Structure of the key toxin in gas gangrene

• Published in: Nature structural biology Vol. 5; no. 8; pp. 738 - 746
• Main Authors: Naylor, C E, Eaton, J T, Howells, A, Justin, N, Moss, D S, Titball, R W, Basak, A K
• Format: Journal Article
• Language: English
• Published: United States 01-08-1998
• Subjects: Amino Acid Sequence; Bacterial Toxins - chemistry; Bacterial Toxins - metabolism; Binding Sites; Calcium - metabolism; Calcium-Binding Proteins - chemistry; Calcium-Binding Proteins - metabolism; Clostridium perfringens; Clostridium perfringens - pathogenicity; Computer Simulation; Crystallography; Gas Gangrene; Hemolysin Proteins - chemistry; Humans; Male; Membranes - metabolism; Metalloproteins - chemistry; Metalloproteins - metabolism; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Conformation; Second Messenger Systems; Sequence Homology, Amino Acid; Synchrotrons; Type C Phospholipases - chemistry; Type C Phospholipases - metabolism; Zinc
• DOI: 10.1038/1447
• ISSN: 1072-8368

Clostridium perfringens alpha-toxin is the key virulence determinant in gas gangrene and has also been implicated in the pathogenesis of sudden death syndrome in young animals. The toxin is a 370-residue, zinc metalloenzyme that has phospholipase C activity, and can bind to membranes in the presence of calcium. The crystal structure of the enzyme reveals a two-domain protein. The N-terminal domain shows an anticipated structural similarity to Bacillus cereus phosphatidylcholine-specific phospholipase C (PC-PLC). The C-terminal domain shows a strong structural analogy to eukaryotic calcium-binding C2 domains. We believe this is the first example of such a domain in prokaryotes. This type of domain has been found to act as a phospholipid and/or calcium-binding domain in intracellular second messenger proteins and, interestingly, these pathways are perturbed in cells treated with alpha-toxin. Finally, a possible mechanism for alpha-toxin attack on membrane-packed phospholipid is described, which rationalizes its toxicity when compared to other, non-haemolytic, but homologous phospholipases C.