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Structure and activity of a functional derivative of Clostridium botulinum neurotoxin B.

Abstract
Botulinum neurotoxins (BoNTs) cause flaccid paralysis by inhibiting neurotransmission at cholinergic nerve terminals. BoNTs consist of three essential domains for toxicity: the cell binding domain (Hc), the translocation domain (Hn) and the catalytic domain (LC). A functional derivative (LHn) of the parent neurotoxin B composed of Hn and LC domains was recombinantly produced and characterised. LHn/B crystallographic structure at 2.8Å resolution is reported. The catalytic activity of LHn/B towards recombinant human VAMP was analysed by substrate cleavage assay and showed a higher specificity for VAMP-1, -2 compared to VAMP-3. LHn/B also showed measurable activity in living spinal cord neurons. Despite lacking the Hc (cell-targeting) domain, LHn/B retained the capacity to internalize and cleave intracellular VAMP-1 and -2 when added to the cells at high concentration. These activities of the LHn/B fragment demonstrate the utility of engineered botulinum neurotoxin fragments as analytical tools to study the mechanisms of action of BoNT neurotoxins and of SNARE proteins.
AuthorsGeoffrey Masuyer, Matthew Beard, Verity A Cadd, John A Chaddock, K Ravi Acharya
JournalJournal of structural biology (J Struct Biol) Vol. 174 Issue 1 Pg. 52-7 (Apr 2011) ISSN: 1095-8657 [Electronic] United States
PMID21078393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 Elsevier Inc. All rights reserved.
Chemical References
  • Vesicle-Associated Membrane Protein 1
  • Vesicle-Associated Membrane Protein 2
  • rimabotulinumtoxinB
  • Botulinum Toxins
  • Botulinum Toxins, Type A
Topics
  • Amino Acid Sequence
  • Animals
  • Botulinum Toxins (chemistry, genetics, metabolism)
  • Botulinum Toxins, Type A
  • Cells, Cultured
  • Clostridium botulinum (metabolism)
  • Crystallography, X-Ray
  • Humans
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Rats
  • Rats, Sprague-Dawley
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship
  • Vesicle-Associated Membrane Protein 1 (metabolism)
  • Vesicle-Associated Membrane Protein 2 (metabolism)

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