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

Reference:

Masuyer, G., Beard, M., Cadd, V. A., Chaddock, J. A. and Acharya, K. R., 2011. Structure and activity of a functional derivative of Clostridium botulinum neurotoxin B. Journal of Structural Biology, 174 (1), pp. 52-57.

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Official URL:

http://dx.doi.org/10.1016/j.jsb.2010.11.010

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 2.8 angstrom 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.

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