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The blockade of the neurotransmitter release apparatus by botulinum neurotoxins

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Abstract

The high toxicity of the seven serotypes of botulinum neurotoxins (BoNT/A to G), together with their specificity and reversibility, includes them in the list A of potential bioterrorism weapons and, at the same time, among the therapeutics of choice for a variety of human syndromes. They invade nerve terminals and cleave specifically the three proteins which form the heterotrimeric SNAP REceptors (SNARE) complex that mediates neurotransmitter release. The BoNT-induced cleavage of the SNARE proteins explains by itself the paralysing activity of the BoNTs because the truncated proteins cannot form the SNARE complex. However, in the case of BoNT/A, the most widely used toxin in therapy, additional factors come into play as it only removes a few residues from the synaptosomal associate protein of 25 kDa C-terminus and this results in a long duration of action. To explain these facts and other experimental data, we present here a model for the assembly of the neuroexocytosis apparatus in which Synaptotagmin and Complexin first assist the zippering of the SNARE complex, and then stabilize and clamp an octameric radial assembly of the SNARE complexes.

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Notes

  1. The dipole moments were calculated from the PDB structure 3RL0 using the partial charge distribution of the AMBER99 force field. We considered residues 191–249 of Syntaxin and 8–79 to 139–200 in SNAP25 (corresponding the chains B, C, and D in the PDB structure, respectively). Chains A (VAMP) and g (Complexin) were subsequently included to estimate their contribution to the global dipole moment of the SNARE at different stages.

Abbreviations

BoNT:

Botulinum neurotoxin

NMJ:

Neuromuscular junction

PIP2:

Phosphatidylinositol 4,5 diphosphate

SNAP25:

Synaptosomal associate protein of 25 kDa

SNARE:

SNAP REceptors

SV:

Synaptic vesicle

TeNT:

Tetanus neurotoxin

TM:

Trans membrane domain

VAMP:

Vesicle-associated membrane protein or synaptobrevin

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  1. Institut Pasteur de Montevideo, Calle Mataojo 2020, CP 11400, Montevideo, Uruguay

    Sergio Pantano

  2. Department of Biomedical Sciences, University of Padova, Padua, Italy

    Cesare Montecucco

  3. Institute of Neuroscience, National Research Council, Viale G. Colombo 3, 35121, Padua, Italy

    Cesare Montecucco

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  1. Sergio Pantano
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Pantano, S., Montecucco, C. The blockade of the neurotransmitter release apparatus by botulinum neurotoxins. Cell. Mol. Life Sci. 71, 793–811 (2014). https://doi.org/10.1007/s00018-013-1380-7

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