Centipede KCNQ Inhibitor SsTx Also Targets K(V)1.3

It was recently discovered that Ssm Spooky Toxin (SsTx) with 53 residues serves as a key killer factor in red-headed centipede’s venom arsenal, due to its potent blockage of the widely expressed KCNQ channels to simultaneously and efficiently disrupt cardiovascular, respiratory, muscular, and nervous systems, suggesting that SsTx is a basic compound for centipedes’ defense and predation. Here, we show that SsTx also inhibits K(V)1.3 channel, which would amplify the broad-spectrum disruptive effect of blocking K(V)7 channels. Interestingly, residue R12 in SsTx extends into the selectivity filter to block K(V)7.4, however, residue K11 in SsTx replaces this ploy when toxin binds on K(V)1.3. Both SsTx and its mutant SsTx_R12A inhibit cytokines production in T cells without affecting the level of K(V)1.3 expression. The results further suggest that SsTx is a key molecule for defense and predation in the centipedes’ venoms and it evolves efficient strategy to disturb multiple physiological targets.