Membrane-Binding Mechanism of Clostridium perfringens Alpha-Toxin

Toxins (Basel). 2015 Dec 3;7(12):5268-75. doi: 10.3390/toxins7124880.

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.

Keywords: C-domain; Clostridium perfringens; TrkA; alpha-toxin; central loop domain; endocytosis; ganglioside GM1a; phospholipid; vaccine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Bacterial Toxins / chemistry
  • Bacterial Toxins / toxicity*
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / toxicity*
  • Cell Membrane / metabolism*
  • Endocytosis
  • Gangliosides / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Type C Phospholipases / chemistry
  • Type C Phospholipases / toxicity*

Substances

  • Bacterial Toxins
  • Calcium-Binding Proteins
  • Gangliosides
  • Type C Phospholipases
  • alpha toxin, Clostridium perfringens