Department of Urology, Boston Children's Hospital, Department of Microbiology and Immunobiology and Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA.
Department of Biochemistry and Biophysics, Stockholm University, SE-106 91 Stockholm, Sweden.
Nat Commun. 2017 Aug 3;8:14130. doi: 10.1038/ncomms14130.
Botulinum neurotoxins are known to have seven serotypes (BoNT/A-G). Here we report a new BoNT serotype, tentatively named BoNT/X, which has the lowest sequence identity with other BoNTs and is not recognized by antisera against known BoNTs. Similar to BoNT/B/D/F/G, BoNT/X cleaves vesicle-associated membrane proteins (VAMP) 1, 2 and 3, but at a novel site (Arg66-Ala67 in VAMP2). Remarkably, BoNT/X is the only toxin that also cleaves non-canonical substrates VAMP4, VAMP5 and Ykt6. To validate its activity, a small amount of full-length BoNT/X was assembled by linking two non-toxic fragments using a transpeptidase (sortase). Assembled BoNT/X cleaves VAMP2 and VAMP4 in cultured neurons and causes flaccid paralysis in mice. Thus, BoNT/X is a novel BoNT with a unique substrate profile. Its discovery posts a challenge to develop effective countermeasures, provides a novel tool for studying intracellular membrane trafficking, and presents a new potential therapeutic toxin for modulating secretions in cells.
肉毒神经毒素已知有七种血清型（BoNT/A-G）。在这里，我们报告了一种新的 BoNT 血清型，暂定名为 BoNT/X，它与其他 BoNTs 的序列同一性最低，并且不能被针对已知 BoNTs 的抗血清识别。与 BoNT/B/D/F/G 相似，BoNT/X 切割囊泡相关膜蛋白（VAMP）1、2 和 3，但在一个新的位点（VAMP2 中的 Arg66-Ala67）。值得注意的是，BoNT/X 是唯一能够切割非典型底物 VAMP4、VAMP5 和 Ykt6 的毒素。为了验证其活性，我们使用转肽酶（sortase）将两个无毒片段连接起来，组装了少量全长的 BoNT/X。组装的 BoNT/X 可切割培养神经元中的 VAMP2 和 VAMP4，并导致小鼠瘫痪。因此，BoNT/X 是一种具有独特底物谱的新型 BoNT。它的发现对开发有效的对策提出了挑战，为研究细胞内膜运输提供了新的工具，并为调节细胞分泌提供了一种新的潜在治疗性毒素。
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