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Isolation, Structural Assessments and Activity on Voltage-Gated Ion University of Southern Denmark GiTx1(β/κ-theraphotoxin-Gi1a), a novel toxin from the venom of Brazilian tarantula Grammostola iheringi (Mygalomorphae, Theraphosidae) Isolation, structural assessments and activity on voltage-gated ion channels Montandon, Gabriela Gontijo; Cassoli, Juliana Silva; Peigneur, Steve; Braga, Thiago Verano; Moreira Dos Santos, Daniel; Bittencourt Paiva, Ana Luiza; Ricardo de Moraes, Éder; Kushmerick, Christopher; Borges, Márcia Helena; Richardson, Michael; Monteiro de Castro Pimenta, Adriano; Kjeldsen, Frank; Vasconcelos Diniz, Marcelo Ribeiro; Tytgat, Jan; Elena de Lima, Maria Published in: Biochimie DOI: 10.1016/j.biochi.2020.07.008 Publication date: 2020 Document version: Accepted manuscript Document license: CC BY-NC-ND Citation for pulished version (APA): Montandon, G. G., Cassoli, J. S., Peigneur, S., Braga, T. V., Moreira Dos Santos, D., Bittencourt Paiva, A. L., Ricardo de Moraes, É., Kushmerick, C., Borges, M. H., Richardson, M., Monteiro de Castro Pimenta, A., Kjeldsen, F., Vasconcelos Diniz, M. R., Tytgat, J., & Elena de Lima, M. (2020). GiTx1(β/κ-theraphotoxin-Gi1a), a novel toxin from the venom of Brazilian tarantula Grammostola iheringi (Mygalomorphae, Theraphosidae): Isolation, structural assessments and activity on voltage-gated ion channels. Biochimie, 176, 138-149. https://doi.org/10.1016/j.biochi.2020.07.008 Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim. Please direct all enquiries to [email protected] Download date: 05. Oct. 2021 1 GiTx1(β/κ-theraphotoxin-Gi1a), a novel toxin from the venom of Brazilian 2 tarantula Grammostola iheringi (Mygalomorphae, Theraphosidae): 3 isolation, structural assessments and activity on voltage-gated ion channels 4 5 Gabriela Gontijo Montandona; Juliana Silva Cassolia,b; Steve Peigneurb; Thiago Verano 6 Bragac,d; Daniel Moreira dos Santosa; Ana Luiza Bittencourt Paivaf; Éder Ricardo de 7 Moraesc; Christopher Kuschmerickc; Márcia Helena Borgesf; Michael Richardsonf; Adriano 8 Monteiro de Castro Pimentaa; Frank Kjeldsend; Marcelo Ribeiro Vasconcelos Dinizf; Jan 9 Tytgatb; Maria Elena de Limaa,h* 10 11 Affiliations 12 13 aDepartamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais - UFMG, 14 Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil. 15 16 bPharmacology and Toxicology, University of Leuven (KULeuven) - Campus Gasthuisberg, 17 PO Box 922, Herestraat 49, 3000 Leuven, Belgium. 18 19 cDepartamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais - UFMG, Av. 20 Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil. 21 22 dProtein Research Group, Department of Biochemistry and Molecular Biology, University of 23 Southern Denmark, Campusvej 55, 5230 Odense M, Denmark. 24 25 fDiretoria de Pesquisa e Desenvolvimento, Fundação Ezequiel Dias, Rua Conde Pereira 26 Carneiro 80, 30510-010 Belo Horizonte, MG, Brazil. 27 28 hSanta Casa de Belo Horizonte: Ensino e Pesquisa, Rua Domingos Vieira, 590, 30.150-240 29 Belo Horizonte, MG, Brazil. 30 31 32 * Corresponding author: Maria Elena de Lima - Santa Casa de Belo Horizonte: Ensino e 33 Pesquisa, Rua Domingos Vieira, 590, 30.150-240 Belo Horizonte, MG, Brazil. 34 E-mail: [email protected]; [email protected] (M.E. de Lima). 35 36 Keywords 37 Grammostola, tarantula venom, GiTx1, β/κ-TRTX-Gi1a, spider toxin 38 39 40 41 42 43 44 1 45 Abstract 46 Spider venoms, despite of their toxicity, represent rich sources of active compounds with 47 biotechnological potential. However, in view of the diversity of the spider species, the full 48 potential of their venom molecules is still far from being known. In this work, we report the 49 purification, the structural and functional characterization of GiTx1 (β/κ-TRTX-Gi1a), the first 50 toxin purified from the venom of the Brazilian tarantula spider Grammostola iheringi. This 51 toxin was isolated by chromatographic procedures, completely sequenced through automated 52 Edman’s degradation and tandem mass spectrometry and its spatial structure was predicted by 53 molecular modeling. It has a MW of 3.585 Da and the following sequence of amino acids: 54 SCQKWMWTCDQRPCCEDMVCKLWCKIIK. The pharmacological activities of GiTx1 55 were characterized by electrophysiology using two different approaches: (i) whole-cell patch 56 clamp on dorsal root ganglia neurons (DRG) and (ii) two-electrode voltage-clamp on voltage- 57 gated sodium and potassium channels subtypes expressed in Xenopus laevis oocytes. GiTx1, 58 at 2 μM, caused a partial block of inward ( 40 %) and outward ( 20 %) currents in DRG 59 cells, blocked rNav1.2, rNav1.4 and mNav1.6 and had a noticeable effect on VdNav, an arachnid 60 sodium channel isoform, among others. IC50 values of 156.39 ± 14.90 nM for Nav1.6 and 61 124.05 ± 12.99 nM for VdNav, were obtained. In addition, this toxin was active on rKv4.3 and 62 hERG isoforms. However, it was not effective on Shaker IR and rKv2.1 potassium channel 63 subtypes. These multiple effects on ion channels characterize GiTx1 as a promiscuous toxin. 64 65 66 67 68 69 70 71 2 72 1. Introduction 73 Spider venoms are complex mixtures of hundreds of compounds that act on different 74 targets when introduced into other organisms due to predatory or defense senses [1]. The 75 chemical nature of these molecules is very diverse, including salts, nucleotides, free amino 76 acids, glucose, neurotransmitters, acylpolyamines, and mainly peptide toxins and proteins 77 [2,3]. Because of the diverse mixture of components, spider venoms venom represent an 78 important source of novel biologically active compounds potentially useful as tools for 79 pharmacological and agricultural researches – e.g. development of drugs and insecticides (for 80 review see: [4,5]). 81 Spiders from the Theraphosidae family (infraorder Mygalomorphae), also called 82 tarantulas and “caranguejeiras”, are a sizable group of large, hairy and diverse spiders species, 83 distribute nearly all over globe. Example are species belonging the genus Theraphosa, 84 Lasiodora and Grammostola, the last mainly found in the Southern region of Brazil, Argentina, 85 Chile, Paraguay Bolivia and Uruguay. 86 Tarantula toxins comprise a group of peptides with 31 - 41 amino acids residues and 3 87 - 4 disulfide bridges, displaying DDH or ICK structural motifs [3,6,7]. Several studies have 88 demonstrated the wide molecular repertoire of toxins from tarantula venoms [3,8–12]. To date, 89 information on 450 toxins from the Theraphosidae family have been deposited in the 90 Arachnoserver database [13], however, few of these toxins have been functionally 91 characterized. 92 The spider Grammostola iheringi is one of best-known spider species from the 93 Theraphosidae family in Brazil. With a broad characterization approach based on 94 Multidimensional Protein Identification Technology (MudPIT) and bioinformatic analysis 95 using PepExplorer tool, our group has identified more than three hundred proteins in the venom 96 of Grammostola iheringi [14]. Through alignments searches in databases, we were able to 97 identify about 30% of these sequences, which include proteins (metalloproteinases, cysteine 3 98 proteinases, aspartic proteinases, carboxypeptidases and cysteine-rich secretory enzymes – 99 CRISP) and toxins. We have found in the G. iheringi venomous extract 63 toxins with 20-86 100 amino acid residues (MW 2-10 kDa) and 6-12 cysteines. Through sequence homology, it was 101 possible to infer functional activity for some of these toxins, including analgesic, 102 antiarrhythmic and insecticidal activity, likely through modulation of ion channels since 103 tarantula’s toxins have been described mainly as ion channel modulators. However, several 104 neurotoxins are yet to be characterized, such as the 24 neurotoxins in the venom of G. iheringi 105 identified by Borges et al, 2016, with remaining unknown targets. 106 In this work, a new short ICK toxin from G. iheringi venom, GiTx1 (β/κ-TRTX-Gi1a), 107 was purified and structurally characterized. Furthermore, its actions on voltage-gated sodium 108 and potassium channels were characterized using whole-cell patch clamp and two electrode 109 voltage-clamp techniques. GiTx1 is the first toxin purified from the venom of G. iheringi and 110 its structural and pharmacological characterization provide a relevant contribution on the 111 venom study of this spider. 112 2. Material and Methods 113 2.1. Animal collection and Venom Extraction 114 Specimens of Grammostola iheringi (Sisgen #A9BCC40) were collected at the border 115 of Santa Catarina and Rio Grande do Sul states (Coordinates: 27°31'31"S, 51°47'7" W), in the 116 south region of Brazil. The species were identified by Dr. Sylvia Lucas from the Arthropod 117 Laboratory of Butantan Institute (Brazil). The venom was obtained from eighteen adult 118 individuals by electrical stimulation (5V) of the chelicerae. Soluble venom was pooled, 119 lyophilized and stored at -20 oC until use.
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