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

作者：Bergeron Zachary L; Chun Joycelyn B; Baker Margaret R; Sandall David W; Peigneur Steve; Yu Peter Y C; Thapa Parashar; Milisen Jeffrey W; Tytgat Jan; Livett Bruce G; Bingham Jon Paul^*

来源：Peptides, 2013, 49: 145-158.

DOI：10.1016/j.peptides.2013.09.004

• alpha-Conotoxin
• Conopeptides
• Conus textile
• Mass spectrometry
• Milked venom
• Radula tooth
• Post-translational modifications
• nAChR

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 alpha-conotoxin TxIC. We assign this conopeptide to the 4/7 alpha-conotoxin family based on the peptide's sequence homology and cDNA pre-propeptide alignment. Pharmacologically, alpha-conotoxin TxIC demonstrates minimal activity on human acetylcholine receptor models (100 mu 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 alpha-conotoxin TxIC, demonstrates differential selectivity for the alpha 3 beta 2 isoform of the nicotinic acetylcholine receptor with maximal inhibition of 96% and an observed IC50 of 5.4 +/- 0.5 mu M. Interestingly its comparative PD50 (3.6 mu Mol kg(-1)) in invertebrates was similar to 100 fold more than that of the native peptide. Differentiating alpha-conotoxin TxIC from other alpha-conotoxinsis the high degree of post-translational modification (44% of residues). This includes the incorporation of gamma-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 alpha-conotoxins and illustrate a potential driver of toxin phyla-selectivity within Conus.

• 出版日期2013-11