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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.
Figure 1. Reversed-phase FPLC of fraction VIIIB resulting from the Ts venom fractionation procedure. The fraction VIIIB was submitted to a reversed-phase chromatography on a C18 column (4.6 mm × 250 mm, 5 μm particles) equilibrated with 0.1% (v/v) of trifluoroacetic acid (TFA). Adsorbed proteins were eluted using a concentration gradient from 0% to 100% of solution B (80% acetonitrile in 0.1% TFA), represented by the dotted line. Flow: 0.8 mL/min. Absorbance was monitored at 214 nm, at 25 °C.
Figure 2. Electrophysiological screening of the effect of Ts4 on 8 different cloned voltage-gated sodium channels. Left panels: representative whole-cell current traces. Right panels: effects of Ts4 on the voltage dependence of steady-state activation and inactivation. Control conditions (open symbols) and after the addition of 500 nM Ts4 (closed symbols). Activation is shown by circles and inactivation by triangles.
Figure 3. Ts4 concentration-response curve on Nav1.6. The concentration-response curve was performed using the ∆INaP. The calculated EC50 value is shown above the curve. Data are presented as the mean ± SEM (n ≥ 3). The data were fitted with the Hill 1 equation.
Figure 4. Cartoon representation of Ts1 structure and Ts4 3D-structural model. The cartoons represent the flattened triangular shape structure of the α-helix/β-sheet motif (CSαβ) of Ts1 (blue) and Ts4 (green). The Ts4 different amino acid residues compared to Ts1 are highlighted in orange. (A,B) Face A (front view): Cysteine residues are shown as red stick. (C,D) Face A (front view): Conserved aromatic cluster (yellow). (E,F) Face B (back view): Important structural positive residues (grey). (G,H) Face C (side view): Residues implicated in voltage-gated sodium channel (Nav) activity. N-terminal amino acid residue (green). Residue implicated in β-toxin activity (magenta). Residue implicated in α-toxin activity (cyan). (I) Sequence alignment of Ts4 and Ts1. The alignment of the Ts4 and Ts1 were created by Clustal Omega version 2.1. (*) identical residues; (:) highly conserved residues. Cysteine residues are highlighted in red. The residues are following (A–H) coloring patterns.
Figure 5. Multiple sequence alignment of sodium channel Ts toxins (Ts1-Ts5). The alignment of the Ts1, Ts2, Ts3, Ts4 and Ts5 and identity (%) were created by Clustal Omega version 2.1. (*) identical residues; (:) highly conserved residues. Cysteine residues are highlighted in black. The Lys1 is in red and the Gly1 is in blue.
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