New Tricks of an Old Pattern STRUCTURAL VERSATILITY OF SCORPION TOXINS WITH COMMON CYSTEINE SPACING

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 cysteines that is assumed to dictate their common three-dimensional folding. In the conventional pattern, two disulfide bridges connect an alpha-helical segment to the C-terminal strand of a double- or triple-stranded beta-sheet, conforming a cystine-stabilized alpha/beta scaffold (CS alpha/beta). Here we show that two K+ channel-blocking peptides from Tityus scorpions conserve the cysteine spacing of common scorpion venom peptides but display an unconventional 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 alpha/beta scaffold, thus revealing 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.