[Structure and function of botulinum toxin].

Abstract

Botulinum toxins (types A to G) inhibit the release of acetylcholine at the neuromuscular junction. These toxins are produced as progenitor toxins of large molecular sizes of 12S (M toxin), 16S (L toxin) and 19S (LL toxin) in culture supernatants. Three different molecular forms have been demonstrated in botulinum type A toxin. L and M toxins are recognized in botulinum type C and D toxins. Type E toxin is exclusively composed of M toxin. In an alkaline condition, M and L toxins dissociate into neurotoxin and nontoxic components. Nontoxic components consist of nontoxic-nonhemagultinin component (nontoxic-nonHA) and hemagultinin (HA). M toxin is made up by association of neurotoxin with nontoxic-nonHA, and L toxin is formed by conjugation of M toxin with HA. HA also consists of several subcomponents. These genes with related functions (progenitor toxin) are closely grouped as operon on the chromosome. Nontoxic-nonHA gene is located only 17 bp (type C) or 27 bp (type E) upstream of the neurotoxin gene. Both genes may be transcribed (right-ward transcription) by a polycistronic mRNA species initiated from a promoter located in the 5'-untranslated region of the nontoxic-nonHA gene. The construction of HA subcomponent genes (HA-33, HA-17, HA-25 and HA-53) also appears operon structure. The gene cluster related HA is located 262 bp upstream of nontoxic-nonHA gene of type C and transcribed (left-ward transcription) by the same mRNA from the 5'-noncoding region of HA-33 gene. Botulinum neurotoxin undergoes cleavage to form a dichain molecule linked through a disulphide bond. The heavy chain correlates with the binding of toxin to peripheral synapses, and the light chain is associated with the intracellular activity of blocking of acetylcholine release. Fifty amino acids in C-terminal region of type C toxin is essential for the binding activity of toxin to the target cells. However, the binding efficiency of type C toxin is not antagonized by the other type of botulinum toxins because of low homology of this binding domain of type C toxin to other types. Furthermore, five highly homologous regions are found in light chain among seven neurotoxins. One of these homologous regions, sequence HEL-H--, shows strong similarity with the active site of zinc-proteases. The inhibition of acetylcholine release is associated with this protease activity which selectively cleaves the synaptic vesicle membrane proteins. These target membrane proteins are key components of the synaptic vesicle docking and fusion.(ABSTRACT TRUNCATED AT 400 WORDS)