Diversification of neurotoxins by C‐tail ‘wiggling’: a scorpion recipe for survival

Abstract

The structure of bioactive surfaces of proteins is a subject of intensive research, yet the mechanisms by which such surfaces have evolved are largely unknown. Polypeptide toxins produced by venomous animals such as sea anemones, cone snails, scorpions, and snakes show multiple routes for active site diversification, each maintaining a typical conserved scaffold. Comparative analysis of an array of genetically related scorpion polypeptide toxins that modulate sodium channels in neuronal membranes suggests a unique route of toxic site diversification. This premise is based on recent identification of bioactive surfaces of toxin representative of three distinct pharmacological groups and a comparison of their 3-dimensional structures. Despite their similar scaffold, the bioactive surfaces of the various toxins vary considerably, but always coincide with the molecular exterior onto which the C-tail is anchored. Superposition of the toxin structures indicates that the C-tails diverge from a common structural start point, which suggests that the pharmacological versatility displayed by these toxins might have been achieved along evolution via structural reconfiguration of the C-tail, leading to reshaping of new bioactive surfaces.

Common Features in the Functional Surface of Scorpion β-Toxins and Elements That Confer Specificity for Insect and Mammalian Voltage-gated Sodium Channels

“…However, despite the structural resemblance and similar spatial arrangement of a number of residues in this toxin pair, this loop differs in length and amino acid composition among various ␤-toxins (Fig. 1) (16) indicates that a residue of hydrophobic nature (Phe-17 in Css4) is spatially conserved in this loop. Other residues of this loop that have been found to be important for activity in Css4 (Leu-19 and Asn-22; Table II) or Bj-xtrIT (10) do not match equivalent or any other residues in Ts1 or LqhIT2 (Figs.…”

“…In Bj-xtrIT, this cluster is formed by a stretch of hydrophobic residues (Val-71, Gln-72, Ile-73, and Ile-74) positioned on the C-tail (9, 10), which is unique in length and configuration in excitatory toxins (Figs. 1 and 6B) (8,16). In Css4, the only C-tail residue important for activity is Trp-58 (Table II), and sulfenylation of its equivalent residue (Trp-54; Figs.…”

“…However, Bj-xtrIT differs prominently from anti-mammalian ␤-toxins (e.g. Cn2 from Centruroides noxius, Css2, and Css4) in specificity (5,9,(12)(13)(14) and structure (8,15,16). It shares only 27% sequence identity with Css4, and the spatial arrangement of the fourth disulfide bridge and C-tail configuration vary greatly ( Fig.…”

Modular Organization of α-Toxins from Scorpion Venom Mirrors Domain Structure of Their Targets, Sodium Channels

“…Two positions, 39 and 41, reside in the ␤ 2 -␤ 3 loop, thereby supporting our finding that this loop is part of the SM. It was also mentioned in the literature that the C terminus of scorpion toxins has gone through structural rearrangements during evolution, probably to adapt toward new target sites (68).…”

Differential effects of five ‘classical’ scorpion β-toxins on rNav1.2a and DmNav1 provide clues on species-selectivity

“…The second category comprises the depressant insect-selective toxins which induce a slow progressive onset of paralysis preceded by a short transient phase of contraction. Typical depressant toxins include BjIT2 from Buthotus judaicus and LqqIT2 from Leiurus quinquestriatus quinquestriatus (Pelhate and Zlotkin, 1982;Zlotkin et al, 1985;Zlotkin et al, 1991;Moskowitz et al, 1998;Froy et al, 1999;Gurevitz et al, 2001;Gordon et al, 2003;Cohen et al, 2004;Karbat et al, 2004). Previous studies on VASCs have already highlighted the importance of DII as a whole and more specific residues like Pro782 and Glu779 in DII S1-S2; Glu837, Leu840 and Gly845 in DII S3-S4, Arg850 and Arg853 in DII for binding of the β-toxin to the channels (Cestele et al, 1998;Cestele and Catterall, 2000;Cestele et al, 2001;Mantegazza and Cestele, 2005).…”