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Double Receptor Anchorage of Botulinum Neurotoxins Accounts for their Exquisite Neurospecificity

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Botulinum Neurotoxins

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 364))

Abstract

The high potency of the botulinum neurotoxins (BoNT) and tetanus neurotoxin (TeNT) is mainly due to their neurospecific binding which is mediated by the interaction with two receptor components. TeNT and all BoNT bind first to complex polysialo-gangliosides abundantly present on the outer leaflet of neuronal membranes. The ganglioside binding occurs in BoNT/A, B, E, F and G via a conserved ganglioside binding pocket within the most carboxyl-terminal 25 kDa domain HCC whereas TeNT, BoNT/C and D display two different ganglioside binding sites within their HCC-domain. Subsequently, upon exocytosis the intraluminal domains of synaptic vesicle proteins are exposed and can be accessed by the surface accumulated neurotoxins. BoNT/B and G bind with their HCC-domain to a 20-mer membrane juxtaposed segment of the intraluminal domain of synaptotagmin-I and -II, respectively. BoNT/A and E employ the intraluminal domain 4 of the synaptic vesicle glycoprotein 2 (SV2) as protein receptor. Whereas the 50 kDa cell binding domain HC of BoNT/A interacts with all three SV2 isoforms, BoNT/E HC only binds SV2A and SV2B. Also, BoNT/D, F, and TeNT employ SV2 for binding and uptake. Thereafter, the synaptic vesicle is recycled and the anchored neurotoxin is endocytosed. Acidification of the vesicle lumen triggers membrane insertion of the translocation domain followed by pore formation and finally translocation of the enzymatically active light chain to its site of action leading to block of neurotransmitter release.

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Abbreviations

BoNT:

botulinum neurotoxin

BoNT/X:

serotype X of BoNT, X = A–G

BoNT/XY:

subtype Y of serotype BoNT/X, Y = 1–8

Cer:

ceramide

CNT:

clostridial neurotoxins

NMJ:

neuromuscular junction

Gal:

β-galactose

GBS:

ganglioside binding site

Glc:

β-glucose

GPI:

glycosylphosphatidylinositol

GT1b, GD1b, GD1a, GM1, GM3, GT2:

sialo ganglioside

HC/X:

heavy chain of BoNT serotype X/TeNT

HCX:

50 kDa cell binding fragment of BoNT/TeNT

HCC :

25 kDa C-terminal domain of the HC

HCN :

25 kDa N-terminal domain of the HC

HNX:

50 kDa translocation domain of BoNT/TeNT

Lac:

lactose

LacCer:

lactose-ceramide

LC/X:

light chain, catalytic domain of BoNT serotype X/TeNT

MS:

mass spectrometry

NAcGal:

N-acetyl-β-galactosamine

NAcNeu:

N-acetylneuraminic acid, sialic acid, Sia

SNAP-25:

synaptosomal associated protein of 25 kDa

SNARE:

soluble N-ethylmaleimide-sensitive factor attachment protein receptor

SV2:

synaptic vesicle glycoprotein 2

Syt-X:

Isoform X of synaptotagmin, X = I-XV

syntaxin-X:

Isoform X of syntaxin, X = 1–19

TeNT:

tetanus neurotoxin

VAMP-2:

synaptobrevin-2

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Acknowledgments

The author is thankful to Dr. Thomas Binz for critically reviewing the manuscript and to his colleagues and collaborators for contributing to this research. Special thanks are due to Drs. Jasmin Strotmeier, Johannes Bigalke and Stefan Mahrhold, and to Nadja Krez and Anna Magdalena Kruel.

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  1. Institut für Toxikologie, Medizinische Hochschule Hannover, 30623, Hannover, Germany

    Andreas Rummel

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  1. , Institut für Toxikologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, Hannover, 30625, Germany

    Andreas Rummel

  2. , Institut für Physiologische Chemie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, Hannover, 30625, Germany

    Thomas Binz

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Rummel, A. (2012). Double Receptor Anchorage of Botulinum Neurotoxins Accounts for their Exquisite Neurospecificity. In: Rummel, A., Binz, T. (eds) Botulinum Neurotoxins. Current Topics in Microbiology and Immunology, vol 364. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-33570-9_4

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