A 'conovenomic' analysis of the milked venom from the mollusk-hunting cone snail Conus textile--the pharmacological importance of post-translational modifications.

ABSTRACT: Cone snail venoms provide a largely untapped source of novel peptide drug leads. To enhance the discovery phase, a detailed comparative proteomic analysis was undertaken on milked venom from the mollusk-hunting cone snail, Conus textile, from three different geographic locations (Hawai'i, American Samoa and Australia's Great Barrier Reef). A novel milked venom conopeptide rich in post-translational modifications was discovered, characterized and named ?-conotoxin TxIC. We assign this conopeptide to the 4/7 ?-conotoxin family based on the peptide's sequence homology and cDNA pre-propeptide alignment. Pharmacologically, ?-conotoxin TxIC demonstrates minimal activity on human acetylcholine receptor models (100 ?M, <5% inhibition), compared to its high paralytic potency in invertebrates, PD50 = 34.2 nMol kg(-1). The non-post-translationally modified form, [Pro](2,8)[Glu](16)?-conotoxin TxIC, demonstrates differential selectivity for the ?3?2 isoform of the nicotinic acetylcholine receptor with maximal inhibition of 96% and an observed IC50 of 5.4 ± 0.5 ?M. Interestingly its comparative PD50 (3.6 ?Mol kg(-1)) in invertebrates was ~100 fold more than that of the native peptide. Differentiating ?-conotoxin TxIC from other ?-conotoxins is the high degree of post-translational modification (44% of residues). This includes the incorporation of ?-carboxyglutamic acid, two moieties of 4-trans hydroxyproline, two disulfide bond linkages, and C-terminal amidation. These findings expand upon the known chemical diversity of ?-conotoxins and illustrate a potential driver of toxin phyla-selectivity within Conus.

SUBMITTER: Bergeron ZL 

PROVIDER: S-EPMC6013274 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature