Cone snail venom comprises
many 1000s of venom peptides that have evolved for prey capture and defence
from a smaller set of transcriptomic sequences. Deep venomics has revealed
surprising messiness in the venom at the proteomic level that arises from variable
peptide processing by endoproteases. This “messy” processing generates ragged
N- and C-terminal processing underlying much of the peptide diversity found at
low levels using high sensitivity LC/MS techniques, in addition to a smaller
number of predicted major cleavage products. Recently, we have uncovered
another layer of venom peptide messiness seen at the transcriptomic level in
cone snails. A surprisingly large
number of conopeptide gene sequences were found to be expressed at low-levels,
including a series of single amino acid variants, as well as sequences
containing deletions and frame and stop codon shifts. Some of the toxin
variants generated alternative cleavage sites, interrupted or elongated
cysteine frameworks, and highly variable isoforms within families that could be
identified at the peptide level. Together with variable peptide processing, this
background biological messiness explains the hypervariability of venom
peptides. Variable processing and transcriptomic messiness likely contributes
to the rapidly evolution of venoms with new or altered function and might be
exploited in non-venomous species and prove useful in expanding structure-function
studies.