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A型肉毒毒素和 E 型肉毒毒素对 t-SNARE 造成动态去稳定化作用，从而损害 SNARE 组装和膜融合。

Botulinum Toxins A and E Inflict Dynamic Destabilization on t-SNARE to Impair SNARE Assembly and Membrane Fusion.

机构信息

Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA 50011, USA.

Roy J. Carver Department of Biochemistry, Biophysics & Molecular Biology, Iowa State University, Ames, IA 50011, USA.

出版信息

Structure. 2017 Nov 7;25(11):1679-1686.e5. doi: 10.1016/j.str.2017.09.004. Epub 2017 Oct 12.

DOI:10.1016/j.str.2017.09.004
PMID:29033286
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5685167/
Abstract

Botulinum toxins (BoNTs) A and E block neurotransmitter release by specifically cleaving the C- terminal ends of SNAP-25, a plasma membrane SNARE protein. Here, we find that SNAP-25A and E, the cleavage products of BoNT A and E, respectively, terminate membrane fusion via completely different mechanisms. Combined studies of single-molecule FRET and single-vesicle fusion assays reveal that SNAP-25E is incapable of supporting SNARE pairing and thus, vesicle docking. In contrast, SNAP-25A facilitates robust SNARE pairing and vesicle docking with somewhat reduced SNARE zippering, which leads to severe impairment of fusion pore opening. The electron paramagnetic resonance results show that the discrepancy between SNAP-25A and E might stem from the extent of the dynamic destabilization of the t-SNARE core at the N-terminal half, which plays a pivotal role in nucleating SNARE complex formation. Thus, the results provide insights into the structure/dynamics-based mechanism by which BoNT A and E impair membrane fusion.

摘要

肉毒杆菌毒素 (BoNTs) A 和 E 通过特异性切割 SNAP-25 的 C 末端来阻断神经递质的释放，SNAP-25 是一种质膜 SNARE 蛋白。在这里，我们发现 BoNT A 和 E 的裂解产物 SNAP-25A 和 E 通过完全不同的机制终止膜融合。单分子 FRET 和单囊泡融合测定的联合研究表明，SNAP-25E 不能支持 SNARE 配对，因此也不能进行囊泡对接。相比之下，SNAP-25A 促进了强大的 SNARE 配对和囊泡对接，但 SNARE 拉链的速度略有降低，这导致融合孔的打开严重受损。电子顺磁共振结果表明，SNAP-25A 和 E 之间的差异可能源于 N 端半部分 t-SNARE 核心的动态去稳定程度，这在引发 SNARE 复合物形成中起着关键作用。因此，这些结果为 BoNT A 和 E 破坏膜融合的基于结构/动力学的机制提供了深入的了解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcd5/5685167/4596c0422cff/nihms907135f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcd5/5685167/7977db667192/nihms907135f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcd5/5685167/b648e5b287d7/nihms907135f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcd5/5685167/08f187011ac9/nihms907135f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcd5/5685167/4596c0422cff/nihms907135f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcd5/5685167/7977db667192/nihms907135f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcd5/5685167/b648e5b287d7/nihms907135f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcd5/5685167/08f187011ac9/nihms907135f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fcd5/5685167/4596c0422cff/nihms907135f4.jpg

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