Elapid venom toxins:: multiple recruitments of ancient scaffolds

Nigroxins A and B, two myotoxic phospholipases A(2) (PLA(2)s) from the venom of the American elapid Micrurus nigrocinctus, belong to a new PLA(2) subclass. Their primary structures were established and compared with those of PLA(2)s that have already been studied with respect to myotoxic activity. The combination of amino acid residues Arg15, Ala100, Asn108 and a hydrophobic residue at position 109 is present exclusively in class I PLA(2)s that display myotoxic activity. These residues cluster within a surface region rich 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 myotoxic PLA(2)s resulted from recruitment of an ancient scaffold. Dendrotoxins and a-neurotoxins are similarly derived from other old structures, which are, however, now also present in nontoxic proteins that are widely distributed throughout the animal kingdom. The evolutionary pathways by which elapid PLA(2)s acquired myotoxicity and dendrotoxins acquired K+-channel blocker activity are traced. They demonstrate how existing scaffolds were adapted stepwise to serve toxic functions by exchange of a few surface-exposed residues.