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Solution structure and functional analysis of HelaTx1: the first toxin member of the リ-KTx5 subfamily
Jae IL Kim1,*
1Department of Life Sciences, Gwangju Institute of Science and Technology,
2Toxicology and Pharmacology, University of Leuven,
3Department of Environmental Sciences, Fukuoka Women's University
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 リ-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 モ-sheets, resembling the molecular folding of other cysteine-stabilized helix-loop-helix (Cs メ/メ) scorpion toxins such as リ-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.
Abstract, Accepted Manuscript(in press) [Submitted on October 26, 2019, Accepted on November 11, 2019]
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