New Tricks of an Old Pattern STRUCTURALVERSATILITYOFSCORPIONTOXINSWITHCOMMONCYSTEINESPACING

Scorpion venoms are a rich source of K channel-blocking peptides. For the most part, they are structurally related small disulfide-rich proteins containing a conserved pattern of six cys- teines that is assumed to dictate their common three-dimen- sional folding. In the conventional pattern, two disulfide bridges connect an-helical segment to the C-terminal strand of a dou- ble- or triple-stranded -sheet, conforming a cystine-stabilized / scaffold (CS/). Here we show that two K channel-block- ing peptides from Tityus scorpions conserve the cysteine spac- ing of common scorpion venom peptides but display an uncon- ventional disulfide pattern, accompanied by a complete rearrangement of the secondary structure topology into a CS helix-loop-helix fold. Sequence and structural comparisons of the peptides adopting this novel fold suggest that it would be a new elaboration of the widespread CS/ scaffold, thus reveal- ing an unexpected structural versatility of these small disulfide- rich proteins. Acknowledgment of such versatility is important to understand how venom structural complexity emerged on a limited number of molecular scaffolds.