Wide phylogenetic distribution of Scorpine and long-chain β-KTx-like peptides in scorpion venoms: Identification of “orphan” components

Diego‐García, Elia; Schwartz, Elisabeth Ferroni; D’Suze, Gina; Román-González, Sergio A.; Batista, Cesar Vicente Ferreira; García, Blanca I.; Vega, Ricardo C. Rodrí­guez de la; Possani, Lourival D.

doi:10.1016/j.peptides.2006.06.012

Cited by 72 publications

(56 citation statements)

References 24 publications

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“…The ␤-KTx group contains long-chain toxins of 50 -75 amino acids, which can be considered as an N-terminal extension on the ␣-KTx scaffold. Some examples include BmTXK␤, Hge␤KTx, TcoKIK, TdiKIK, Tst␤KTx, and TtrKIK (10). Recombinant BmTXK␤ has been confirmed to be a blocker of transient outward K ϩ current (I to ) in rabbit atrial myocytes that is fast inactivating and associated with heteromultimeric channels with Kv4.2 and Kv4.3 subunits (11), whereas native Tst␤KTx is a blocker of Kv1.1 with an IC 50 of 96 nM (10).…”

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confidence: 99%

Molecular Diversity and Functional Evolution of Scorpion Potassium Channel Toxins

Zhu

Peigneur

Gao

et al. 2011

Molecular & Cellular Proteomics

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Scorpion toxins affecting K؉ channels (KTxs) represent important pharmacological tools and potential drug candidates. Here, we report molecular characterization of seven new KTxs in the scorpion Mesobuthus eupeus by cDNA cloning combined with biochemical approaches. Comparative modeling supports that all these KTxs share a conserved cysteine-stabilized ␣-helix/␤-sheet structural motif despite the differences in protein sequence and size. We investigated functional diversification of two orthologous ␣-KTxs (MeuTXK␣1 from M. eupeus and BmP01 from Mesobuthus martensii) by comparing their K ؉ channel-blocking activities. Pharmacologically, Meu-TXK␣1 selectively blocked Kv1.3 channel with nanomolar affinity (IC 50 , 2.36 ؎ 0.9 nM), whereas only 35% of Kv1.1 currents were inhibited at 3 M concentration, showing more than 1271-fold selectivity for Kv1.3 over Kv1.1. This peptide displayed a weak effect on Drosophila Shaker channel and no activity on Kv1.2, Kv1.4, Kv1.5, Kv1.6, and human ether-a-go-go-related gene (hERG) K ؉ channels. Although BmB01 and MeuTXK␣1 have a similar channel spectrum, their affinity and selectivity for these channels largely varies. In comparison with MeuTXK␣1, BmP01 only exhibits a submicromolar affinity (IC 50 , 133.72 ؎ 10.98 nM) for Kv1.3, showing 57-fold less activity than Meu-TXK␣1. Moreover, it lacks the ability to distinguish between Kv1.1 and Kv1.3. We also found that MeuTXK␣1 inhibited the proliferation of activated T cells induced by phorbol myristate acetate and ionomycin at micromolar concentrations. Our results demonstrate that accelerated evolution drives affinity variations of orthologous ␣-KTxs on Kv channels and indicate that MeuTXK␣1 is a promising candidate to develop an immune modulation agent for human autoimmune diseases.

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confidence: 99%

Molecular Diversity and Functional Evolution of Scorpion Potassium Channel Toxins

Zhu

Peigneur

Gao

et al. 2011

Molecular & Cellular Proteomics

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“…This trend is not new or restricted to spiders, as the older arachnid group of scorpions also give some examples as previously assumed (41)(42)(43). The strategy of spiders to combine different venom compounds to enhance synergistically the toxicity of single compounds is evolutionarily optimized in the case of CsTx-1 and CpTx-1a (3,14) with a proposed synergistic interaction even within one peptide.…”

Section: Discussionmentioning

confidence: 94%

“…The putative ␣-helical N-terminal part is followed by the C-terminal region, which is structured according to the cysteine-stabilized ␣␤ motif (41). Different members of this family exhibit both activities: cytolytic in the N-terminal part and K v -channel blocking in the C-terminal part (41,42).…”

Section: Discussionmentioning

confidence: 99%

A Venom-derived Neurotoxin, CsTx-1, from the Spider Cupiennius salei Exhibits Cytolytic Activities

Kuhn‐Nentwig

Федорова

Lüscher

et al. 2012

Journal of Biological Chemistry

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Background: CsTx-1, an ICK motif containing neurotoxin, acts as L-type Ca 2ϩ -channel inhibitor. Results: The partial ␣-helical C terminus of CsTx-1 exhibits cytolytic activity toward prokaryotic and eukaryotic cell membranes. Conclusion: CsTx-1 is one peptide with different domains for ion channel inhibition and cytolytic activity. Significance: Shown is an important new mechanism for the evolution of spider venomous peptides.

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“…(b) Two-domain modular toxins have been subsequently described, widening the known arachnid toxic arsenal. The scorpine family of modular peptides from the venom of P. imperator and other scorpions includes an N-terminal linear cationic ␣-helical domain, showing similarities to many MAPs, including some ␣-helical antimicrobial peptides (AMPs), and a C-terminal CS␣␤ domain, common to a wealth of peptides, including scorpion neurotoxins and plant defensins (62). More recently, cyto-insectotoxins (CITs), giant linear peptides exhibiting equally potent antimicrobial, cytolytic, and insecticidal activities, were discovered in the venom of L. tarabaevi.…”

Section: Discussionmentioning

confidence: 99%

Novel Class of Spider Toxin

Vassilevski

Федорова

Maleeva

et al. 2010

Journal of Biological Chemistry

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Venom of the yellow sac spider Cheiracanthium punctorium (Miturgidae) was found unique in terms of molecular composition. Its principal toxic component CpTx 1 (15.1 kDa) was purified, and its full amino acid sequence (134 residues) was established by protein chemistry and mass spectrometry techniques. CpTx 1 represents a novel class of spider toxin with modular architecture. It consists of two different yet homologous domains (modules) each containing a putative inhibitor cystine knot motif, characteristic of the widespread single domain spider neurotoxins. Venom gland cDNA sequencing provided precursor protein (prepropeptide) structures of three CpTx 1 isoforms (a-c) that differ by single residue substitutions. The toxin possesses potent insecticidal (paralytic and lethal), cytotoxic, and membrane-damaging activities. In both fly and frog neuromuscular preparations, it causes stable and irreversible depolarization of muscle fibers leading to contracture. This effect appears to be receptor-independent and is inhibited by high concentrations of divalent cations. CpTx 1 lyses cell membranes, as visualized by confocal microscopy, and destabilizes artificial membranes in a manner reminiscent of other membrane-active peptides by causing numerous defects of variable conductance and leading to bilayer rupture. The newly discovered class of modular polypeptides enhances our knowledge of the toxin universe.With over 40,000 species described to date (1), spiders represent one of the most diverse and successful groups of living organisms. Initial studies of spider venoms focused on those few dangerous to human health or threatening domestic animals (2). These include the widow spiders from the genus Latrodectus (Theridiidae) (3), the recluse spiders from the genus Loxosceles (Sicariidae) (4), the wandering spiders from the genus Phoneutria (Ctenidae) (5), and the Australian funnelweb spiders from the genera Atrax and Hadronyche (Hexathelidae) (6). Today, however, spider venoms attract more research because they represent vast evolutionary-edited natural pharmacopoeias (7). These can be sources of indispensable tools for fundamental studies. For instance, -agatoxins from Agelenopsis aperta and hanatoxins from Grammostola rosea are used ubiquitously as specific ligands of voltage-gated calcium and potassium channels, respectively (8, 9). At the very same time, spider toxins that specifically recognize different targets may serve as leads for drug and insecticide discovery and thus find application in medicine and green biotechnology (10 -13).Spider venoms are complex mixtures of compounds of diverse chemical nature varying from inorganic salts to high molecular weight proteins (7,14). However, preference is usually given to a certain chemical framework, and the major active constituents of spider venoms currently known can be allocated into four large structural groups. (a) Acylpolyamine toxins that block ionotropic receptors and ion channels with average low specificity are produced by several families of spiders, most nota...

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Wide phylogenetic distribution of Scorpine and long-chain β-KTx-like peptides in scorpion venoms: Identification of “orphan” components

Cited by 72 publications

References 24 publications

Molecular Diversity and Functional Evolution of Scorpion Potassium Channel Toxins

Molecular Diversity and Functional Evolution of Scorpion Potassium Channel Toxins

A Venom-derived Neurotoxin, CsTx-1, from the Spider Cupiennius salei Exhibits Cytolytic Activities

Novel Class of Spider Toxin

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