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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Solution structure and functional analysis of HelaTx1: the first toxin member of the κ-KTx5 subfamily

  • Park, Bong Gyu (Department of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Peigneur, Steve (Toxicology and Pharmacology, University of Leuven (KU Leuven)) ;
  • Esaki, Nao (Department of Environmental Sciences, Fukuoka Women's University) ;
  • Yamaguchi, Yoko (Department of Environmental Sciences, Fukuoka Women's University) ;
  • Ryu, Jae Ha (Department of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Tytgat, Jan (Toxicology and Pharmacology, University of Leuven (KU Leuven)) ;
  • Kim, Jae Il (Department of Life Sciences, Gwangju Institute of Science and Technology) ;
  • Sato, Kazuki (Department of Environmental Sciences, Fukuoka Women's University)
  • Received : 2019.10.26
  • Accepted : 2019.11.11
  • Published : 2020.05.31
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Abstract

Scorpion venom comprises a cocktail of toxins that have proven to be useful molecular tools for studying the pharmacological properties of membrane ion channels. HelaTx1, a short peptide neurotoxin isolated recently from the venom of the scorpion Heterometrus laoticus, is a 25 amino acid peptide with two disulfide bonds that shares low sequence homology with other scorpion toxins. HelaTx1 effectively decreases the amplitude of the K+ currents of voltage-gated Kv1.1 and Kv1.6 channels expressed in Xenopus oocytes, and was identified as the first toxin member of the κ-KTx5 subfamily, based on a sequence comparison and phylogenetic analysis. In the present study, we report the NMR solution structure of HelaTx1, and the major interaction points for its binding to voltage-gated Kv1.1 channels. The NMR results indicate that HelaTx1 adopts a helix-loop-helix fold linked by two disulfide bonds without any β-sheets, resembling the molecular folding of other cysteine-stabilized helix-loop-helix (Cs α/α) scorpion toxins such as κ-hefutoxin, HeTx, and OmTx, as well as conotoxin pl14a. A series of alanine-scanning analogs revealed a broad surface on the toxin molecule largely comprising positively-charged residues that is crucial for interaction with voltage-gated Kv1.1 channels. Interestingly, the functional dyad, a key molecular determinant for activity against voltage-gated potassium channels in other toxins, is not present in HelaTx1.

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References

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