title: Molecular basis for the toxin insensitivity of scorpion voltage-gated potassium channel MmKv1.
abstract: Scorpions are insensitive to their own venoms, which contain various neurotoxins specific for mammalian or insect ion channels, whose molecular mechanism remains unsolved. Using MmKv1, a potassium channel identified from the genome of the scorpion Mesobuthus martensii, channel kinetic experiments showed that MmKv1 was a classical voltage-gated potassium channel with a voltage-dependent fast activation and slow inactivation. Compared with the human Kv1.3 channel (hKv1.3), the MmKv1 channel exhibited a remarkable insensitivity to both scorpion venom and toxin. The chimaeric channels of MmKv1 and hKv1.3 revealed that both turret and filter regions of the MmKv1 channel were critical for the toxin insensitivity of MmKv1. Furthermore, mutagenesis of the chimaeric channel indicated that two basic residues (Arg(399) and Lys(403)) in the MmKv1 turret region and Arg(425) in the MmKv1 filter region significantly affected its toxin insensitivity. Moreover, when these three basic residues of MmKv1 were simultaneously substituted with the corresponding residues from hKv1.3, the MmKv1-R399T/K403S/R425H mutant channels exhibited similar sensitivity to both scorpion venom and toxin to hKv1.3, which revealed the determining role of these three basic residues in the toxin insensitivity of the MmKv1 channel. More strikingly, a similar triad sequence structure is present in all Shaker-like channels from venomous invertebrates, which suggested a possible convergent functional evolution of these channels to enable them to resist their own venoms. Together, these findings first illustrate the mechanism by which scorpions are insensitive to their own venoms at the ion channel receptor level and enrich our knowledge of the insensitivity of scorpions and other venomous animals to their own venoms.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Chuangeng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Xie
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Yange
authors.initials: Y
authors.lastname: Lang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Weishan
authors.initials: W
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China Center for BioDrug Research, Wuhan University, Wuhan 430072, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zongyun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China Center for BioDrug Research, Wuhan University, Wuhan 430072, China zjcao@whu.edu.cn ylwu@whu.edu.cn.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China Center for BioDrug Research, Wuhan University, Wuhan 430072, China zjcao@whu.edu.cn ylwu@whu.edu.cn.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D060829:Arthropod Proteins / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000502:physiology*; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D012604:Scorpion Venoms / Q000494:pharmacology*; D012605:Scorpions / Q000235:genetics / Q000378:metabolism*
chemical_list: D060829:Arthropod Proteins; D051664:Kv1.3 Potassium Channel; D012604:Scorpion Venoms
keywords: convergent evolution; molecular mechanism; potassium channel; scorpion; toxin resistance