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KMID : 0624620200530050260
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BMB Reports
2020 Volume.53 No. 5 p.260 ~ p.265
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Solution Structure and Functional Analysis of HelaTx1: The First Toxin Member of the κ-KTx5 Subfamily
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Park Bong-Gyu
Peigneur Steve
Esaki Nao
Yamaguchi Yoko
Ryu Jae-Ha
Tytgat Jan
Kim Jae-Il
Sato Kazuki
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Abstract
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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 voltagegated 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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KEYWORD
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Alanine-scanning analog, HelaTx1, Scorpion toxin, Structural topology, Voltage-gated potassium channels
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