Conantokin-P, an unusual conantokin with a long disulfide loop

Area of Science:

• Biochemistry
• Neuroscience
• Marine Biology

Background:

• Conantokins are venom peptides from Conus snails that antagonize N-methyl-d-aspartate (NMDA) receptors.
• Most conantokins are linear and lack disulfide bridges, but contain gamma-carboxyglutamate (Gla) residues essential for their helical structure.
• These peptides are crucial for understanding NMDA receptor function and developing novel therapeutics.

Purpose of the Study:

• To investigate novel conantokins from fish-hunting cone snails, Conus purpurascens and Conus ermineus.
• To characterize the biochemical properties, structure, and NMDA receptor antagonist activity of these new conantokins.

Main Methods:

• Isolation and sequencing of novel conantokins (conantokin-P and conantokin-E).
• Analysis of post-translational modifications, including gamma-carboxyglutamate residues.
• Oxidative folding studies and circular dichroism to determine structural features.
• Electrophysiological assays to assess NMDA receptor antagonist potency and subtype-selectivity.

Main Results:

• Two novel conantokins, conantokin-P and conantokin-E, were identified, each 24 amino acids long with five gamma-carboxyglutamate residues.
• These peptides feature a distinct long disulfide loop and exhibit reduced helical structure compared to previously known conantokins.
• Conantokin-P demonstrated submicromolar potency in blocking NMDA receptors containing the NR2B subunit, with differing subtype-selectivity.

Conclusions:

• Different evolutionary lineages of cone snails have developed distinct conantokin families with unique biochemical characteristics.
• The novel conantokins from C. purpurascens and C. ermineus represent a unique branch with specialized structural and functional properties.
• These findings expand our understanding of conantokin diversity and their interactions with NMDA receptors.