Botulinum neurotoxin: a marvel of protein design

Annu Rev Biochem. 2010;79:591-617. doi: 10.1146/annurev.biochem.051908.125345.

Abstract

Botulinum neurotoxin (BoNT), the causative agent of botulism, is acknowledged to be the most poisonous protein known. BoNT proteases disable synaptic vesicle exocytosis by cleaving their cytosolic SNARE (soluble NSF attachment protein receptor) substrates. BoNT is a modular nanomachine: an N-terminal Zn(2+)-metalloprotease, which cleaves the SNAREs; a central helical protein-conducting channel, which chaperones the protease across endosomes; and a C-terminal receptor-binding module, consisting of two subdomains that determine target specificity by binding to a ganglioside and a protein receptor on the cell surface and triggering endocytosis. For BoNT, functional complexity emerges from its modular design and the tight interplay between its component modules--a partnership with consequences that surpass the simple sum of the individual component's action. BoNTs exploit this design at each step of the intoxication process, thereby achieving an exquisite toxicity. This review summarizes current knowledge on the structure of individual modules and presents mechanistic insights into how this protein machine evolved to this level of sophistication. Understanding the design principles underpinning the function of such a dynamic modular protein remains a challenging task.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Botulinum Toxins / chemistry*
  • Botulinum Toxins / genetics*
  • Botulinum Toxins / toxicity
  • Endocytosis
  • Neurotoxins
  • Protein Structure, Tertiary

Substances

  • Neurotoxins
  • Botulinum Toxins