Structure of the key toxin in gas gangrene.
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.
Naylor
C E
CE
Department of Crystallography, Birkbeck College, London, England.
Eaton
J T
JT
Howells
A
A
Justin
N
N
Moss
D S
DS
Titball
R W
RW
Basak
A K
AK
D000595:Amino Acid Sequence; D001427:Bacterial Toxins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D003016:Clostridium perfringens / Q000472:pathogenicity*; D003198:Computer Simulation; D003461:Crystallography; D005738:Gas Gangrene; D006460:Hemolysin Proteins / Q000737:chemistry; D006801:Humans; D008297:Male; D008566:Membranes / Q000378:metabolism; D008667:Metalloproteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D015290:Second Messenger Systems; D017386:Sequence Homology, Amino Acid; D017356:Synchrotrons; D010738:Type C Phospholipases / Q000737:chemistry* / Q000378:metabolism; D015032:Zinc
D001427:Bacterial Toxins; D002135:Calcium-Binding Proteins; D006460:Hemolysin Proteins; D008667:Metalloproteins; D010738:Type C Phospholipases; C040649:alpha toxin, Clostridium perfringens; D015032:Zinc; D002118:Calcium