Journal Article

Botulinum neurotoxins: genetic, structural and mechanistic insights

Montecucco, Cesare, Rossetto, Ornella, Pirazzini, Marco

2014

Overview

Key Points Botulinum neurotoxins (BoNTs) are produced by neurotoxigenic clostridia and are a diverse group that consists of approximately 40 different BoNT types (and various subtypes), all of which cause persistent paralysis of peripheral nerve terminals — a condition known as botulism. Recent studies have solved various structures of BoNT complexes, which has provided insights into their modes of entry into the general circulation as well as the ability of these toxins to survive for long periods of time in the ex vivo environment. The molecular basis of the specificity of BoNT binding to nerve terminals is explored, as well as the ensuing cellular events, including toxin endocytosis and the targeting and cleavage of SNARE proteins. A molecular model for the essential process of membrane translocation of the metalloprotease domain of BoNTs into the neuronal cytosol is presented. Open questions and future areas of research are outlined with respect to the development of novel therapeutic agents that are based on BoNTs. Botulinum neurotoxins, which are the most powerful known toxins, are produced by toxigenic clostridia and cause persistent paralysis of peripheral nerve terminals by blocking neurotransmitter release. In this Review, Montecucco and colleagues discuss recent structural and molecular insights into the mechanisms of toxin entry into nerve terminals, membrane translocation and neuroparalysis. Botulinum neurotoxins (BoNTs) are produced by anaerobic bacteria of the genus Clostridium and cause a persistent paralysis of peripheral nerve terminals, which is known as botulism. Neurotoxigenic clostridia belong to six phylogenetically distinct groups and produce more than 40 different BoNT types, which inactivate neurotransmitter release owing to their metalloprotease activity. In this Review, we discuss recent studies that have improved our understanding of the genetics and structure of BoNT complexes. We also describe recent insights into the mechanisms of BoNT entry into the general circulation, neuronal binding, membrane translocation and neuroparalysis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/326/41/1319 / 631/326/41/2531 / 631/326/41/2536 / Anaerobic bacteria / Animals / Bacteria / Botulinum toxin / Botulism / Botulism - metabolism / Botulism - microbiology / Botulism - physiopathology / Clostridium / Clostridium botulinum / Clostridium botulinum - genetics / Clostridium botulinum - pathogenicity / Food contamination / Genes / Genetic aspects / Genetic research / Genetics / Humans / Hypotheses / Infectious Diseases / Invertebrates / Life Sciences / Medical Microbiology / Microbiological research / Microbiology / Neurotoxins / Neurotoxins - blood / Neurotoxins - chemistry / Neurotoxins - genetics / Neurotoxins - metabolism / Paralysis / Paralysis - metabolism / Paralysis - microbiology / Parasitology / Presynaptic Terminals - metabolism / Properties / Protein Binding / Protein Transport / review-article / Tetanus / Toxins / Translocation / Virology / Virulence (Microbiology)