Clostridial neurotoxins: mechanism of SNARE cleavage and outlook on potential substrate specificity reengineering.
Clostridial neurotoxins: mechanism of SNARE cleavage and outlook on potential substrate specificity reengineering.
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DOI：
10.3390/toxins2040665
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发表时间：
2010-04
期刊：
影响因子：
4.2
通讯作者：
Mahrhold S
中科院分区：
文献类型：
--
作者：
Binz T;Sikorra S;Mahrhold S
梭菌神经毒素家族由破伤风神经毒素和七种不同的肉毒杆菌神经毒素组成，它们会导致破伤风和肉毒杆菌中毒。这些毒素的极端效力不仅取决于它们特异性进入运动神经元的能力，还取决于它们的催化域在突触前运动神经元末梢内表现出的活性。在神经毒素结合和内吞作用之后，催化结构域跨内体膜易位，并蛋白水解三种可溶性 N-乙基马来酰亚胺敏感融合蛋白附着受体 (SNARE)、囊泡相关膜蛋白/突触短蛋白、25 kDa 突触体相关蛋白或突触蛋白之一的独特肽键。由于这些底物蛋白是囊泡膜融合装置的核心成分，任何底物分子的裂解都会导致神经递质释放的阻断。本综述总结了目前关于特定底物识别和裂解机制的分子基础的知识，并评估了重新设计催化结构域以水解三个 SNARE 家族非底物成员的可行性，以扩大肉毒杆菌神经毒素的治疗应用。
The clostridial neurotoxin family consists of tetanus neurotoxin and seven distinct botulinum neurotoxins which cause the diseases tetanus and botulism. The extreme potency of these toxins primarily relies not only on their ability to specifically enter motoneurons but also on the activity their catalytic domains display inside presynaptic motoneuronal terminals. Subsequent to neurotoxin binding and endocytosis the catalytic domains become translocated across endosomal membranes and proteolyze unique peptide bonds of one of three soluble N-ethylmaleimide-sensitive fusion protein attachment receptors (SNAREs), vesicle associated membrane protein/synaptobrevin, synaptosome associated protein of 25 kDa, or syntaxin. As these substrate proteins are core components of the vesicular membrane fusion apparatus, cleavage of any of the substrate molecules results in the blockade of neurotransmitter release. This review summarizes the present knowledge about the molecular basis of the specific substrate recognition and cleavage mechanism and assesses the feasibility of reengineering catalytic domains to hydrolyze non-substrate members of the three SNARE families in order to expand the therapeutic application of botulinum neurotoxins.
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影响因子：
56.9
作者：
Dong, M;Yeh, F;Chapman, ER
通讯作者：
Chapman, ER
影响因子：
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作者：
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作者：
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DOI：
10.1073/pnas.0903111106
发表时间：
2009-06-09
影响因子：
11.1
作者：
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通讯作者：
Barbieri, Joseph T.
影响因子：
2.9
作者：
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