Molecular basis for tetanus toxin coreceptor interactions
Molecular basis for tetanus toxin coreceptor interactions
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DOI：
10.1021/bi800640y
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发表时间：
2008-07-08
期刊：
影响因子：
2.9
通讯作者：
Barbieri, Joseph T.
中科院分区：
文献类型：
--
作者：
Chen, Chen;Baldwin, Michael R.;Barbieri, Joseph T.
破伤风毒素（TeNT）通过切割中枢神经系统神经元间连接处的神经元中的囊泡相关膜蛋白-2（VAMP-2）来诱发痉挛性麻痹。虽然TeNT逆行交通从外周神经末梢到神经元间连接，但对破伤风毒素最初进入神经细胞所利用的神经元受体的了解有限。早期的研究涉及破伤风毒素进入神经元的辅助受体：神经节苷脂结合口袋和唾液酸结合口袋，GT 1b结合到每个口袋。在这项研究中，一个固相分析的特点是神经节苷脂结合特异性和功能特性的两个糖结合口袋的TeNT。神经节苷脂结合口袋识别神经节苷脂糖骨架Gal-GalNAc，不依赖于唾液酸-（5）和唾液酸-（7），并且GM 1a是该口袋的最佳底物，而唾液酸结合口袋识别唾液酸-（5）和唾液酸-（7），相对于“a”系列神经节苷脂，“B”系列神经节苷脂优选。神经节苷脂与TeNT HCR的高亲和力结合需要功能性神经节苷脂和唾液酸结合口袋，支持与辅助受体的协同结合。该分析提供了破伤风毒素如何利用辅助受体与神经元进行高亲和力结合的模型。
Tetanus toxin (TeNT) elicits spastic paralysis through the cleavage of vesicle-associated membrane protein-2 (VAMP-2) in neurons at the interneuronal junction of the central nervous system. While TeNT retrograde traffics from peripheral nerve endings to the interneuronal junction, there is limited understanding of the neuronal receptors utilized by tetanus toxin for the initial entry into nerve cells. Earlier studies implicated a coreceptor for tetanus toxin entry into neurons: a ganglioside binding pocket and a sialic acid binding pocket and that GT1b bound to each pocket. In this study, a solid phase assay characterized the ganglioside binding specificity and functional properties of both carbohydrate binding pockets of TeNT. The ganglioside binding pocket recognized the ganglioside sugar backbone, Gal-GalNAc, independent of sialic acid-(5) and sialic acid-(7) and GM1a was an optimal substrate for this pocket, while the sialic acid binding pocket recognized sialic acid-(5) and sialic acid-(7) with "b" series of gangliosides preferred relative to "a" series gangliosides. The high-affinity binding of gangliosides to TeNT HCR required functional ganglioside and sialic acid binding pockets, supporting synergistic binding to coreceptors. This analysis provides a model for how tetanus toxin utilizes coreceptors for high-affinity binding to neurons.