A Conotoxin from Conus textile with Unusual Posttranslational Modifications Reduces Presynaptic Ca2+ Influx

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 10; pp. 5758 - 5763
• Main Authors: Rigby, Alan C., Lucas-Meunier, Estelle, Kalume, Dário E., Czerwiec, Eva, Hambe, Björn, Dahlovist, Ingrid, Fossier, Philippe, Baux, Gérard, Roepstorff, Peter, Baleja, James D., Furie, Barbara C., Furie, Bruce, Stenflo, Johan
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 11.05.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: 1-Carboxyglutamic Acid; 1-Carboxyglutamic Acid - chemistry; Amino acids; Animals; Aplysia; Aplysia - metabolism; Biochemistry; Biological Sciences; Calcium; Calcium - metabolism; Calcium Channels; Calcium Channels - drug effects; Conotoxins; Disulfides; Disulfides - chemistry; Life Sciences; Magnetic Resonance Spectroscopy; Mollusk Venoms; Mollusk Venoms - chemistry; Mollusks; Neurology; Neurons; Neurons and Cognition; Neurotransmitters; Peptides; Peptides - chemistry; Peptides - pharmacology; Post translational modification; Predation; Protein Processing, Post-Translational; Protein Processing, Post-Translational - genetics; Receptors; Snails; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Textiles; Toxins; Venoms
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.10.5758

Cone snails are gastropod mollusks of the genus Conus that live in tropical marine habitats. They are predators that paralyze their prey by injection of venom containing a plethora of small, conformationally constrained peptides (conotoxins). We report the identification, characterization, and structure of a γ -carboxyglutamic acid-containing peptide, conotoxin ε -TxIX, isolated from the venom of the molluscivorous cone snail, Conus textile. The disulfide bonding pattern of the four cysteine residues, an unparalleled degree of posttranslational processing including bromination, hydroxylation, and glycosylation define a family of conotoxins that may target presynaptic Ca2+ channels or act on G protein-coupled presynaptic receptors via another mechanism. This conotoxin selectively reduces neurotransmitter release at an Aplysia cholinergic synapse by reducing the presynaptic influx of Ca2+ in a slow and reversible fashion. The three-dimensional structure, determined by two-dimensional 1H NMR spectroscopy, identifies an electronegative patch created by the side chains of two γ -carboxyglutamic acid residues that extend outward from a cavernous cleft. The glycosylated threonine and hydroxylated proline enclose a localized hydrophobic region centered on the brominated tryptophan residue within the constrained intercysteine region.