Dynamic diversification from a putative common ancestor of scorpion toxinsaffecting sodium, potassium, and chloride channels

Scorpions have survived successfully over millions of years without detecta ble changes in their morphology. Instead, they have developed an efficient alomonal machinery and a stinging device supporting their needs for prey an d defense. They produce a large variety of polypeptidic toxins that bind an d modulate ion channel conductance in excitable tissues. The binding site, mode of action, and chemical properties of many toxins have been studied ex tensively, but little is known about their genomic organization and diversi ty. Genes representing each of the major classes of Buthidae scorpion toxin s, namely, "long" toxins, affecting sodium channels (alpha, depressant, and excitatory), and "short" toxins, affecting potassium and chloride channels , were isolated from a single scorpion segment and analyzed. Each toxin typ e was found to be encoded by a gene family. Regardless of toxin length, 3-D structure, and site of action, all genes contain A+T-rich introns that spl it, at a conserved location, an amino acid codon of the signal sequence. Th e introns vary in length and sequence but display identical boundaries, agr ee with the GT/AG splice junctions, and contain T-runs downstream of a puta tive branch point, 5'-TAAT-3'. Despite little sequence similarity among all toxin classes, the conserved gene organization, intron features, and commo n cysteine-stabilized alpha-helical (CSH) core connecting an alpha-helix to a three-stranded beta-sheet suggest, that they evolved from an ancestral c ommon progenitor. Furthermore, the vast diversity found among genomic copie s, cDNAs, and their protein products for each toxin suggests an extensive e volutionary process of the scorpion "pharmaceutical factory," whose success is due, most likely, to the inherent permissiveness of the toxin exterior to structural alterations.