Molecular Phylogeny, Classification and Evolution of Conopeptides

Abstract

Conopeptides are toxins expressed in the venom duct of cone snails (Conoidea, Conus). These are mostly well-structured peptides and mini-proteins with high potency and selectivity for a broad range of cellular targets. In view of these properties, they are widely used as pharmacological tools and many are candidates for innovative drugs. The conopeptides are primarily classified into superfamilies according to their peptide signal sequence, a classification that is thought to reflect the evolution of the multigenic system. However, this hypothesis has never been thoroughly tested. Here we present a phylogenetic analysis of 1,364 conopeptide signal sequences extracted from GenBank. The results validate the current conopeptide superfamily classification, but also reveal several important new features. The so-called "cysteine-poor" conopeptides are revealed to be closely related to "cysteine-rich" conopeptides; with some of them sharing very similar signal sequences, suggesting that a distinction based on cysteine content and configuration is not phylogenetically relevant and does not reflect the evolutionary history of conopeptides. A given cysteine pattern or pharmacological activity can be found across different superfamilies. Furthermore, a few conopeptides from GenBank do not cluster in any of the known superfamilies, and could represent yet-undefined superfamilies. A clear phylogenetically based classification should help to disentangle the diversity of conopeptides, and could also serve as a rationale to understand the evolution of the toxins in the numerous other species of conoideans and venomous animals at large.

Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks

“…Despite a weak correlation between gene superfamilies and pharmacological properties, some functional redundancy among members of a same superfamily exists (56). To date, 16 empirical gene superfamilies (designated as A, D, I1, I2, I3, J, L, M, O1, O2, O3, P, S, T, V, Y) have been annotated (57), plus 31 novel superfamilies have been discovered during the past two years (38,39,46,(57)(58)(59)(60).…”

Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications

“…Peptides with none or one disulfide bonds are disulfide-poor conopeptides and those having two or more disulfides are disulfide-rich conopeptides [6], also termed as conotoxins. It is suggested that a distinction of conopeptides on the basis of cysteine content and arrangement is not phylogenetically justified [7]. Conopeptides can be classified into following three categories on the basis of their signal sequence, cysteine pattern or framework and molecular target.…”

Genus Profundiconus Kuroda, 1956 (Gastropoda, Conoidea): Morphological and molecular studies, with the description of five new species from the Solomon Islands and New Caledonia

“…Whereas most of the toxinological studies on cone snails carried out during the last three decades have focused on species that belong to only a few lineages (Puillandre et al 2012), several lineages remain largely understudied or even not studied at all, as is the case for Profundiconus (Puillandre et al 2014). Radular morphology suggests a most likely vermivorous diet.…”