title: SjAPI-2 is the first member of a new neurotoxin family with Ascaris-type fold and KCNQ1 inhibitory activity.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei, China.
authors.forename: Chuangeng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: 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. Electronic address: chenzy2005@126.com.
authors.forename: Zongyun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Hubei, China. Electronic address: ylwu@whu.edu.cn.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D060829:Arthropod Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001483:Base Sequence; D003001:Cloning, Molecular; D057809:HEK293 Cells; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D055550:Protein Stability; D017433:Protein Structure, Secondary; D012604:Scorpion Venoms / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D012605:Scorpions / Q000737:chemistry
chemical_list: D060829:Arthropod Proteins; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D026902:Potassium Channel Blockers; D012604:Scorpion Venoms
keywords: KCNQ1; Scorpion toxin; Structural fold