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Synchronized Chaperone Function of Botulinum Neurotoxin Domains Mediates Light Chain Translocation into Neurons

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Botulinum Neurotoxins

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

Abstract

Clostridium botulinum neurotoxin (BoNT) is a multidomain protein in which the individual modules work in synchronized cooperative action in order to enter into neurons and inhibit synaptic transmission. The di-chain protein is made up of the ~50 kD light chain and the ~100 kD heavy chain. The HC can be further subdivided into the N-terminal translocation domain (HN) and the C-terminal Receptor Binding Domain (HC). BoNT entry into neurons requires the toxin to utilize the host cell’s endocytosis pathway where it exploits the acidic environment of the endosome. Within the endosome the HC triggers the HN to change conformation from a soluble protein to a membrane inserted protein-conducting channel in precise timing with LC refolding. The LC must partially unfold to a translocation competent conformation in order to be translocated by the HN channel in an N to C terminal direction. Upon completion of translocation, the LC is released from the HC and allowed to interact with its substrate SNARE protein. This article discusses the individual functions of each module as well as the mechanisms by which each domain serves as a chaperone for the others, working in concert to achieve productive intoxication.

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Abbreviations

γ:

Single channel conductance

BoNT:

Botulinum neurotoxin

CD:

Circular dichroism

EPR:

Electron paramagnetic resonance

HC:

Heavy chain

HC :

Receptor binding domain

HCC :

25 kDa C-terminal subdomain of the HC

HCN :

25 kDa N-terminal subdomain of the HC

HN :

Translocation domain

HN-belt :

Beltless translocation domain

LC:

Light chain

LHN :

LC + HN

PA:

Protective antigen

P o :

Probability of the channel to remain in the open state

SNAP-25:

Synaptosomal-associated protein of 25 kDa

SNARE:

Soluble NSF attachment protein receptor

T1/2 :

Half-time for a single growing conductance event

TeNT:

Tetanus neurotoxin

TSDN:

Toosendanin

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Acknowledgments

This work was supported by the Johns Hopkins University Applied Physics Laboratory post-doctoral grant.

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The author declares that there are no conflicts of interest.

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  1. Asymmetric Operations Department, Johns Hopkins University Applied Physics Laboratory, Laurel, MD 20723, USA

    Audrey Fischer

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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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Fischer, A. (2012). Synchronized Chaperone Function of Botulinum Neurotoxin Domains Mediates Light Chain Translocation into Neurons. 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_6

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