Role of the heavy and light chains of botulinum neurotoxin in neuromuscular paralysis.
Botulinum neurotoxin (NT) is synthesized by Clostridium botulinum in any of seven antigenically distinct forms called types A-G. NT, when fully active, is a dichain protein, composed of two polypeptides, a heavy (H) and a light (L) chain (approximately 100,000 and approximately 50,000 Da, respectively) that are held together by noncovalent bonds and at least one disulfide bond. Two types of dichain NT, A and B, and their respective H and L chains were applied to nerve-muscle (NM) preparations (phrenic nerve-hemidiaphragm of the mouse), in order to develop a broader, comparative understanding of the neuroparalytic actions of NT types. It was found that the paralysis induced by dichain NT was delayed or antagonized if NM preparations were incubated with isolated and purified H chain prior to, or during, incubation with the parent, dichain NT. NM preparations preincubated with H chain and then washed free of unbound H chain became paralyzed after subsequent incubation with L chain. Paralysis did not occur if NM preparations were incubated first with L chain, washed, and then incubated with H chain. These observations suggest that the H chain binds with specific sites on the nerve terminal. This binding appears to permit the L chain, or some combination of the L and H chain, to bring about neuroparalysis through a mechanism very similar to that of the parent, dichain NT.
D000818:Animals; D001905:Botulinum Toxins / Q000494:pharmacology*; D001906:Botulism / Q000150:complications; D046911:Macromolecular Substances; D051379:Mice; D008970:Molecular Weight; D009469:Neuromuscular Junction / Q000187:drug effects*; D010243:Paralysis / Q000209:etiology*; D013329:Structure-Activity Relationship; D009435:Synaptic Transmission / Q000187:drug effects
D046911:Macromolecular Substances; D001905:Botulinum Toxins