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A unified nomenclature for short-chain peptides isolated from scorpion venoms: α-KTx molecular subfamilies

https://doi.org/10.1016/S0165-6147(99)01398-XGet rights and content

Abstract

Peptidyl toxins are used extensively to determine the pharmacology of ion channels. Four families of peptides have been purified from scorpion venom. In this article, the classification of K+-channel-blocking peptides belonging to family 2 peptides and comprising 30–40 amino acids linked by three or four disulfide bridges, will be discussed. Evidence is provided for the existence of 12 molecular subfamilies, named α-KTx1–12, containing 49 different peptides. Because of the pharmacological divergence of these peptides, the principle of classification was based on a primary sequence alignment, combined with maximum parsimony and Neighbour-Joining analysis.

Section snippets

Pharmacology of K+ channels

K+ channels can be divided into two major groups: voltage-gated and ligand-gated channels. Because of their high selectivity for K+ ions and given the wide tissue distribution of these proteins, K+ channels have been postulated to play a major role in a variety of physiological processes such as cell excitability, release of neurotransmitters, secretion of hormones, regulation of fluid secretion and lymphocyte activation. To assess the functional role of a specific K+ channel in the cell,

Principle of classification

The principle of our classification is based on the alignment of cysteine and other highly conserved residues (Fig. 1). In addition, the amino acid sequences of Fig. 1 were subjected to phylogenetic tree reconstruction using the program paup (Ref. 16) and analysed by maximum parsimony and Neighbour-Joining. Parsimony analysis involved extensive heuristic searching that yielded a total of 132 trees of length 506 (substitutions) in two islands (tree not shown). The groupings of peptides by both

α-KTx molecular subfamilies

Originally, three molecular subfamilies were proposed17 (Fig. 1). (1) Charybdotoxin-type subfamily 1; peptides have sequences with phenylalanine at position 2 and tryptophan at position 14. (2) Noxiustoxin-type subfamily 2; toxins have a residue insertion between the third and fourth cysteine. (3) Kaliotoxin-type subfamily 3; peptides display a point deletion between the third and fourth cysteine.

The presence of a fourth subfamily, the tityustoxin-type, with its only member TsII-9 (Ref. 12),

Concluding remarks

In Fig. 2, a consensus sequence for each of the 12 α-KTx subfamilies emerging from our classification is presented. These sequences represent useful tools for the classification of newly identified peptides. During the preparation of this manuscript, recent evidence has emerged to suggest the existence of two new subfamilies of K+-channel-blocking peptides from scorpion venom: long-chain peptides with 60–64 amino acids containing only six cysteines (such as TsTxKβ and AaTxKβ; Ref. 3), and a

Uncited references

21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44

Acknowledgements

We thank M. Lazdunski for critical reading and helpful suggestions and C. Miller for supporting our efforts. J. T., a research associate of the FWO-Vlaanderen, is sponsored by the Ministry of the Flemish Community (BIL96). J. J. v. d. W. is sponsored by the FRD of South Africa and L. D. P. is partially sponsored by the Howard Hughes Medical Institute (75197-52107).

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