Interaction of a Toxin from the Scorpion Tityus serrulatus with a Cloned K+ Channel from Squid (sqKv1A)

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Abstract
A toxin from the scorpion Tityus serrulatus (TsTX-Kα) blocks native squid K+ channels and their cloned counterpart, sqKv1A, at pH 8 (nativeKd ≈ 20 nM; sqKv1AKd ≈ 10 nM). In both cases, decreasing the pH below 7.0 significantly diminishes the TsTX-Kα effect (pK = 6.6). In the cloned squid channel, the pH dependence of the block is abolished by a single point mutation (H351G), and no change in toxin affinity was observed at higher pH values (pH ≥8.0). To further investigate the TsTX-Kα−sqKv1A interaction, the three-dimensional structure of TsTX-Kα was determined in solution by NMR spectroscopy, and a model of the TsTX-Kα−sqKv1A complex was generated. As found for other α-K toxins such as charybdotoxin (CTX), site-directed mutagenesis at toxin residue K27 (K27A, K27R, and K27E) significantly reduced the toxin's affinity for sqKv1A channels. This is consistent with the TsTX-Kα−sqKv1A model reported here, which has K27 of the toxin inserted into the ion conduction pathway of the K+ channel. This toxin-channel model also illustrates a possible mechanism for the pH-dependent block whereby lysine residues from TsTX-Kα (K6 and K23) are repelled by protonated H351 on sqKv1A at low pH.