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PubMed2004

Isolation and characterization of three novel Gla-containing Conus marmoreus venom peptides, one with a novel cysteine pattern.

One defining characteristic of Conus venom peptides is the high frequency of posttranslational modifications found. We report the discovery and initial characterization of three novel gamma-carboxyglutamic acid (Gla)-containing conotoxins, Gla-MrII, Gla-MrIII, and Gla-MrIV, isolated from the venom of the mollusc-hunting cone snail Conus marmoreus. Peptide Gla-MrII, a 50 amino acid residue peptide, carries eight cysteine residues arranged in a novel cysteine pattern, and five gamma-carboxyglutamic acid residues. The monoisotopic molecular mass was determined by electrospray ionization mass spectrometry to 5860.23 Da, consistent with the peptide having the cysteine residues disulphide-bonded and having a free acid C-terminus. Peptides Gla-MrIII and Gla-MrIV each contain two gamma-carboxyglutamic acid residues and share little sequence similarity to previously identified conotoxins. Both peptides contain four cysteine residues that are positioned in the linear sequence in a manner reminiscent of conotoxins belonging to cysteine scaffold superfamily T (scaffold T-1). Determination of the monoisotopic molecular masses revealed that Gla-MrIII is amidated at its C-terminus while Gla-MrIV has a free C-terminal acid.

1-Carboxyglutamic Acid↗

PubMed2005

Biochemical and gene expression analyses of conotoxins in Conus textile venom ducts.

Each Conus snail species produces 50-200 unique peptide-based conotoxins, derived from a number of different gene superfamilies. Conotoxins are synthesized and secreted in a long venom duct, but biochemical and molecular aspects of their biosynthesis remain poorly understood. Here, we analyzed expression patterns of conotoxin genes belonging to different superfamilies in Conus textile venom ducts. The results demonstrate that specific gene families are expressed in particular regions of the venom duct. Biochemical analysis using liquid chromatography and mass spectrometry revealed an even more localized accumulation of individual conotoxins. This study demonstrates for the first time that specialization of gene expression, processing, and secretion of conotoxins occurs in different regions of the venom duct.

Amino Acid Sequence↗

PubMed2000

A conserved motif within the vitamin K-dependent carboxylase gene is widely distributed across animal phyla.

The vitamin K-dependent gamma-glutamyl carboxylase catalyzes the posttranslational conversion of glutamic acid to gamma-carboxyglutamic acid, an amino acid critical to the function of the vitamin K-dependent blood coagulation proteins. Given the functional similarity of mammalian vitamin K-dependent carboxylases and the vitamin K-dependent carboxylase from Conus textile, a marine invertebrate, we hypothesized that structurally conserved regions would identify sequences critical to this common functionality. Furthermore, we examined the diversity of animal species that maintain vitamin K-dependent carboxylation to generate gamma-carboxyglutamic acid. We have cloned carboxylase homologs in full-length or partial form from the beluga whale (Delphinapterus leucas), toadfish (Opsanus tau), chicken (Gallus gallus), hagfish (Myxine glutinosa), horseshoe crab (Limulus polyphemus), and cone snail (Conus textile) to compare these structures to the known bovine, human, rat, and mouse cDNA sequences. Comparison of the predicted amino acid sequences identified a nearly perfectly conserved 38-amino acid residue region in all of these putative carboxylases. In addition, this amino acid motif is also present in the Drosophila genome and identified a Drosophila homolog of the gamma-carboxylase. Assay of hagfish liver demonstrated vitamin K-dependent carboxylase activity in this hemichordate. These results demonstrate the broad distribution of the vitamin K-dependent carboxylase gene, including a highly conserved motif that is likely critical for enzyme function. The vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid appears to be a highly conserved function in the animal kingdom.

Amino Acid Motifs↗

PubMed2003

Sodium channel modulating activity in a delta-conotoxin from an Indian marine snail.

A 26 residue peptide (Am 2766) with the sequence CKQAGESCDIFSQNCCVG-TCAFICIE-NH(2) has been isolated and purified from the venom of the molluscivorous snail, Conus amadis, collected off the southeastern coast of India. Chemical modification and mass spectrometric studies establish that Am 2766 has three disulfide bridges. C-terminal amidation has been demonstrated by mass measurements on the C-terminal fragments obtained by proteolysis. Sequence alignments establish that Am 2766 belongs to the delta-conotoxin family. Am 2766 inhibits the decay of the sodium current in brain rNav1.2a voltage-gated Na(+) channel, stably expressed in Chinese hamster ovary cells. Unlike delta-conotoxins have previously been isolated from molluscivorous snails, Am 2766 inhibits inactivation of mammalian sodium channels.

Amino Acid Sequence↗

PubMed1987

Transmitter release from presynaptic terminals of electric organ: inhibition by the calcium channel antagonist omega Conus toxin.

Cholinergic synaptosomes from electroplax of the ray Ommata discopyge release both ATP and ACh when depolarized with high K+ concentration in the presence of Ca2+. Others have shown that the ATP and ACh are released in the molar ratio found in isolated synaptic vesicles. Thus, it is assumed that the release of ATP reflects exocytosis of synaptic vesicles, and that transmitter release can be indirectly monitored by assaying ATP release. We present further evidence for this assumption and examine the effects of presynaptic neurotoxins on this ATP release. As expected for transmitter release, we find that depolarization-evoked ATP release is supported by Sr2+ and Ba2+ and is inhibited by the Ca channel antagonists Co2+ and Mn2+. Likewise, the presynaptic toxins omega-CmTX and omega-CgTX, omega peptides from the venom of the marine snails Conus magus and Conus geographus, respectively, inhibit 80% of the depolarization-evoked ATP release. Half-maximal inhibition of ATP release occurs with approximately 0.5 microM of either toxin. The toxins' effects are reversible, and when toxin is washed away, the time dependence of recovery of release is approximately first order and half complete within 40 min with omega-CmTX and 15 min with omega-CgTX. The Ca2+ ionophore A23187 induces Ca2+-dependent ATP release from resting synaptosomes. As would be expected of a Ca channel antagonist, omega-CmTX does not affect this ionophore-induced release. Leptinotarsin-d (LPTd), a putative Ca channel agonist from the Colorado potato beetle, evokes Ca2+-dependent ATP release from resting synaptosomes. omega-CmTX does not block LPTd-evoked release of ATP, which suggests that omega-CmTX and LPTd act at different sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed2004

Using the deadly mu-conotoxins as probes of voltage-gated sodium channels.

Mu-Conotoxins (mu-CTX) are potent Na channel inhibitory peptides isolated from the venom of the predatory marine snail Conus geographus. Mu-CTXs exert their biological action by physically occluding the ion-conducting pore of voltage-gated Na (Na(v)) channels with a 1:1 stoichiometry in an all-or-none fashion. This article reviews our current knowledge of the mechanism of mu-CTX and the associated structural and functional insights into its molecular target--Na(v) channels.

Animals↗

PubMed1994

New mollusc-specific alpha-conotoxins block Aplysia neuronal acetylcholine receptors.

Two mollusc-specific neurotoxic peptides from the venom of the molluscivorous snail Conus pennaceus are described. These new toxins block acetylcholine receptors (AChR) of cultured Aplysia neurons. Bath application of 0.5-1 microM toxin induces 5-10-mV membrane depolarization, which recovers to the control level within 1-3 min in the presence of the toxin. This response is blocked by 1 mM hexamethonium. Concomitantly with the transient depolarization, the toxins block approximately 90% of the depolarizing responses evoked by brief iontophoretic application of acetylcholine. The pharmacology and amino acid sequences of the toxins (alpha PnIA, GCCSLPPCAANNPDYC-NH2; alpha PnIB, GCCSLPPCALSNPDYC-NH2) enable their classification as novel alpha-conotoxins. The sequences differ from those of previously described alpha-conotoxins in a number of features, the most striking of which is the presence of a single negatively charged residue in the C-terminal loop. This loop contains a positively charged residue in piscivorous venom alpha-conotoxins. In contrast to other alpha-conotoxins, which are selective for vertebrate skeletal muscle nicotinic ACh receptors, these Conus pennaceus toxins block neuronal ACh receptors in molluscs. As such they are new probes which can be used to define subtypes of ACh receptors, and they should be useful tools in the study of structure-function relationships in ACh receptors.

Amino Acid Sequence↗

PubMed1999

Speciation of cone snails and interspecific hyperdivergence of their venom peptides. Potential evolutionary significance of introns.

All 500 species of cone snails (Conus) are venomous predators. From a biochemical/genetic perspective, differences among Conus species may be based on the 50-200 different peptides in the venom of each species. Venom is used for prey capture as well as for interactions with predators and competitors. The venom of every species has its own distinct complement of peptides. Some of the interspecific divergence observed in venom peptides can be explained by differential expression of venom peptide superfamilies in different species and of peptide superfamily branching in various Conus lineages into pharmacologic groups with different targeting specificity. However, the striking interspecific divergence of peptide sequences is the dominant factor in the differences observed between venoms. The small venom peptides (typically 10-35 amino acids in length) are processed from larger prepropeptide precursors (ca. 100 amino acids). If interspecific comparisons are made between homologous prepropeptides, the three different regions of a Conus peptide precursor (signal sequence, pro-region, mature peptide) are found to have diverged at remarkably different rates. Analysis of synonymous and nonsynonymous substitution rates for the different segments of a prepropeptide suggests that mutation frequency varies by over an order of magnitude across the segments, with the mature toxin region undergoing the highest rate. The three sections of the prepropeptide which exhibit apparently different mutation rates are separated by introns. This striking segment-specific rate of divergence of Conus prepropeptides suggests a role for introns in evolution: exons separated by introns have the potential to evolve very different mutation rates. Plausible mechanisms that could underlie differing mutational frequency in the different exons of a gene are discussed.

Amino Acid Sequence↗

PubMed1993

Acetylcholine receptor binding characteristics of snake and cone snail venom postsynaptic neurotoxins: further studies with a non-radioactive assay.

The binding of postsynaptic neurotoxins from snake and marine cone snail (Conus sp.) venoms to nicotinic acetylcholine receptor (AchR) was investigated with an ELISA-based, non-radioactive assay. Three snake postsynaptic toxins from the long-chain group (Naja naja kaouthia cobratoxin, Naja oxiana neurotoxin I, Bungarus multicinctus alpha-bungarotoxin) and short-chain group (Naja naja atra cobrotoxin, Naja oxiana neurotoxin II, and Laticauda semifasciata erabutoxin b) were studied. Both types of snake postsynaptic toxins showed a dose-response with constant AchR (50 micrograms/ml) and varying toxin concentrations (50-0.035 micrograms/ml). The minimum detection limits of the assay for snake toxins ranged from 310 to 1240 ng/ml (40-160 pmole/ml), depending on the toxin. Unlike any of the short-chain toxins, long-chain toxins consistently bound less receptor and reached maximum absorbance levels with toxin concentrations of 10-50 micrograms/ml. Competition for AchR binding between cone snail postsynaptic neurotoxins (conotoxins GI, MI, SI) and alpha-bungarotoxin or cobrotoxin resulted in a dose-response. The postsynaptic conotoxins were uniformly better competitors for AchR binding with alpha-bungarotoxin than with cobrotoxin. Heat stability studies with neurotoxin I, erabutoxin b, or cobrotoxin revealed a loss in AchR binding activity with increasing temperature. alpha-Bungarotoxin heated at 90 degrees C had increased AchR binding activity by 105%, relative to 25 degrees C samples, but lost the majority of its binding activity after 100 degrees C. The enhanced binding of heated alpha-bungarotoxin to AchR was specific, as evidenced by a competitive dose-response with unheated alpha-bungarotoxin, but heated toxin lacked any biological activity in the mouse lethal assay. When conotoxins GI or MI were heated at 100 degrees C, there was no detectable loss in AchR binding activity, and only a slight decrease in mouse lethality.

Animals↗

PubMed1984

Gamma-carboxyglutamate in a neuroactive toxin.

The venom of a fish-hunting cone snail (Conus geographus) contains a novel toxin, the "sleeper" peptide, which induces a sleep-like state in mice when injected intracerebrally. We demonstrate that this peptide contains 5 mol of gamma-carboxyglutamate (Gla) in 17 amino acids. The amino acid sequence of the sleeper peptide is Gly-Glu-Gla-Gla-Leu-Gln-Gla-Asn-Gln-Gla-Leu-Ile-Arg-Gla-Lys-Ser-Asn-NH2.

1-Carboxyglutamic Acid↗

PubMed1994

A nicotinic acetylcholine receptor ligand of unique specificity, alpha-conotoxin ImI.

We report the isolation, characterization, and total synthesis of a small peptide ligand for nicotinic acetylcholine receptors (nAChRs). It is highly active against the neuromuscular receptor in frog but not in mice. In contrast, it induces seizures when injected centrally in mice and rats, suggesting that it may target neuronal nAChRs in mammals. Although such receptors may be important in both normal cognition and the pathophysiology of several neuropsychiatric disorders, there are few ligands to discriminate between the multiple receptor subtypes. The new peptide is a highly divergent alpha-conotoxin from the snail Conus imperialis, which preys on polychaete worms. In this article, the purification, structural analysis, synthesis, and preliminary physiological characterization of alpha-conotoxin ImI (alpha-CTx-ImI) are reported. The sequence of the peptide is: Gly-Cys-Cys-Ser-Asp-Pro-Arg-Cys-Ala-Trp-Arg-Cys-NH2. The peptide shows striking sequence differences from all alpha-conotoxins of fish-hunting Conus, but its disulfide-bridging is similar: [2-8; 3-12]. We suggest that cone venoms may provide an array of ligands with selectivity for various neuronal nAChR subtypes.

Amino Acid Sequence↗

PubMed1990

Conantokin-T. A gamma-carboxyglutamate containing peptide with N-methyl-d-aspartate antagonist activity.

Conantokin-T, a 21-amino acid peptide which induces sleep-like symptoms in young mice was purified from the venom of the fish-hunting cone snail, Conus tulipa. The amino acid sequence of the peptide was determined and verified by chemical synthesis. The peptide has 4 residues of the modified amino acid, gamma-carboxyglutamate (Gla). The sequence of the peptide is: Gly-Glu-Gla-Gla-Tyr-Gln-Lys-Met-Leu-Gla-Asn-Leu-Arg-Gla-Ala-Glu-Val-Lys- Lys-Asn-Ala-NH2. Conantokin-T inhibits N-methyl-D-aspartate (NMDA) receptor-mediated calcium influx in central nervous system neurons. This observation suggests that like conantokin-G (a homologous Conus peptide with recently identified NMDA antagonist activity) conantokin-T has NMDA antagonist activity. A sequence comparison of conantokins-T and -G identifies the 4 Gla residues and the N-terminal dipeptide sequence as potential key elements for the biological activity of this peptide.

1-Carboxyglutamic Acid↗

PubMed2003

Alpha-conotoxin PIA is selective for alpha6 subunit-containing nicotinic acetylcholine receptors.

Until now, there have been no antagonists to discriminate between heteromeric nicotinic acetylcholine receptors (nAChRs) containing the very closely related alpha6 and alpha3 subunits. nAChRs containing alpha3, alpha4, or alpha6 subunits in combination with beta2, occasionally beta4, and sometimes beta3 or alpha5 subunits, are thought to play important roles in cognitive function, pain perception, and the reinforcing properties of nicotine. We cloned a novel gene from the predatory marine snail Conus purpurascens. The predicted peptide, alpha-conotoxin PIA, potently blocks the chimeric alpha6/alpha3beta2beta3 subunit combination as expressed in oocytes but neither the muscle nor the major neuronal nAChR alpha4beta2. Additionally, this toxin is the first described ligand to discriminate between nAChRs containing alpha6 and alpha3 subunits. Exploiting the unusual intron conservation of conotoxin genes may represent a more general approach for defining conotoxin ligand scaffolds to discriminate among closely related receptor populations.

Amino Acid Sequence↗

PubMed1995

Solution structure of omega-conotoxin MVIIA using 2D NMR spectroscopy.

The solution structure of omega-conotoxin MVIIA (SNX-111), a peptide toxin from the fish hunting cone snail Conus magus and a high-affinity blocker of N-type calcium channels, was determined by 2D NMR spectroscopy. The backbones of the best 44 structures match with an average pairwise RMSD of 0.59 angstroms. The structures contain a short segment of triple-stranded beta-sheet involving residues 6-8, 20-21, and 24-25. The structure of this toxin is very similar to that of omega-conotoxin GVIA with which is has only 40% sequence homology, but very similar calcium channel binding affinity and selectivity.

Amino Acid Sequence↗

PubMed1987

Effects of synthetic omega-conotoxin GVIA (omega-CgTX GVIA) on the membrane calcium current of an identifiable giant neurone, d-RPLN, of an African giant snail (Achatina fulica Ferussac), measured under the voltage clamp condition.

1. The sodium and the calcium inward currents (INa and ICa) of an identifiable giant neurone, d-RPLN (dorsal-right parietal large neurone), of an African giant snail (Achatina fulica Férussac), were measured separately under the voltage clamp condition. 2. The effects of synthetic omega-conotoxin GVIA (omega-CgTX GVIA) on the calcium current of the neuromembrane were examined. 3. omega-CgTX GVIA is a peptide venom originally isolated from a fish-hunting marine snail (Conus geographus L.); the peptide venom has been demonstrated to block markedly calcium channels in vertebrates. 4. In the case of the d-RPLN membrane, the ICa was much larger than INa. The command voltage (Vc) to get the ICa in maximum was about 0 mV; the maximum value of ICa in a representative experimental case, was measured as approximately 0.8 microA. 5. With respect to the ICa of a molluscan giant neurone, d-RPLN, synthetic omega-CgTX GVIA at a high concentration, 5 X 10(-5) M, showed almost no effect, in spite of reporting the peptide venom affecting the ICa in vertebrate preparations.

Amino Acid Sequence↗

PubMed1990

Constant and hypervariable regions in conotoxin propeptides.

Conotoxins are small cysteine rich peptides found in the venom of the predatory cone snails (Conus) which have prove to be useful high affinity ligands for various receptors and ion channels. The first cloning data for conotoxins, reported here, were obtained for the King-Kong peptide, a 27 amino acid conotoxin found in the venom of the cloth-of-gold cone, Conus textile. Analysis of cDNA clones of the King-Kong peptide revealed a family of related toxin transcripts. Three different propeptide cDNA sequences were obtained; only one of these encoded sequence for the King-Kong peptide. The other cDNA sequences encoded two different peptides (KK-1 and KK-2). When the predicted propeptide sequences are compared, well defined conserved and hypervariable regions can be identified. The hypervariable regions comprise four regions between Cys residues in the final peptide toxins; the remainder of the propeptide sequences, i.e. the excised N-terminal regions and the disulfide bonded Cys residues, are highly conserved. We suggest that the conserved regions may direct the formation of a specific disulfide configuration in the King-Kong family of conotoxins.

Amino Acid Sequence↗

PubMed2000

Structural and dynamic characterization of omega-conotoxin MVIIA: the binding loop exhibits slow conformational exchange.

omega-Conotoxin MVIIA is a 25-residue, disulfide-bridged polypeptide from the venom of the sea snail Conus magus that binds to neuronal N-type calcium channels. It forms a compact folded structure, presenting a loop between Cys8 and Cys15 that contains a set of residues critical for its binding. The loop does not have a unique defined structure, nor is it intrinsically flexible. Broadening of a subset of resonances in the NMR spectrum at low temperature, anomalous temperature dependence of the chemical shifts of some resonances, and exchange contributions to J(0) from (13)C relaxation measurements reveal that conformational exchange affects the residues in this loop. The effects of this exchange on the calculated structure of omega-conotoxin MVIIA are discussed. The exchange appears to be associated with a change in the conformation of the disulfide bridge Cys8-Cys20. The implications for the use of the omega-conotoxins as a scaffold for carrying other functions is discussed.

Animals↗

PubMed2003

A novel conotoxin inhibiting vertebrate voltage-sensitive potassium channels.

Toxins from cone snail (Conus species) venoms are multiple disulfide bonded peptides. Based on their pharmacological target (ion channels, receptors) and their disulfide pattern, they have been classified into several toxin families and superfamilies. Here, we report a new conotoxin, which is the first member of a structurally new superfamily of Conus peptides and the first conotoxin affecting vertebrate K+ channels. The new toxin, designated conotoxin ViTx, has been isolated from the venom of Conus virgo and comprises a single chain of 35 amino acids cross-linked by four disulfide bridges. Its amino acid sequence (SRCFPPGIYCTSYLPCCWGICCSTCRNVCHLRIGK) was partially determined by Edman degradation and deduced from the nucleotide sequence of the toxin cDNA. Nucleic acid sequencing also revealed a prepropeptide comprising 67 amino acid residues and demonstrated a posttranslational modification of the protein by releasing a six-residue peptide from the C-terminal. Voltage clamp studies on various ion channels indicated that the toxin inhibits the vertebrate K+ channels Kv1.1 and Kv1.3 but not Kv1.2. The chemically synthesized product exhibited the same physiological activity and identical molecular mass (3933.7 Da) as the native toxin.

Amino Acid Sequence↗