title: Membrane-Binding Mechanism of Clostridium perfringens Alpha-Toxin.
abstract: 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 (1-250 aa, N-domain), which is the catalytic site, and a C-terminal domain (251-370 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 (55-93 aa), especially H….SW(84)Y(85)….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 PLCγ-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.
authors.affiliation: 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. masataka@dent.niigata-u.ac.jp.
authors.forename: Masataka
authors.initials: M
authors.lastname: Oda
authors.affiliation: 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. terao@dent.niigata-u.ac.jp.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Terao
authors.affiliation: Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan. sakuraijun7400@gmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Sakurai
authors.affiliation: Department of Microbiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan. nagahama@ph.bunri-u.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nagahama
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry / Q000633:toxicity*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000633:toxicity*; D002462:Cell Membrane / Q000378:metabolism*; D004705:Endocytosis; D005732:Gangliosides / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D010738:Type C Phospholipases / Q000737:chemistry / Q000633:toxicity*
chemical_list: D001427:Bacterial Toxins; D002135:Calcium-Binding Proteins; D005732:Gangliosides; D010738:Type C Phospholipases; C040649:alpha toxin, Clostridium perfringens
keywords: C-domain; Clostridium perfringens; TrkA; alpha-toxin; central loop domain; endocytosis; ganglioside GM1a; phospholipid; vaccine