Molecular evolution of scorpion a-toxins----Accelerated substitutions and functional divergence

Scorpion a-toxins are a family of toxic proteins with similar scaffold, but possess divergent pharmacological properties. Analysis of cDNA sequences reveals that the numbers of nucleotide substitutions per site ( K ) for 5' and 3' UTRs are smaller than those per synonymous site ( Ks) for the mature peptide-coding sequences, whereas the numbers of nucleotide substitutions per nonsynonymous site (-Ka) are close to or larger than Ks values for relevant pairs of cDNAs. These results, together with phylogenetic analysis, indicate that scorpion a-toxins have evolved by accelerated substitutions in the mature toxin regions. In addition, the 15 amino acids, absolutely conserved in all the scorpion a-toxins described so far. are mostly located in molecular interior, which may be involved in structural constraints for stabilizing the CSa(3 fold in evolution of these molecules. Four hot spot mutation sites in the molecular surface are found to distribute in the putative functional regions of a-toxins. suggesting that positive Darwinian selection drives the accelerated evolution of scorpion a-toxins. These findings reasonably explain the relationship between three-dimensional structure conservation and functional divergence of scorpion a-toxins and are of important value in guiding us in our engineering experiments to obtain higher affinity ligands to Na+ channels.

Molecular evolution of scorpion a-toxins----Accelerated substitutions and functional divergence

Scorpion a-toxins are a family of toxic proteins with similar scaffold, but possess divergent pharmacological properties. Analysis of cDNA sequences reveals that the numbers of nucleotide substitutions per site ( K ) for 5' and 3' UTRs are smaller than those per synonymous site ( Ks) for the mature peptide-coding sequences, whereas the numbers of nucleotide substitutions per nonsynonymous site (-Ka) are close to or larger than Ks values for relevant pairs of cDNAs. These results, together with phylogenetic analysis, indicate that scorpion a-toxins have evolved by accelerated substitutions in the mature toxin regions. In addition, the 15 amino acids, absolutely conserved in all the scorpion a-toxins described so far. are mostly located in molecular interior, which may be involved in structural constraints for stabilizing the CSa(3 fold in evolution of these molecules. Four hot spot mutation sites in the molecular surface are found to distribute in the putative functional regions of a-toxins. suggesting that positive Darwinian selection drives the accelerated evolution of scorpion a-toxins. These findings reasonably explain the relationship between three-dimensional structure conservation and functional divergence of scorpion a-toxins and are of important value in guiding us in our engineering experiments to obtain higher affinity ligands to Na+ channels.