Functional evolution of scorpion venom peptides with an inhibitor cystine knot fold

Gao, Bin, Harvey, Peta J., Craik, David J., Ronjat, Michel, De Waard, Michel and Zhu, Shunyi (2013) Functional evolution of scorpion venom peptides with an inhibitor cystine knot fold. Bioscience Reports, 33 3: e00047.1-e00047.15. doi:10.1042/BSR20130052

Author Gao, Bin
Harvey, Peta J.
Craik, David J.
Ronjat, Michel
De Waard, Michel
Zhu, Shunyi
Title Functional evolution of scorpion venom peptides with an inhibitor cystine knot fold
Journal name Bioscience Reports   Check publisher's open access policy
ISSN 0144-8463
Publication date 2013-01-01
Year available 2013
Sub-type Article (original research)
DOI 10.1042/BSR20130052
Open Access Status DOI
Volume 33
Issue 3
Start page e00047.1
End page e00047.15
Total pages 16
Place of publication London, United Kingdom
Publisher Portland Press Ltd
Language eng
Formatted abstract
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 λ-MeuKTx-1) with an ICK fold through gene cloning, chemical synthesis, nuclear magnetic resonance spectroscopy, Ca2+ release measurements and electrophysiological recordings. λ-MeuKTx-1 was found to adopt an ICK fold that contains a three-strand anti-parallel β-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 λ-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 λ-MeuKTx-1. The presence of a functional dyad in λ-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.
Keyword Cysteine stabilized alpha helical and beta sheet motif
Functional dyad
Ryanodine Receptors
Scorpion Toxin
Solution structure
Voltage gated ion channel
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Institute for Molecular Bioscience - Publications
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