Light Chain Role in Action of Botulinum Toxins/Clostridial Neurotoxins

Document Type

Contribution to Book

Publication Date

2023

Publisher

Springer

Source Publication

Handbook of Neurotoxicity

Source ISSN

978-3031150791

Original Item ID

DOI: 10.1007/978-3-031-15080-7_201

Abstract

The clostridial neurotoxins (CNT), botulinum neurotoxins (BT) and tetanus neurotoxin (TT), are the most toxic protein toxins for humans. BT isolates are comprised of seven immunologically distinct serotypes, BT/A-G, while TT isolates are >97% genetically identical. In addition, bioinformatic studies have identified several BT analogs within bacterial genomes, which share sequence and/or structural homology with BT. Synthesized as a single polypeptide, CNTs are cleaved by clostridial or host proteases into two chains: the light chain (LC) and the heavy chain (HC). The HC encodes two sub-domains, the translocation domain (HCN) and the receptor binding domain (HCC). The LC is a zinc-dependent metalloprotease, which cleaves neuronal soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). LCs have a high specificity for their substrate, but each LC serotype has a unique affinity and rate of catalysis for their respective SNARE substrate(s). The LC defines the duration of BT/A action in cells and animal models of botulism. Understanding LC action has allowed the engineering of LCs that recognize alternative SNARE substrates. Continued studies on the LCs will increase our understanding of the molecular and cellular properties of the CNTs that may extend the development of novel therapeutics against human neurological diseases and identify host factors as targets for human therapies against CNT intoxication.

Comments

"Light Chain Role in Action of Botulinum Toxins/Clostridial Neurotoxins" in Handbook of Neurotoxicity. Ed. Richard M. Kostrzewa. Cham: Springer, 2023: 1145-1154. DOI.

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