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The first gamma-carboxyglutamic acid-containing contryphan - A selective L-type calcium ion channel blocker isolated from the venom of conus marmoreus

In English

Författare

Summary, in English

Contryphans constitute a group of conopeptides that are known to contain an unusual density of post-translational modifications including tryptophan bromination, amidation of the C-terminal residue, leucine, and tryptophan isomerization, and proline hydroxylation. Here we report the identification and characterization of a new member of this family, glacontryphan-M from the venom of Conus marmoreus. This is the first known example of a contryphan peptide carrying glutamyl residues that have been post-translationally carboxylated to {gamma}-carboxyglutamyl (Gla) residues. The amino acid sequence of glacontryphan-M was determined using automated Edman degradation and electrospray ionization mass spectrometry. The amino acid sequence of the peptide is: Asn-Gla-Ser-Gla-Cys-Pro-D-Trp-His-Pro-Trp-Cys. As with most other contryphans, glacontryphan-M is amidated at the C terminus and maintains the five-residue intercysteine loop. The occurrence of a D-tryptophan residue was confirmed by chemical synthesis and HPLC elution profiles. Using fluorescence spectroscopy we demonstrated that the Gla-containing peptide binds calcium with a KD of 0.63 mM. Cloning of the full-length cDNA encoding glacontryphan-M revealed that the primary translation product carries an N-terminal signal/propeptide sequence that is homologous to earlier reported contryphan signal/propeptide sequences up to 10 amino acids preceding the toxin region. Electrophysiological experiments, carried out on mouse pancreatic B-cells, showed that glacontryphan-M blocks L-type voltage-gated calcium ion channel activity in a calcium-dependent manner. Glacontryphan-M is the first contryphan reported to modulate the activity of L-type calcium ion channels.

Publiceringsår

2004

Språk

Engelska

Sidor

32453-32463

Publikation/Tidskrift/Serie

Journal of Biological Chemistry

Volym

279

Issue

31

Dokumenttyp

Artikel i tidskrift

Förlag

American Society for Biochemistry and Molecular Biology

Ämne

  • Medicinal Chemistry
  • Endocrinology and Diabetes

Status

Published

Forskningsgrupp

  • Clinical Chemistry, Malmö
  • Diabetes - Islet Cell Exocytosis
  • Islet cell physiology

ISBN/ISSN/Övrigt

  • ISSN: 1083-351X