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8. The Tarantula Venom Peptide Eo1a Binds to the Domain II S3-S4 Extracellular Loop of Voltage-Gated Sodium Channel NaV1.8 to Enhance Activation

Author

Deuis, Jennifer R., primary, Ragnarsson, Lotten, additional, Robinson, Samuel D., additional, Dekan, Zoltan, additional, Chan, Lerena, additional, Jin, Ai-Hua, additional, Tran, Poanna, additional, McMahon, Kirsten L., additional, Li, Shengnan, additional, Wood, John N., additional, Cox, James J., additional, King, Glenn F., additional, Herzig, Volker, additional, and Vetter, Irina, additional

Published
2022
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19. The Tarantula Venom Peptide Eo1a Binds to the Domain II S3-S4 Extracellular Loop of Voltage-Gated Sodium Channel NaV1.8 to Enhance Activation.

Author

Deuis, Jennifer R., Ragnarsson, Lotten, Robinson, Samuel D., Dekan, Zoltan, Chan, Lerena, Jin, Ai-Hua, Tran, Poanna, McMahon, Kirsten L., Li, Shengnan, Wood, John N., Cox, James J., King, Glenn F., Herzig, Volker, and Vetter, Irina

Subjects
SODIUM channels, PEPTIDES, VENOM, TARANTULAS, CONUS, BINDING sites
Abstract

Venoms from cone snails and arachnids are a rich source of peptide modulators of voltage-gated sodium (NaV) channels, however relatively few venom-derived peptides with activity at the mammalian NaV1.8 subtype have been isolated. Here, we describe the discovery and functional characterisation of β-theraphotoxin-Eo1a, a peptide from the venom of the Tanzanian black and olive baboon tarantula Encyocratella olivacea that modulates NaV1.8. Eo1a is a 37-residue peptide that increases NaV1.8 peak current (EC50 894 ± 146 nM) and causes a large hyperpolarising shift in both the voltage-dependence of activation (ΔV50–20.5 ± 1.2 mV) and steady-state fast inactivation (ΔV50–15.5 ± 1.8 mV). At a concentration of 10 μM, Eo1a has varying effects on the peak current and channel gating of NaV1.1–NaV1.7, although its activity is most pronounced at NaV1.8. Investigations into the binding site of Eo1a using NaV1.7/NaV1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of NaV1.8 to toxin activity. Results from this work may form the basis for future studies that lead to the rational design of spider venom-derived peptides with improved potency and selectivity at NaV1.8. [ABSTRACT FROM AUTHOR]

Published
2022
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26. Conotoxins: Chemistry and Biology

Author

Jin, Ai-Hua, primary, Muttenthaler, Markus, additional, Dutertre, Sebastien, additional, Himaya, S.W.A., additional, Kaas, Quentin, additional, Craik, David J., additional, Lewis, Richard J., additional, and Alewood, Paul F., additional

Published
2019
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32. Isolation and characterization of a structurally unique β-hairpin venom peptide from the predatory ant Anochetus emarginatus

Author

Touchard, Axel, primary, Brust, Andreas, additional, Cardoso, Fernanda Caldas, additional, Chin, Yanni K.-Y., additional, Herzig, Volker, additional, Jin, Ai-Hua, additional, Dejean, Alain, additional, Alewood, Paul F., additional, King, Glenn F., additional, Orivel, Jérôme, additional, and Escoubas, Pierre, additional

Published
2016
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33. α-Conotoxin MrIC is a biased agonist at α7 nicotinic acetylcholine receptors

Author

Bastien Dutertre, Sé, Mueller, Alexander, Starobova, Hana, Inserra, Marco, Jin, Ai-Hua, Deuis, Jennifer, Dutertre, Sébastien, Lewis, Richard, Alewood, Paul, Daly, Norelle, Vetter, Irina, Institut for Molecular Bioscience, University of Southern Queensland (USQ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Institute of Molecular Bioscience, and University of Queensland [Brisbane]

Subjects
Agonist, Conotoxin, Magnetic Resonance Spectroscopy, alpha7 Nicotinic Acetylcholine Receptor, medicine.drug_class, [SDV]Life Sciences [q-bio], Allosteric regulation, Alpha (ethology), Pharmacology, Nicotinic, Biochemistry, chemistry.chemical_compound, Cell Line, Tumor, medicine, Humans, Allosteric, Ion channel, HEPES, Chemistry, Biological activity, Alpha7, NMR, Nicotinic agonist, Biophysics, Conotoxins
Abstract

MrIC is a recently described selective agonist of endogenously expressed alpha 7 nAChR. In this study, we further characterize the pharmacological activity of MrIC using Ca2+ imaging approaches in SH-SY5Y cells endogenously expressing alpha 7 nAChR and demonstrate that MrIC exclusively activates alpha 7 nAChR modulated by type II positive allosteric modulators, including PNU120596. MrIC was a full agonist at PNU120596-modulated alpha 7 nAChR compared with choline, albeit with slower kinetics, but failed to elicit a Ca2+ response in the absence of PNU120596. Interestingly, the NMR structure of MrIC showed a typical 4/7 alpha-conotoxin fold, indicating that its unusual pharmacological activity is likely sequence-dependent. Overall, our results suggest that MrIC acts as a biased agonist that can only activate alpha 7 nAChR modified by type II positive allosteric modulators, and thus represents a valuable tool to probe the pharmacological properties of this important ion channel. (C) 2015 Elsevier Inc. All rights reserved.

Published
2014

47. Transcriptomic Messiness in the Venom Duct of Conus milesContributes to Conotoxin Diversity*

Author

Jin, Ai-hua, Dutertre, Sébastien, Kaas, Quentin, Lavergne, Vincent, Kubala, Petra, Lewis, Richard J., and Alewood, Paul F.

Abstract

Marine cone snails have developed sophisticated chemical strategies to capture prey and defend themselves against predators. Among the vast array of bioactive molecules in their venom, peptide components called conotoxins or conopeptides dominate, with many binding with high affinity and selectivity to a broad range of cellular targets, including receptors and transporters of the nervous system. Whereas the conopeptide gene precursor organization has a conserved topology, the peptides in the venom duct are highly processed. Indeed, deep sequencing transcriptomics has uncovered on average fewer than 100 toxin gene precursors per species, whereas advanced proteomics has revealed >10-fold greater diversity at the peptide level. In the present study, second-generation sequencing technologies coupled to highly sensitive mass spectrometry methods were applied to rapidly uncover the conopeptide diversity in the venom of a worm-hunting species, Conus miles. A total of 662 putative conopeptide encoded sequences were retrieved from transcriptomic data, comprising 48 validated conotoxin sequences that clustered into 10 gene superfamilies, including 3 novel superfamilies and a novel cysteine framework (C-C-C-CCC-C-C) identified at both transcript and peptide levels. A surprisingly large number of conopeptide gene sequences were expressed at low levels, including a series of single amino acid variants, as well as sequences containing deletions and frame and stop codon shifts. Some of the toxin variants generate alternative cleavage sites, interrupted or elongated cysteine frameworks, and highly variable isoforms within families that could be identified at the peptide level. Together with the variable peptide processing identified previously, background genetic and phenotypic levels of biological messiness in venoms contribute to the hypervariability of venom peptides and their ability to evolve rapidly.

Published
2013
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48. The Tarantula Venom Peptide Eo1a Binds to the Domain II S3-S4 Extracellular Loop of Voltage-Gated Sodium Channel Na V 1.8 to Enhance Activation.

Author

Deuis JR, Ragnarsson L, Robinson SD, Dekan Z, Chan L, Jin AH, Tran P, McMahon KL, Li S, Wood JN, Cox JJ, King GF, Herzig V, and Vetter I

Abstract

Venoms from cone snails and arachnids are a rich source of peptide modulators of voltage-gated sodium (Na V ) channels, however relatively few venom-derived peptides with activity at the mammalian Na V 1.8 subtype have been isolated. Here, we describe the discovery and functional characterisation of β-theraphotoxin-Eo1a, a peptide from the venom of the Tanzanian black and olive baboon tarantula Encyocratella olivacea that modulates Na V 1.8. Eo1a is a 37-residue peptide that increases Na V 1.8 peak current (EC 50 894 ± 146 nM) and causes a large hyperpolarising shift in both the voltage-dependence of activation (ΔV 50 -20.5 ± 1.2 mV) and steady-state fast inactivation (ΔV 50 -15.5 ± 1.8 mV). At a concentration of 10 μM, Eo1a has varying effects on the peak current and channel gating of Na V 1.1-Na V 1.7, although its activity is most pronounced at Na V 1.8. Investigations into the binding site of Eo1a using Na V 1.7/Na V 1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of Na V 1.8 to toxin activity. Results from this work may form the basis for future studies that lead to the rational design of spider venom-derived peptides with improved potency and selectivity at Na V 1.8., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Deuis, Ragnarsson, Robinson, Dekan, Chan, Jin, Tran, McMahon, Li, Wood, Cox, King, Herzig and Vetter.)

Published
2022
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49. Discovery of novel peptide neurotoxins from sea anemone species.

Author

Fu J, Liao Y, Jin AH, and Gao B

Subjects
Animals, Neurotoxins toxicity, Peptides, Sea Anemones
Abstract

As primitive metazoa, sea anemones are rich in various bioactive peptide neurotoxins. These peptides have been applied to neuroscience research tools or directly developed as marine drugs. To date, more than 1100 species of sea anemones have been reported, but only 5% of the species have been used to isolate and identify sea anemone peptide neurotoxins. There is an urgent need for more systematic discovery and study of peptide neurotoxins in sea anemones. In this review, we have gathered the currently available methods from crude venom purification and gene cloning to venom multiomics, employing these techniques for discovering novel sea anemone peptide neurotoxins. In addition, the three-dimensional structures and targets of sea anemone peptide neurotoxins are summarized. Therefore, the purpose of this review is to provide a reference for the discovery, development, and utilization of sea anemone peptide neurotoxins., (© 2021 The Author(s). Published by BRI.)

Published
2021
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50. Conotoxin Φ-MiXXVIIA from the Superfamily G2 Employs a Novel Cysteine Framework that Mimics Granulin and Displays Anti-Apoptotic Activity.

Author

Jin AH, Dekan Z, Smout MJ, Wilson D, Dutertre S, Vetter I, Lewis RJ, Loukas A, Daly NL, and Alewood PF

Subjects
Amino Acid Sequence, Cell Proliferation drug effects, Conotoxins chemistry, Disulfides chemistry, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Conformation, Sequence Homology, Amino Acid, Apoptosis drug effects, Conotoxins pharmacology, Cysteine chemistry, Granulins pharmacology, Molecular Mimicry
Abstract

Conotoxins are a large family of disulfide-rich peptides that contain unique cysteine frameworks that target a broad range of ion channels and receptors. We recently discovered the 33-residue conotoxin Φ-MiXXVIIA from Conus miles with a novel cysteine framework comprising three consecutive cysteine residues and four disulfide bonds. Regioselective chemical synthesis helped decipher the disulfide bond connectivity and the structure of Φ-MiXXVIIA was determined by NMR spectroscopy. The 3D structure displays a unique topology containing two β-hairpins that resemble the N-terminal domain of granulin. Similar to granulin, Φ-MiXXVIIA promotes cell proliferation (EC 50 17.85 μm) while inhibiting apoptosis (EC 50 2.2 μm). Additional framework XXVII sequences were discovered with homologous signal peptides that define the new conotoxin superfamily G2. The novel structure and biological activity of Φ-MiXXVIIA expands the repertoire of disulfide-rich conotoxins that recognize mammalian receptors., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2017
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