Elapid venom toxins: multiple recruitments of ancient scaffolds

Nigroxins A and B, two myotoxic phospholipases A(2) (PLA(2)s) from the veno m of the American elapid Micrurus nigrocinctus, belong to a new PLA(2) subc lass. Their primary structures were established and compared with those of PLA(2)s that have already been studied with respect to myotoxic activity. T he combination of amino acid residues Arg15, Ala100, Asn108 and a hydrophob ic residue at position 109 is present exclusively in class I PLA(2)s that d isplay myotoxic activity. These residues cluster within a surface region ri ch in positive charges and are suggested to play a role in the interaction with the target membrane of the muscle fibers. It is concluded that the myo toxic PLA(2)s resulted from recruitment of an ancient scaffold. Dendrotoxin s and a-neurotoxins are similarly derived from other old structures, which are, however, now also present in nontoxic proteins that are widely distrib uted throughout the animal kingdom. The evolutionary pathways by which elap id PLA(2)s acquired myotoxicity and dendrotoxins acquired K+-channel blocke r activity are traced. They demonstrate how existing scaffolds were adapted stepwise to serve toxic functions by exchange of a few surface-exposed res idues.