Botulinum Neurotoxin A4 Has a 1000-Fold Reduced Potency Due to Three Single Amino Acid Alterations in the Protein Receptor Binding Domain.
Botulinum Neurotoxin A4 Has a 1000-Fold Reduced Potency Due to Three Single Amino Acid Alterations in the Protein Receptor Binding Domain.
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DOI：
10.3390/ijms24065690
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发表时间：
2023-03-16
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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肉毒杆菌神经毒素 A4 亚型 (BoNT/A4) 的效力比 BoNT/A1 低约 1000 倍。本研究解决了 BoNT/A4 效力低的基础。利用 BoNT/A1-A4 和 BoNT/A4-A1 轻链-重链 (LC-HC) 嵌合体，HC-A4 导致 BoNT/A4 效力较低。早期研究表明，BoNT/A1 受体结合结构域 (Hcc) 与 BoNT/A 蛋白受体 SV2C 的管腔结构域 4 (LD4) 内的 β 链肽 (556-564) 和聚糖-N559 结合。相对于 BoNT/A1，BoNT/A4 的 Hcc 在 β-肽结合界面内拥有两个氨基酸变体（D1141 和 N1142），以及位于 SV2C 聚糖-N559 附近的一个氨基酸变体（R1292）。将BoNT/A4 β-链肽变体（D1141和N1142）引入BoNT/A1将毒素效力降低30倍，并且额外引入BoNT/A4聚糖-N559变体（D1141、N1142和R1292）进一步降低毒素效力以接近BoNT/A4。虽然将 BoNT/A1 聚糖-N559 变体 (G1292) 引入 BoNT/A4 不会改变毒素效力，但额外引入 BoNT/A1 β-链肽变体 (G1141、S1142 和 G1292) 导致效力接近 BoNT/A1 效力。因此，这些功能和建模研究的结果表明，在啮齿动物模型中，Hcc -SV2C β-肽和-聚糖-N559相互作用的破坏介导低BoNT/A4效力，而在人类运动神经元中，单独破坏Hcc-SV2C β-肽介导低BoNT/A4效力，这与SV2C563的物种特异性变异有关。
Botulinum neurotoxin subtype A4 (BoNT/A4) is ~1000-fold less potent than BoNT/A1. This study addresses the basis for low BoNT/A4 potency. Utilizing BoNT/A1-A4 and BoNT/A4-A1 Light Chain-Heavy Chain (LC-HC) chimeras, HC-A4 was responsible for low BoNT/A4 potency. Earlier studies showed BoNT/A1-receptor binding domain (Hcc) bound a β-strand peptide (556–564) and glycan-N559 within Luminal Domain 4 (LD4) of SV2C, the BoNT/A protein receptor. Relative to BoNT/A1, the Hcc of BoNT/A4 possesses two amino acid variants (D1141 and N1142) within the β-peptide binding interface and one amino acid variant (R1292) located near the SV2C glycan-N559. Introduction of BoNT/A4 β-strand peptide variant (D1141 and N1142) into BoNT/A1 reduced toxin potency 30-fold, and additional introduction of the BoNT/A4 glycan-N559 variant (D1141, N1142, and R1292) further reduced toxin potency to approach BoNT/A4. While introduction of BoNT/A1 glycan-N559 variant (G1292) into BoNT/A4 did not alter toxin potency, additional introduction of BoNT/A1 β-strand peptide variants (G1141, S1142, and G1292) resulted in potency approaching BoNT/A1 potency. Thus, outcomes from these functional and modeling studies indicate that in rodent models, disruption of Hcc -SV2C β-peptide and -glycan-N559 interactions mediate low BoNT/A4 potency, while in human motor neurons, disruption of Hcc-SV2C β-peptide alone mediates low BoNT/A4 potency, which link to a species-specific variation at SV2C563.
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