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Solution structure of APETx2, a specific peptide inhibitor of ASIC3 proton-gated channels

¹ Architecture et Fonction des Macromolécules Biologiques (AFMB), Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 6098 and Universités d’Aix-Marseille I and II, Marseille Cedex 20, France
² Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 6097, Valbonne, France

(RECEIVED January 27, 2005; FINAL REVISION May 11, 2005; ACCEPTED May 17, 2005)

Acid-sensing ion channels (ASIC) are proton-gated sodium channels that have been implicated in pain transduction associated with acidosis in inflamed or ischemic tissues. APETx2, a peptide toxin effector of ASIC3, has been purified from an extract of the sea anemone Anthopleura elegantissima. APETx2 is a 42-amino-acid peptide cross-linked by three disulfide bridges. Its three-dimensional structure, as determined by conventional two-dimensional ¹H-NMR, consists of a compact disulfidebonded core composed of a four-stranded -sheet. It belongs to the disulfide-rich all- structural family encompassing peptide toxins commonly found in animal venoms. The structural characteristics of APETx2 are compared with that of PcTx1, another effector of ASIC channels but specific to the ASIC1a subtype and to APETx1, a toxin structurally related to APETx2, which targets the HERG potassium channel. Structural comparisons, coupled with the analysis of the electrostatic characteristics of these various ion channel effectors, led us to suggest a putative channel interaction surface for APETx2, encompassing its N terminus together with the type I- turn connecting -strands III and IV. This basic surface (R31 and R17) is also rich in aromatic residues (Y16, F15, Y32, and F33). An additional region made of the type II'- turn connecting -strands I and II could also play a role in the specificity observed for these different ion effectors.

Keywords: Anthopleura elegantissima; APETx2; sea anemone toxin; structure determination; sodium channel inhibitor; ASIC; NMR

Abbreviations: APETx2, Anthopleura elegantissima toxin 2 • ASIC, acid-sensing ion channel

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.051378905.

Reprint requests to: Hervé Darbon, AFMB, CNRS UMR 6098 and Universités d’Aix-Marseille I and II, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France; e-mail: herve{at}afmb.cnrs-mrs.fr; fax: +33 (0)4-91-16-45-36.

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