Structure-function relations of scorpion neurotoxins

Abstract

Chemical modification of some trifunctional amino acid residues in toxins I, II, and III of the scorpion Androctonus australis Hector have been performed. The results indicate: (1) Reduction and methylation of one disulfide bridge destroy toxic activity of toxin II. (2) The only tryptophan residue of toxin II (position 38) is not included in the active site of the molecule. (3) Modification of five carboxylates out of the seven contained in toxin II suppresses the toxic activity. (4) Acetylation of the lysine and tyrosine residues in toxin II leads to the loss of both toxic and antigenic activity. Treatment of the acetylated toxin by hydroxylamine restores partially the antigenic activity. In the case of toxin I, total acetylation abolishes only the toxic activity. It is concluded that at least one tyrosine residue must be involved in an antigenic site of toxin II. (5) Citraconylation of toxins II and III leads to complete loss of toxicity; decitraconylation restores full activity. (6) Guanidination of toxin II does not affect its toxicity significantly. (7) Alkylation of toxin II by iodoacetic acid affects both amino groups and histidine residues. The loss of toxicity is mainly due to the modification of the lysine residues. In the case of toxin I, the kinetics of toxicity loss closely parallel the covalent modification of one lysine residue.

Three-dimensional structure of a protein from scorpion venom: a new structural class of neurotoxins.

“…4. Chemical modification studies of toxins I and II from A. australis have also indicated that amino acid side chains at regions away from the flat surface of the molecule can be modified without concomitant loss of activity (24,25). It seems likely that this conserved surface of the molecule may be somehow involved in the interactions that mediate the biological effects of scorpion toxins.…”

Voltage-gated ion channels and gating modifier toxins

“…Subsequent site-directed mutagenesis studies further identified individual amino acid residues in the extracellular loop connecting the S3 and S4 segments in domain IV, which appear to be essential for both binding and action of these toxins (Rogers et al, 1996). Since basic amino acid residues of the toxins are known to be implicated in the interaction with the channels (Habersetzer- Rochat and Sampieri, 1976;El Ayeb et al, 1986;Kharrat et al, 1989;Gallagher and Blumenthal, 1994;Khera et al, 1994), it is of interest that E1613 was identified as a major determinant for both α-scorpion toxin and sea-anemone toxin binding (Table 1; Rogers et al, 1996). Likewise, the mutation of the homologous residue in cardiac (D1612) and skeletal muscle (D1428) sodium channels alters the binding of sea-anemone toxins (Benziger et al, 1998).…”

NMR solution structure of Cn12, a novel peptide from the Mexican scorpion Centruroides noxius with a typical β‐toxin sequence but with α‐like physiological activity

“…In addition, none of the different types and subtypes of Na + channel have had their 3D structure determined, unlike the K + channels [52]. Previous studies conducted with both a and b Na-ScTxs showed that small differences such as single amino-acid modifications or deletion of short stretches of sequence were enough to cause a dramatic change in toxicity to mice [53,54]. In recent years, many publications have contributed novel data and identified possible residues directly involved in the recognition and binding to Na + channels [4,5,18,33,[55][56][57][58][59][60][61][62][63][64][65].…”