Proteogenomic Assessment of Intraspecific Venom Variability: Molecular Adaptations in the Venom Arsenal of Conus purpurascens

Meghan Grandal,Mickelene Hoggard,Benjamin Neely,W Clay Davis,Frank Marí

doi:10.1016/j.mcpro.2021.100100

Abstract

Cone snails produce venom that contains diverse groups of peptides (conopeptides/conotoxins) and display a wide mass range, high rate of posttranslational modifications, and many potential pharmacological targets. Here we employ a proteogenomic approach to maximize conopeptide identification from the injected venom of Conus purpurascens. mRNA sequences from C. purpurascens venom ducts were assembled into a search database and complemented with known sequences and de novo approaches. We used a top-down peptidomic approach and tandem mass spectrometry identification to compare injected venom samples of 27 specimens. This intraspecific analysis yielded 543 unique conopeptide identifications, which included 33 base conopeptides and their toxiforms, 21 of which are novel. The results reveal two distinct venom profiles with different synergistic interactions to effectively target neural pathways aimed to immobilize prey. These venom expression patterns will aid target prediction, a significant step toward developing conotoxins into valuable drugs or neural probes.

Highlights

We analyzed the injected venom of 27 specimens of Conus purpurascens. We found 543 unique conopeptide identifications. We identified 21 novel base conopeptides. We found two distinct venom profiles with different synergistic interactions
Intraspecific venom plasticity expands the molecular adaptations of venomous animals, and in doing so it augments the repository of compounds with medicinal applications, such as Captopril from the Brazilian pit viper venom, Exenatide from the Gila monster, and Ziconotide/Prialt from cone snail venom [16]
Four of these peptides were identified from C. purpurascens UniProt entries (α-PIA, α-PIB, κ-PIVF, PVIF), and three conopeptides were sequenced de novo and added to our in-house search database (Contryphan-P4, PIF, and PIG)

Summary

Introduction

Cone snails produce venom that contains diverse groups of peptides (conopeptides/conotoxins) and display a wide mass range, high rate of posttranslational modifications, and many potential pharmacological targets. The results reveal two distinct venom profiles with different synergistic interactions to effectively target neural pathways aimed to immobilize prey These venom expression patterns will aid target prediction, a significant step toward developing conotoxins into valuable drugs or neural probes. The molecular diversity of cone snail venom is extraordinary as its expression is species-specific with little overlap of components among the more than 800 extant species [28] This complexity is compounded by intraspecific and intraspecimen venom variations due to predatory or defensive venom profiles [10, 11, 13].

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Conclusion