Journal
BIOSCIENCE REPORTS
Volume 33, Issue -, Pages 513-U163Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BSR20130052
Keywords
cysteine stabilized alpha-helical and beta-sheet motif; functional dyad; ryanodine receptor; scorpion toxin; solution structure; voltage-gated ion channel
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Funding
- National Basic Research Programme of China [2010CB945300]
- National Natural Science Foundation of China [31221091]
- National Health and Medical Research Council (Australia)
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The ICK (inhibitor cystine knot) defines a large superfamily of polypeptides with high structural stability and functional diversity. Here, we describe a new scorpion venom-derived K+ channel toxin (named lambda-MeuKTx-1) with an ICK fold through gene cloning, chemical synthesis, nuclear magnetic resonance spectroscopy, Ca2+ release measurements and electrophysiological recordings. lambda-MeuKTx-1 was found to adopt an ICK fold that contains a three-strand anti-parallel beta-sheet and a 3(10)-helix. Functionally, this peptide selectively inhibits the Drosophila Shaker K+ channel but is not capable of activating skeletal-type Ca2+ release channels/ryanodine receptors, which is remarkably different from the previously known scorpion venom ICK peptides. The removal of two C-terminal residues of lambda-MeuKTx-1 led to the loss of the inhibitory activity on the channel, whereas the C-terminal amidation resulted in the emergence of activity on four mammalian K+ channels accompanied by the loss of activity on the Shaker channel. A combination of structural and pharmacological data allows the recognition of three putative functional sites involved in channel blockade of lambda-MeuKTx-1. The presence of a functional dyad in lambda-MeuKTx-1 supports functional convergence among scorpion venom peptides with different folds. Furthermore, similarities in precursor organization, exon-intron structure, 3D-fold and function suggest that scorpion venom ICK-type K+ channel inhibitors and Ca2+ release channel activators share a common ancestor and their divergence occurs after speciation between buthidae and non-buthids. The structural and functional characterizations of the first scorpion venom ICK toxin with K+ channel-blocking activity sheds light on functionally divergent and convergent evolution of this conserved scaffold of ancient origin.
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