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.
Highlights
Scorpion envenoming is recognized as an important problem in specific tropical/subtropical areas of the world [1]
The α-toxins can be divided into 3 groups: α-classic, α-insect and α-like. (a) The α-classic are highly active in mammals and their binding affinity to sodium channels is [15] reduced by membrane depolarization, (b) The α-insect show high toxicity towards Nav channels of insects and their binding to neuronal membranes is independent of membrane potential, and (c) α-like, that are active on both mammals and insects Nav channels, with a preference for insects [16]
The Tityus serrulatus (Ts). serrulatus venom was fractionated using the improved CM-cellulose method described by Cerni et al, (2014)
Summary
Scorpion envenoming is recognized as an important problem in specific tropical/subtropical areas of the world [1]. Ts venom presents neurotoxins specific to sodium and potassium channels. Sodium channel specific toxins (NaTxs) are peptides of 61–76 amino acid residues with four disulfide bridges and based on their binding and physiological effect they can be classified into α- and β-toxins [11,12,13,14]. These toxins are classified according to their binding site. (a) The α-classic are highly active in mammals and their binding affinity to sodium channels is [15] reduced by membrane depolarization, The α-toxins can be divided into 3 groups: α-classic, α-insect and α-like. (a) The α-classic are highly active in mammals and their binding affinity to sodium channels is [15] reduced by membrane depolarization,
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