Structural secrets

Abstract

Botulinum toxins and the related tetanus toxin are extremely potent neurotoxins produced by Clostridium botulinum and Clostridium tetani, respectively. The discovery that these toxins act as zinc proteases to cleave SNARE proteins involved in vesicle fusion sparked off interest in the mechanisms of exocytosis in mammalian cells. Recently, another significant advance was made by Lacy et al.[ 1 Lacy B.D. et al. Crystal structure of botulinum neurotoxin type A and implications for toxicity. Nat. Struct. Biol. 1998; 5: 898-902 Crossref PubMed Scopus (664) Google Scholar ], who have obtained the first complete crystal structure of a clostridial neurotoxin, botulinum neurotoxin type A (BoNT/A). The toxin is composed of three structural domains: the receptor-binding, translocation and catalytic domains. The receptor-binding domain is structurally homologous to the equivalent domain in tetanus toxin; the main differences are in the loop regions that link the structural β sheets, which could represent the residues defining receptor interaction. The translocation domain, which is involved in movement of the catalytic domain from endocytosed vesicles to the cytoplasm, consists of a pair of a helices forming an unusually long coiled-coil domain. Unlike the translocation domains in other di-chain bacterial toxins, e.g. diphtheria toxin and Pseudomonas exotoxin A, this resembles the coiled-coil structures seen in viral proteins, such as HIV-1 gp41. This, together with another unusual feature whereby part of the translocation domain wraps around the catalytic domain, points to a novel mechanism for the insertion of the catalytic domain of bacterial toxins into the cytosol. As expected from its zinc metalloprotease activity, the catalytic domain structurally resembles other metalloproteases, most notably thermolysin from Bacillus thermoproteolyticus and leishmanolysin from Leishmania major. The structure of BoNT/A, together with the recent crystal structure of the SNARE complex (Sutton et al.[ 2 Sutton R.B. et al. Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4Å resolution. Nature. 1998; 395: 347-353 Crossref PubMed Scopus (1899) Google Scholar ]), will undoubtedly increase our understanding of the mechanism of action of the clostridial neurotoxin family.