Chen Jing, Zhang Chuangeng, Yang Weishan, Cao Zhijian, Li Wenxin, Chen Zongyun, Wu Yingliang
Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Hubei University of Medicine, Hubei, China; State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei, China.
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei, China.
Int J Biol Macromol. 2015 Aug;79:504-10. doi: 10.1016/j.ijbiomac.2015.05.027. Epub 2015 May 23.
Peptides with Ascaris-type fold are a new kind of toxins founded from venomous animals recently. Functionally, these unique toxin peptides had been identified as potent protease inhibitors, which was similar to other known Ascaris-type peptides from non-venomous animals. Whether Ascaris-type peptides from venom animals have neurotoxin activities remains unclear. Here, a scorpion toxin SjAPI-2 with Ascaris-type fold was characterized to have a neurotoxin activity, which can selectively inhibit KCNQ1 potassium channel. SjAPI-2 had 62 amino acid residues, including 10 cysteine residues. Charged residue analyses showed that two acidic residues of SjAPI-2 were regionally distributed, and 10 basic residues were distributed widely throughout the whole peptide, which was similar to classical potassium channel toxins. Pharmacological studies confirmed that SjAPI-2 was a selective KCNQ1 potassium channel inhibitor with weak effects on other potassium channels, such as Kv1.1, Kv1.2, Kv1.3, SKCa2, SKCa3, and IKCa channels. Concentration-dependent studies showed that SjAPI-2 inhibited the KCNQ1 potassium channel with an IC50 of 771.5±169.9 nM. To the best of our knowledge, SjAPI-2 is the first neurotoxin with a unique Ascaris-type fold, providing novel insights into the divergent evolution of neurotoxins from venomous animals.
具有蛔虫型折叠的肽是最近从有毒动物中发现的一类新型毒素。在功能上，这些独特的毒素肽已被鉴定为有效的蛋白酶抑制剂，这与来自无毒动物的其他已知蛔虫型肽类似。来自有毒动物的蛔虫型肽是否具有神经毒素活性仍不清楚。在此，一种具有蛔虫型折叠的蝎子毒素SjAPI-2被表征为具有神经毒素活性，它可以选择性抑制KCNQ1钾通道。SjAPI-2有62个氨基酸残基，包括10个半胱氨酸残基。带电残基分析表明，SjAPI-2的两个酸性残基呈区域分布，10个碱性残基广泛分布于整个肽段，这与经典的钾通道毒素相似。药理学研究证实，SjAPI-2是一种选择性KCNQ1钾通道抑制剂，对其他钾通道如Kv1.1、Kv1.2、Kv1.3、SKCa2、SKCa3和IKCa通道的作用较弱。浓度依赖性研究表明，SjAPI-2抑制KCNQ1钾通道的IC50为771.5±169.9 nM。据我们所知，SjAPI-2是第一种具有独特蛔虫型折叠的神经毒素，为有毒动物神经毒素的趋异进化提供了新的见解。
