glcbeta1Cer (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 beta1,4-N-acetylgalactosaminyltransferase knock-out mice, which lack the a-series gangliosides that contain GM1a, but was highly toxic in alpha2,8-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. |
