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首页> 外文期刊>Biochemistry >Molecular Basis of Activation of Endopeptidase Activity of Botulinum Neurotoxin Type E
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Molecular Basis of Activation of Endopeptidase Activity of Botulinum Neurotoxin Type E

机译：E型肉毒杆菌神经毒素激活内肽酶活性的分子基础

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摘要

Botulinum neurotoxins (BoNTs) are a group of large proteins that are responsible for the clinical syndrome of botulism. The seven immunologically distinct serotypes of BoNTs (A —G), each produced by various strains of Clostridium botulinum, act on the neuromuscular junction by blocking the release of the neurotransmitter acetylcholine, thereby resulting in flaccid muscle paralysis. BoNTs are synthesized as single inactive polypeptide chains that are cleaved by endogenous or exogenous proteases to generate the active dichain form of the toxin. Nicking of the single chain BoNT/E to the dichain form is associated with 100-fold increase in toxicity. Here we investigated the activation mechanism of botulinum neurotoxin type E upon nicking and subsequent reduction of disulfide bond. It was observed that nicking of BoNT/ E significantly enhances its endopeptidase activity and that at the physiological temperature of 37 °C the reduced form of nicked BoNT/E adopts a dynamically flexible conformation resulting from the exposure of hydrophobic segments and facilitating optimal cleavage of its substrate SNAP-25. Such reduction-induced increase in the flexibility of the polypeptide folding provides a rationale for the mechanism of BoNT/E endopeptidase against its intracellular substrate, SNAP-25, and complements current understanding of the mechanistics of interaction between the substrate and BoNT endopeptidase.
机译：肉毒杆菌神经毒素（BoNT）是一组导致肉毒中毒临床综合症的大蛋白。 BoNT的7种在免疫学上不同的血清型（分别由肉毒梭菌菌株产生）通过阻断神经递质乙酰胆碱的释放而作用于神经肌肉接头，从而导致松弛的肌肉麻痹。 BoNTs合成为单个非活性多肽链，可被内源性或外源性蛋白酶裂解以产生毒素的活性二链形式。单链BoNT / E形成双链的切口与毒性增加100倍有关。在这里，我们研究了切口形成的肉毒杆菌神经毒素的激活机制以及随后的二硫键还原作用。观察到，BoNT / E的切口显着增强了其内肽酶的活性，在37°C的生理温度下，切口形式的BoNT / E的切口形式具有动态柔性的构象，该构象是由于疏水链段的暴露而导致的，并且有利于其分子的最佳裂解底物SNAP-25。这种减少诱导的多肽折叠柔性的增加为BoNT / E内肽酶对抗其细胞内底物SNAP-25的机理提供了原理，并补充了对底物与BoNT内肽酶之间相互作用机制的当前理解。

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