AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation
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....
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doaj-a6ef1af31bb04aac9c53ea6ac181d6912020-11-25T01:05:26ZengMDPI AGMarine Drugs1660-33972018-10-01161036010.3390/md16100360md16100360AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels ActivationDiego J. B. Orts0Steve Peigneur1Laíz Costa Silva-Gonçalves2Manoel Arcisio-Miranda3José Eduardo P. W. Bicudo4Jan Tytgat5Department of Physiology, Institute of Biosciences, University of São Paulo, 05508-090 São Paulo, BrazilToxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg O&N2, Herestraat 49, P.O. Box 922, 3000 Leuven, BelgiumLaboratório de Neurobiologia Estrutural e Funcional (LaNEF), Departamento de Biofísica, Universidade Federal de São Paulo, 04023-062 São Paulo, BrazilLaboratório de Neurobiologia Estrutural e Funcional (LaNEF), Departamento de Biofísica, Universidade Federal de São Paulo, 04023-062 São Paulo, BrazilDepartment of Physiology, Institute of Biosciences, University of São Paulo, 05508-090 São Paulo, BrazilToxicology and Pharmacology, University of Leuven (KU Leuven), Campus Gasthuisberg O&N2, Herestraat 49, P.O. Box 922, 3000 Leuven, BelgiumVoltage-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.http://www.mdpi.com/1660-3397/16/10/360sea anemone neurotoxinActinia bermudensispotassium channeltype 6 KV-toxinsAlanine point mutation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Diego J. B. Orts Steve Peigneur Laíz Costa Silva-Gonçalves Manoel Arcisio-Miranda José Eduardo P. W. Bicudo Jan Tytgat |
spellingShingle |
Diego J. B. Orts Steve Peigneur Laíz Costa Silva-Gonçalves Manoel Arcisio-Miranda José Eduardo P. W. Bicudo Jan Tytgat AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation Marine Drugs sea anemone neurotoxin Actinia bermudensis potassium channel type 6 KV-toxins Alanine point mutation |
author_facet |
Diego J. B. Orts Steve Peigneur Laíz Costa Silva-Gonçalves Manoel Arcisio-Miranda José Eduardo P. W. Bicudo Jan Tytgat |
author_sort |
Diego J. B. Orts |
title |
AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation |
title_short |
AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation |
title_full |
AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation |
title_fullStr |
AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation |
title_full_unstemmed |
AbeTx1 Is a Novel Sea Anemone Toxin with a Dual Mechanism of Action on Shaker-Type K+ Channels Activation |
title_sort |
abetx1 is a novel sea anemone toxin with a dual mechanism of action on shaker-type k+ channels activation |
publisher |
MDPI AG |
series |
Marine Drugs |
issn |
1660-3397 |
publishDate |
2018-10-01 |
description |
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. |
topic |
sea anemone neurotoxin Actinia bermudensis potassium channel type 6 KV-toxins Alanine point mutation |
url |
http://www.mdpi.com/1660-3397/16/10/360 |
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