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….SW84Y85….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.
Highlights
Clostridium perfringens alpha-toxin is an important agent in gas gangrene [1,2], and causes hemolysis, platelet aggregation, contraction of blood vessels, superoxide generation, cytokine storm, and death [3,4,5,6,7,8,9]
Comparative analysis of the putative amino acid sequences encoded by the genes for alpha-toxin and Bacillus cereus PLC indicates that alpha-toxin belongs to a family of bacterial zinc-metallo phospholipase C enzymes [9]
C-domain (PLAT domain) of alpha-toxin contains a phospholipid-binding site [10,18,39]; our results suggest that the ganglioside-binding site in the loop domain plays an important role in the tethering of alpha-toxin to membrane
Summary
Clostridium perfringens alpha-toxin is an important agent in gas gangrene [1,2], and causes hemolysis, platelet aggregation, contraction of blood vessels, superoxide generation, cytokine storm, and death [3,4,5,6,7,8,9]. Based on crystallographic data and a site-directed mutagenesis analysis, the relationship between the alpha-toxin amino acid residues, co-ordination of zinc ions, and biological activity has been revealed [4]. PLAT the PLAT (Polycystin-1, Lipoxygenase, Alpha-toxin) domain, is a membrane binding domain[14]. This (Polycystin‐1, Alpha‐toxin) domain, is a membrane binding domain structure forms a beta-sandwich composed of two sheets of four strand each. C-domain plays a plays role inabinding are inserted phospholipid bilayer membranes. C-domain into the bilayer membrane may play an essential role in its action. Invasion of the C‐domain into the bilayer membrane may play an essential role in its action
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