title: Revealing the Function and the Structural Model of Ts4: Insights into the "Non-Toxic" Toxin from Tityus serrulatus Venom.
abstract: The toxin, previously described as a "non-toxic" toxin, was isolated from the scorpion venom of Tityus serrulatus (Ts), responsible for the most severe and the highest number of accidents in Brazil. In this study, the subtype specificity and selectivity of Ts4 was investigated using six mammalian Nav channels (Nav1.2→Nav1.6 and Nav1.8) and two insect Nav channels (DmNav1 and BgNav). The electrophysiological assays showed that Ts4 specifically inhibited the fast inactivation of Nav1.6 channels, the most abundant sodium channel expressed in the adult central nervous system, and can no longer be classified as a "non-toxic peptide". Based on the results, we could classify the Ts4 as a classical α-toxin. The Ts4 3D-structural model was built based on the solved X-ray Ts1 3D-structure, the major toxin from Ts venom with which it shares high sequence identity (65.57%). The Ts4 model revealed a flattened triangular shape constituted by three-stranded antiparallel β-sheet and one α-helix stabilized by four disulfide bonds. The absence of a Lys in the first amino acid residue of the N-terminal of Ts4 is probably the main responsible for its low toxicity. Other key amino acid residues important to the toxicity of α- and β-toxins are discussed here.
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil. manupucca@usp.br.
authors.forename: Manuela B
authors.initials: MB
authors.lastname: Pucca
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil. cerni@fcfrp.usp.br.
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Cerni
authors.affiliation: Toxicology and Pharmacology, University of Leuven, O&N 2, Herestraat 49, P.O. Box 922, Leuven 3000, Belgium. steve.peigneur@pharm.kuleuven.be.
authors.forename: Steve
authors.initials: S
authors.lastname: Peigneur
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil. karla@fcfrp.usp.br.
authors.forename: Karla C F
authors.initials: KC
authors.lastname: Bordon
authors.affiliation: Toxicology and Pharmacology, University of Leuven, O&N 2, Herestraat 49, P.O. Box 922, Leuven 3000, Belgium. jan.tytgat@pharm.kuleuven.be.
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
authors.affiliation: Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil. ecabraga@fcfrp.usp.br.
authors.forename: Eliane C
authors.initials: EC
authors.lastname: Arantes
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry* / Q000633:toxicity; D009865:Oocytes; D020033:Protein Isoforms; D012604:Scorpion Venoms / Q000737:chemistry* / Q000633:toxicity; D012605:Scorpions / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000633:toxicity; D061566:Voltage-Gated Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D009498:Neurotoxins; D020033:Protein Isoforms; D012604:Scorpion Venoms; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; C120263:scorpion toxin Ts1, Tityus; C068452:toxin TsTX-VI
keywords: Nav1.6; Tityus serrulatus; envenomation; scorpion toxin; sodium channel