AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation
| Autor: | Diego J. B. Orts, Steve Peigneur, Laíz Costa Silva-Gonçalves, Manoel Arcisio-Miranda, José Eduardo P. W. Bicudo, Jan Tytgat |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Marine Drugs, Vol 16, Iss 10, p 360 (2018) |
| Druh dokumentu: | article |
| ISSN: | 1660-3397 16100360 |
| DOI: | 10.3390/md16100360 |
| Popis: | Voltage-gated potassium (KV) channels regulate diverse physiological processes and are an important target for developing novel therapeutic approaches. Sea anemone (Cnidaria, Anthozoa) venoms comprise a highly complex mixture of peptide toxins with diverse and selective pharmacology on KV channels. From the nematocysts of the sea anemone Actinia bermudensis, a peptide that we named AbeTx1 was purified and functionally characterized on 12 different subtypes of KV channels (KV1.1–KV1.6; KV2.1; KV3.1; KV4.2; KV4.3; KV11.1; and, Shaker IR), and three voltage-gated sodium channel isoforms (NaV1.2, NaV1.4, and BgNaV). AbeTx1 was selective for Shaker-related K+ channels and is capable of inhibiting K+ currents, not only by blocking the K+ current of KV1.2 subtype, but by altering the energetics of activation of KV1.1 and KV1.6. Moreover, experiments using six synthetic alanine point-mutated analogs further showed that a ring of basic amino acids acts as a multipoint interaction for the binding of the toxin to the channel. The AbeTx1 primary sequence is composed of 17 amino acids with a high proportion of lysines and arginines, including two disulfide bridges (Cys1–Cys4 and Cys2–Cys3), and it is devoid of aromatic or aliphatic amino acids. Secondary structure analysis reveals that AbeTx1 has a highly flexible, random-coil-like conformation, but with a tendency of structuring in the beta sheet. Its overall structure is similar to open-ended cyclic peptides found on the scorpion κ-KTx toxins family, cone snail venoms, and antimicrobial peptides. |
| Databáze: | Directory of Open Access Journals |
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