{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:34:08Z","timestamp":1790426048998,"version":"4.1.0"},"reference-count":52,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2015,12,3]],"date-time":"2015-12-03T00:00:00Z","timestamp":1449100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Clostridium perfringens alpha-toxin is a key mediator of gas gangrene, which is a life-threatening infection that manifests as fever, pain, edema, myonecrosis, and gas production. Alpha-toxin possesses phospholipase C and sphingomyelinase activities. The toxin is composed of an N-terminal domain (1\u2013250 aa, N-domain), which is the catalytic site, and a C-terminal domain (251\u2013370 aa, C-domain), which is the membrane-binding site. Immunization of mice with the C-domain of alpha-toxin prevents the gas gangrene caused by C. perfringens, whereas immunization with the N-domain has no effect. The central loop domain (55\u201393 aa), especially H\u2026.SW84Y85\u2026.G, plays an important role in the interaction with ganglioside GM1a. The toxin binds to lipid rafts in the presence of a GM1a\/TrkA complex, and metabolites from phosphatidylcholine to diacylglycerol through the enzymatic activity of alpha-toxin itself. These membrane dynamics leads to the activation of endogenous PLC\u03b3-1 via TrkA. In addition, treatment with alpha-toxin leads to the formation of diacylglycerol at membrane rafts in ganglioside-deficient DonQ cells; this in turn triggers endocytosis and cell death. This article summarizes the current the membrane-binding mechanism of alpha-toxin in detail.<\/jats:p>","DOI":"10.3390\/toxins7124880","type":"journal-article","created":{"date-parts":[[2015,12,3]],"date-time":"2015-12-03T11:12:09Z","timestamp":1449141129000},"page":"5268-5275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Membrane-Binding Mechanism of Clostridium perfringens Alpha-Toxin"],"prefix":"10.3390","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7384-4429","authenticated-orcid":false,"given":"Masataka","family":"Oda","sequence":"first","affiliation":[{"name":"Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, 2-5274, Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Terao","sequence":"additional","affiliation":[{"name":"Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, 2-5274, Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Nagahama","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1128\/br.26.2_pt_1-2.177-274.1962","article-title":"The histotoxic clostridial infections of man","volume":"26","author":"Maclennan","year":"1962","journal-title":"Bacteriol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1086\/315756","article-title":"Clostridial gas gangrene. I. Cellular and molecular mechanisms of microvascular dysfunction induced by exotoxins of Clostridium perfringens","volume":"182","author":"Bryant","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1086\/315757","article-title":"Clostridial gas gangrene. II. Phospholipase C\u2014Induced activation of platelet gpiibiiia mediates vascular occlusion and myonecrosis in Clostridium perfringens gas gangrene","volume":"182","author":"Bryant","year":"2000","journal-title":"J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1093\/jb\/mvh161","article-title":"Clostridium perfringens alpha-toxin: Characterization and mode of action","volume":"136","author":"Sakurai","year":"2004","journal-title":"J. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1128\/IAI.74.5.2876-2886.2006","article-title":"Signal transduction mechanism involved in Clostridium perfringens alpha-toxin-induced superoxide anion generation in rabbit neutrophils","volume":"74","author":"Oda","year":"2006","journal-title":"Infect. Immun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1124\/jpet.108.143677","article-title":"Effect of erythromycin on biological activities induced by Clostridium perfringens alpha-toxin","volume":"327","author":"Oda","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"12181","DOI":"10.1074\/jbc.M307046200","article-title":"Clostridium perfringens alpha-toxin activates the sphingomyelin metabolism system in sheep erythrocytes","volume":"279","author":"Ochi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_8","unstructured":"Stevens, D.L., and Bryant, A.E. (1999). The Comprehensive Sourcebook of Bacterial Protein Toxins, Academic Press. [2nd ed.]."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1128\/mr.57.2.347-366.1993","article-title":"Bacterial phospholipases C","volume":"57","author":"Titball","year":"1993","journal-title":"Microbiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/1447","article-title":"Structure of the key toxin in gas gangrene","volume":"5","author":"Naylor","year":"1998","journal-title":"Nat. Struct. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"91","DOI":"10.2174\/1389203003381487","article-title":"The C-terminal domain of pancreatic lipase: Functional and structural analogies with C2 domains","volume":"1","author":"Chahinian","year":"2000","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1438-4221(00)80040-5","article-title":"Opening of the active site of Clostridium perfringens alpha-toxin may be triggered by membrane binding","volume":"290","author":"Titball","year":"2000","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/338357a0","article-title":"High-resolution (1.5 \u00c5) crystal structure of phospholipase C from bacillus cereus","volume":"338","author":"Hough","year":"1989","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"R588","DOI":"10.1016\/S0960-9822(99)80380-7","article-title":"The PLAT domain: A new piece in the PKD1 puzzle","volume":"9","author":"Bateman","year":"1999","journal-title":"Curr. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1006\/jmbi.1999.3279","article-title":"Characterisation of the calcium-binding C-terminal domain of Clostridium perfringens alpha-toxin","volume":"294","author":"Naylor","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/S0014-5793(01)02385-7","article-title":"Tyrosine 331 and phenylalanine 334 in Clostridium perfringens alpha-toxin are essential for cytotoxic activity","volume":"495","author":"Jepson","year":"2001","journal-title":"FEBS Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5191","DOI":"10.1046\/j.1432-1327.2000.01588.x","article-title":"Identification of residues critical for toxicity in Clostridium perfringens phospholipase c, the key toxin in gas gangrene","volume":"267","author":"Guillouard","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1111\/j.1348-0421.2002.tb02748.x","article-title":"Role of the C-domain in the biological activities of Clostridium perfringens alpha-toxin","volume":"46","author":"Nagahama","year":"2002","journal-title":"Microbiol. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2940","DOI":"10.1016\/j.bbamem.2007.08.016","article-title":"Effect of unsaturated bonds in the sn-2 acyl chain of phosphatidylcholine on the membrane-damaging action of Clostridium perfringens alpha-toxin toward liposomes","volume":"1768","author":"Nagahama","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/0264-410X(93)90051-X","article-title":"A genetically engineered vaccine against the alpha-toxin of Clostridium perfringens protects mice against experimental gas gangrene","volume":"11","author":"Williamson","year":"1993","journal-title":"Vaccine"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/j.1574-6968.1993.tb06293.x","article-title":"Biochemical and immunological properties of the C-terminal domain of the alpha-toxin of Clostridium perfringens","volume":"110","author":"Titball","year":"1993","journal-title":"FEMS Microbiol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1086\/422691","article-title":"Immunization with the C-domain of alpha -toxin prevents lethal infection, localizes tissue injury, and promotes host response to challenge with Clostridium perfringens","volume":"190","author":"Stevens","year":"2004","journal-title":"J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.molimm.2015.01.005","article-title":"Immunization with recombinant bivalent chimera r-Cpae confers protection against alpha toxin and enterotoxin of Clostridium perfringens type A in murine model","volume":"65","author":"Shreya","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1111\/1348-0421.12036","article-title":"A recombinant carboxy-terminal domain of alpha-toxin protects mice against Clostridium perfringens","volume":"57","author":"Nagahama","year":"2013","journal-title":"Microbiol. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"913","DOI":"10.2174\/1389201014666131226124348","article-title":"Vaccines against Clostridium perfringens alpha-toxin","volume":"14","author":"Nagahama","year":"2013","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S0022-2836(02)00290-5","article-title":"Crystal structure of the C. perfringens alpha-toxin with the active site closed by a flexible loop region","volume":"319","author":"Eaton","year":"2002","journal-title":"J. Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.jmb.2003.07.016","article-title":"Clostridium absonum alpha-toxin: New insights into clostridial phospholipase C substrate binding and specificity","volume":"333","author":"Clark","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.micpath.2007.12.003","article-title":"Identification of the receptor-binding sites in the carboxyl-terminal half of the heavy chain of botulinum neurotoxin types C and D","volume":"44","author":"Tsukamoto","year":"2008","journal-title":"Microb. Pathog."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33070","DOI":"10.1074\/jbc.M112.393801","article-title":"Clostridium perfringens alpha-toxin recognizes the GM1a-Trka complex","volume":"287","author":"Oda","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26001","DOI":"10.1074\/jbc.273.40.26001","article-title":"Glucosylceramide synthase inhibitor inhibits the action of nerve growth factor in PC12 cells","volume":"273","author":"Mutoh","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1042\/BJ20070090","article-title":"Fucoganglioside alpha-fucosyl(alpha-galactosyl)-GM1: A novel member of lipid membrane microdomain components involved in PC12 cell neuritogenesis","volume":"407","author":"Yamazaki","year":"2007","journal-title":"Biochem. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1046\/j.1471-4159.2002.00831.x","article-title":"GM1 ganglioside induces phosphorylation and activation of Trk and Erk in brain","volume":"81","author":"Duchemin","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1242\/jcs.030338","article-title":"Binding of laminin-1 to monosialoganglioside GM1 in lipid rafts is crucial for neurite outgrowth","volume":"122","author":"Ichikawa","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Takagishi, T., Oda, M., Kabura, M., Kurosawa, M., Tominaga, K., Urano, S., Ueda, Y., Kobayashi, K., Kobayashi, T., and Sakurai, J. (2015). Clostridium perfringens alpha-toxin induces GM1a clustering and TrkA phosphorylation in the host cell membrane. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0120497"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3284","DOI":"10.1096\/fj.12-226548","article-title":"Sphingomyelin regulates the transbilayer movement of diacylglycerol in the plasma membrane of madin-darby canine kidney cells","volume":"27","author":"Ueda","year":"2013","journal-title":"FASEB J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e1000129","DOI":"10.1371\/journal.ppat.1000129","article-title":"Crystal structure of botulinum neurotoxin type A in complex with the cell surface co-receptor GT1b-insight into the toxin-neuron interaction","volume":"4","author":"Stenmark","year":"2008","journal-title":"PLoS Pathog."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1042\/BJ20101042","article-title":"Botulinum neurotoxin serotype D attacks neurons via two carbohydrate-binding sites in a ganglioside-dependent manner","volume":"431","author":"Strotmeier","year":"2010","journal-title":"Biochem. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8117","DOI":"10.1021\/bi100865f","article-title":"Identification of a unique ganglioside binding loop within botulinum neurotoxins C and D-SA","volume":"49","author":"Karalewitz","year":"2010","journal-title":"Biochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1128\/IAI.67.7.3297-3301.1999","article-title":"Differences in the carboxy-terminal (putative phospholipid binding) domains of Clostridium perfringens and Clostridium bifermentans phospholipases C influence the hemolytic and lethal properties of these enzymes","volume":"67","author":"Jepson","year":"1999","journal-title":"Infect. Immun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/cmi.12237","article-title":"Internalization of Clostridium perfringens alpha-toxin leads to ERK activation and is involved on its cytotoxic effect","volume":"16","author":"Mora","year":"2014","journal-title":"Cell Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nrm2216","article-title":"Pathways of clathrin-independent endocytosis","volume":"8","author":"Mayor","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nrm2122","article-title":"The multiple faces of caveolae","volume":"8","author":"Parton","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1194\/jlr.M700587-JLR200","article-title":"The relationship between the metabolism of sphingomyelin species and the hemolysis of sheep erythrocytes induced by Clostridium perfringens alpha-toxin","volume":"49","author":"Oda","year":"2008","journal-title":"J. Lipid Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/j.bbalip.2012.01.004","article-title":"GPI-anchor remodeling: Potential functions of GPI-anchors in intracellular trafficking and membrane dynamics","volume":"1821","author":"Fujita","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.ceb.2011.03.007","article-title":"Clathrin-independent endocytosis: Mechanisms and function","volume":"23","author":"Sandvig","year":"2011","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1083\/jcb.201002119","article-title":"Clathrin-independent carriers form a high capacity endocytic sorting system at the leading edge of migrating cells","volume":"190","author":"Howes","year":"2010","journal-title":"J. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3590","DOI":"10.1529\/biophysj.105.069476","article-title":"The timing of endocytosis after activation of a G-protein-coupled receptor in a sensory neuron","volume":"90","author":"Wang","year":"2006","journal-title":"Biophys. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1016\/j.bbamem.2011.06.008","article-title":"Unexpected wide substrate specificity of C. perfringens alpha-toxin phospholipase C","volume":"1808","author":"Urbina","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.tibs.2011.06.005","article-title":"Shaping up the membrane: Diacylglycerol coordinates spatial orientation of signaling","volume":"36","author":"Almena","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1016\/j.febslet.2010.02.026","article-title":"Ceramide-rich platforms in transmembrane signaling","volume":"584","author":"Stancevic","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/j.1348-0421.1998.tb02321.x","article-title":"Mechanism of membrane damage by Clostridium perfringens alpha-toxin","volume":"42","author":"Nagahama","year":"1998","journal-title":"Microbiol. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3930","DOI":"10.1128\/iai.64.9.3930-3933.1996","article-title":"Phospholipid metabolism induced by Clostridium perfringens alpha-toxin elicits a hot-cold type of hemolysis in rabbit erythrocytes","volume":"64","author":"Ochi","year":"1996","journal-title":"Infect. Immun."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/7\/12\/4880\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:53:17Z","timestamp":1760215997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/7\/12\/4880"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,3]]},"references-count":52,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2015,12]]}},"alternative-id":["toxins7124880"],"URL":"https:\/\/doi.org\/10.3390\/toxins7124880","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,3]]}}}