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PubMed2004

Sequencing and mass profiling highly modified conotoxins using global reduction/alkylation followed by mass spectrometry.

A novel high-throughput method for characterizing heavily modified peptides from cone snail venom is described. Unpurified cone snail duct venom, consisting primarily of multiply disulfide-bonded peptides, is reduced and alkylated using a global procedure in order to simultaneously reduce and derivatize dozens of disulfide-bonded peptides. Samples of Conus victoriae venom are analyzed by online liquid chromatography-electrospray ionization-ion trap-mass spectrometry (LC-ESI-MS) with collisionally induced dissociation (CID). Comparison of the mass profiles of peptides and CID spectra before and after the global reduction and alkylation enables cysteine-containing conopeptides to be ascertained. In this case, over 40 conotoxins are characterized based on only two LC-ESI-MS experiments in terms of mass, number of disulfide-linked cysteine residues (and hence, potential toxin superfamilies), relative hydrophobicity, and other posttranslational modifications. Using this technique, over half of the amino acids (by mass) of several peptides are defined prior to any detailed sequencing studies. Further comparison of the mass data with previously published genetic information allows sequence verification of three novel peptides, termed vc5b, vc6b and vc6c, based on both LC-ESI-MS CID and nanoelectrospray ionization-ion trap-mass spectrometry (nanoESI-MS) experiments. This global method is ideally suited to the use of larger genetic databases in order to efficiently sequence peptides in Conus venoms and is also applicable to analysis of other disulfide-rich classes of peptides such as defensins, chemokines, and snake, spider, or other venoms.

Alkylation↗
PubMed2006

Genes expressed in a turrid venom duct: divergence and similarity to conotoxins.

The toxoglossate mollusks are a large group of venomous animals (>10,000 species) conventionally divided into three groups, the cone snails, the auger snails, and the turrid snails; turrids account for >90% of the biodiversity of toxoglossans. Only the venoms of cone snails have been intensively investigated, with little work focused on turrids. We report the first broad characterization of genes expressed in venom ducts of any turrid species. Twenty-three different cDNA clones encoding putative toxins were characterized from the venom duct of the turrine species Lophiotoma olangoensis Olivera 2002 and belong to 16 different gene families. Of the 16 different Lophiotoma olangoensis gene families that encode putative toxins, for only 1 was there clear evidence of sequence similarity with any conotoxin gene family. The I-like gene family of Lophiotoma olangoensis was found to be related to the K channel-targeted I(2) conotoxin superfamily. Most putative Lophiotoma toxins are cysteine-rich polypeptides, with a significant fraction much larger (>80 amino acids) than the toxins from cone snails. A small number were not cysteine-rich but had hydrophobic amino acid clusters interspersed with arginine residues. This is only 1 of >10,000 different turrid venoms that needs to be characterized. From this study, a common origin with Conus for one family of putative turrid toxins is indicated.

Amino Acid Sequence↗
PubMed2003

Isolation and characterization of a cone snail protease with homology to CRISP proteins of the pathogenesis-related protein superfamily.

The pathogenesis-related (PR) protein superfamily is widely distributed in the animal, plant, and fungal kingdoms and is implicated in human brain tumor growth and plant pathogenesis. The precise biological activity of PR proteins, however, has remained elusive. Here we report the characterization, cloning and structural homology modeling of Tex31 from the venom duct of Conus textile. Tex31 was isolated to >95% purity by activity-guided fractionation using a para-nitroanilide substrate based on the putative cleavage site residues found in the propeptide precursor of conotoxin TxVIA. Tex31 requires four residues including a leucine N-terminal of the cleavage site for efficient substrate processing. The sequence of Tex31 was determined using two degenerate PCR primers designed from N-terminal and tryptic digest Edman sequences. A BLAST search revealed that Tex31 was a member of the PR protein superfamily and most closely related to the CRISP family of mammalian proteins that have a cysteine-rich C-terminal tail. A homology model constructed from two PR proteins revealed that the likely catalytic residues in Tex31 fall within a structurally conserved domain found in PR proteins. Thus, it is possible that other PR proteins may also be substrate-specific proteases.

Amino Acid Sequence↗
PubMed2002

Conantokin-L, a new NMDA receptor antagonist: determinants for anticonvulsant potency.

Conantokins are N-methyl-D-aspartate receptor antagonist peptides found in the venoms of marine cone snails. Current intense interest in this peptide family stems from the discovery of their therapeutic potential as anticonvulsants. It was recently reported that conantokin-R is a highly potent anticonvulsant compound, with a protective index of 17.5 when tested in the audiogenic mouse model of epilepsy. Conantokin-L was characterized from Conus lynceus and found to have extensive homology with conantokin-R, except For the C-terminal amino acids. Although conantokin-L appears almost as potent as conantokin-R in standard in vivo assays for conantokins and NMDA receptor binding assays, it is far less potent as an anticonvulsant, with a protective index of 1.2 in the audiogenic mouse model. The results suggest that the C-terminal sequences of conantokin-R and conantokin-L are a major determinant of their anticonvulsant potency.

Amino Acid Sequence↗
PubMed2001

Two new classes of conopeptides inhibit the alpha1-adrenoceptor and noradrenaline transporter.

Cone snails use venom containing a cocktail of peptides ('conopeptides') to capture their prey. Many of these peptides also target mammalian receptors, often with exquisite selectivity. Here we report the discovery of two new classes of conopeptides. One class targets alpha1-adrenoceptors (rho-TIA from the fish-hunting Conus tulipa), and the second class targets the neuronal noradrenaline transporter (chi-MrIA and chi-MrIB from the mollusk-hunting C. marmoreus). rho-TIA and chi-MrIA selectively modulate these important membrane-bound proteins. Both peptides act as reversible non-competitive inhibitors and provide alternative avenues for the identification of inhibitor drugs.

Amino Acid Sequence↗
PubMed2005

A novel conotoxin from Conus delessertii with posttranslationally modified lysine residues.

A major peptide, de13a from the crude venom of Conus delessertii collected in the Yucatan Channel, Mexico, was purified. The peptide had a high content of posttranslationally modified amino acids, including 6-bromotryptophan and a nonstandard amino acid that proved to be 5-hydroxylysine. This is the first report of 5-hydroxylysine residues in conotoxins. The sequence analysis, together with cDNA cloning and a mass determination (monoisotopic mass of 3486.76 Da), established that the mature toxin has the sequence DCOTSCOTTCANGWECCKGYOCVNKACSGCTH, where O is 4-hydroxyproline, W 6-bromotryptophan, and K 5-hydroxylysine, the asterisk represents the amidated C-terminus, and the calculated monoisotopic mass is 3487.09 Da. The eight Cys residues are arranged in a pattern (C-C-C-CC-C-C-C) not described previously in conotoxins. This arrangement, for which we propose the designation of framework #13 or XIII, differs from the ones (C-C-CC-CC-C-C and C-C-C-C-CC-C-C) present in other conotoxins which also contain eight Cys residues. This peptide thus defines a novel class of conotoxins, with a new posttranslational modification not previously found in other Conus peptide families.

Amino Acid Sequence↗
PubMed2004

AlphaA-Conotoxin OIVA defines a new alphaA-conotoxin subfamily of nicotinic acetylcholine receptor inhibitors.

The venoms of cone snails are rich in multiply disulfide-crosslinked peptides, the conotoxins. Conotoxins are grouped into families on the basis of shared cysteine patterns and homologous molecular targets. For example, both the kappaA- and alphaA-conotoxin families share the same Class IV Cys pattern (-CC-C-C-C-C-), but differ in their molecular targets. The kappaA-conotoxins are excitatory toxins that purportedly block potassium channels, while the alphaA-conotoxins are paralytic conotoxins that inhibit nicotinic acetylcholine receptors (nAChRs). In this work, we describe the isolation and characterization of a novel Conus peptide from venom milked from Hawaiian specimens of Conus obscurus. This peptide shares the Class IV Cys pattern but differs from both previously characterized alphaA- and kappaA-conotoxins in the spacing of amino acids between Cys resides. However, the peptide is similar to previously characterized alphaA-conotoxins in its paralytic effects on fish and its antagonist activity on the neuromuscular nAChR. Unexpectedly, the peptide differs in its disulfide bonding from alphaA-conotoxin PIVA. We have named this unique peptide alphaA-conotoxin OIVA, and we consider it the defining member of a subfamily of alphaA-conotoxins that we designate the alphaA(1-3)-conotoxins to identify them by their unique disulfide bonding framework. These results indicate that the alphaA-conotoxin family is both more structurally diverse and broadly distributed than previously believed.

Amino Acid Sequence↗
PubMed1995

A new conotoxin affecting sodium current inactivation interacts with the delta-conotoxin receptor site.

We describe a new peptide conotoxin affecting sodium current inactivation, that competes on binding with delta-conotoxin TxVIA (delta TxVIA). The amino acid sequence of the new toxin, designated conotoxin NgVIA (NgVIA), is SKCFSOGTFCGIKOGLCCSVRCFSLFCISFE (where O is trans-4-hydroxyproline). The primary structure of NgVIA has an identical cysteine framework and similar hydrophobicity as delta TxVIA but differs in its net charge. NgVIA competes with delta TxVIA on binding to rat brain synaptosomes and molluscan central nervous system and strongly inhibits sodium current inactivation in snail neurons, as does delta TxVIA. In contrast to delta TxVIA, NgVIA is a potent paralytic toxin in vertebrate systems, its binding appears to be voltage-dependent, and it synergically increases veratridine-induced sodium influx to rat brain synaptosomes. delta TxVIA acts as a partial antagonist to NgVIA in rat brain in vivo. NgVIA appears to act via a receptor site distinct from that of delta TxVIA but similar to that of Conus striatus toxin. This new toxin provides a lead for structure-function relationship studies in the delta-conotoxins and will enable analysis of the functional significance of this complex of receptor sites in gating mechanisms of sodium channels.

Amino Acid Sequence↗
PubMed2004

Species-level phylogeography and evolutionary history of the hyperdiverse marine gastropod genus Conus.

Phylogenetic and paleontological analyses are combined to reveal patterns of species origination and divergence and to define the significance of potential and actual barriers to dispersal in Conus, a species-rich genus of predatory gastropods distributed throughout the world's tropical oceans. Species-level phylogenetic hypotheses are based on nucleotide sequences from the nuclear calmodulin and mitochondrial 16S rRNA genes of 138 Conus species from the Indo-Pacific, eastern Pacific, and Atlantic Ocean regions. Results indicate that extant species descend from two major lineages that diverged at least 33 mya. Their geographic distributions suggest that one clade originated in the Indo-Pacific and the other in the eastern Pacific + western Atlantic. Impediments to dispersal between the western Atlantic and Indian Oceans and the central and eastern Pacific Ocean may have promoted this early separation of Indo-Pacific and eastern Pacific + western Atlantic lineages of Conus. However, because both clades contain both Indo-Pacific and eastern Pacific + western Atlantic species, migrations must have occurred between these regions; at least four migration events took place between regions at different times. In at least three cases, incursions between regions appear to have crossed the East Pacific Barrier. The paleontological record illustrates that distinct sets of Conus species inhabited the Indo-Pacific, eastern Pacific + western Atlantic, and eastern Atlantic + former Tethys Realm in the Tertiary, as is the case today. The ranges of <1% of fossil species (N=841) spanned more than one of these regions throughout the evolutionary history of this group.

Animals↗
PubMed2003

The augertoxins: biochemical characterization of venom components from the toxoglossate gastropod Terebra subulata.

We describe the purification and biochemical characterization of three components from the venom of the toxoglossate gastropod Terebra subulata. The three polypeptide venom components, augertoxins s6a, s7a and s11a, are 40-41AA in length with 3-4 disulfide linkages. The arrangement of Cys residues is reminiscent of certain conopeptide superfamilies, but molecular cloning failed to show the highly conserved sequence features diagnostic of the conopeptide gene superfamily with a similar arrangement of Cys residues. One of the purified peptides, s7a, elicited an uncoordinated twisting syndrome when injected into the nematode Caenorhabditis elegans, but had no effect on mice. T. subulata belongs to the family Terebridae, one of four major groups of toxoglossate gastropods in the superfamily Conacea. The results reveal that some features of the augertoxins and conotoxins are generally similar, such as the organization of prepropeptide precursors and their proteolytic processing into mature toxins; however, Terebra may have evolved generally larger venom components that are less highly post-translationally modified. The results suggest that Conus peptide gene superfamilies probably do not extend to the Terebridae, suggesting that distinctive venom gene superfamilies may be expressed in each major division of Conacean gastropods.

Amino Acid Sequence↗
PubMed2001

Enzymatic glycosylation of contulakin-G, a glycopeptide isolated from Conus venom, with a mammalian ppGalNAc-transferase.

We have determined that the mammalian uridine diphospho-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase T1 (EC 2.4.1.41) has the appropriate acceptor substrate specificity to recognize the non-glycosylated form of contulakin-G (ZSEEGGSNATKKPYIL-OH where Z=pyroglutamic acid) and to transfer GalNAc to the peptide. Both [Thr(10)] contulakin-G and a pre-contulakin-G(30-66) (RGLVPDDITPQLILGSLISRRQSEEGGSNATKKPYIL-OH) were shown to be acceptors for the mammalian enzyme. The site of attachment of the GalNAc residue was determined using chemical and radioactive sequencing techniques. The mammalian enzyme was highly specific for Thr(10) residue, in which the native peptide was found to be glycosylated, compared with either Ser(2) or Ser(7). In the case of pre-contulakin-G, the enzyme was also highly specific for the equivalent threonine residue. These results suggest that the Cone snail uses an enzyme with similar acceptor specificity to that of the mammalian polypeptide N-acetylgalactosaminyltransferase for glycosylating contulakin-G.

Amino Acid Sequence↗
PubMed1997

A noncompetitive peptide inhibitor of the nicotinic acetylcholine receptor from Conus purpurascens venom.

A paralytic peptide, psi-conotoxin Piiie has been purified and characterized from Conus purpurascens venom. Electrophysiological studies indicate that the peptide inhibits the nicotinic acetylcholine receptor (nAChR). However, the peptide does not block the binding of alpha-bungarotoxin, a competitive nAChR antagonist. Thus, psi-conotoxin Piiie appears to inhibit the receptor at a site other than the acetylcholine-binding site. As ascertained by sequence analysis, mass spectrometry, and chemical synthesis, the peptide has the following covalent structure: HOOCCLYGKCRRYOGCSSASCCQR* (O = 4-trans hydroxyproline; * indicates an amidated C-terminus). The disulfide connectivity of the toxin is unrelated to the alpha- or the alphaA-conotoxins, the Conus peptide families that are competitive inhibitors of the nAChR, but shows homology to the mu-conotoxins (which are Na+ channel blockers).

Amino Acid Sequence↗
PubMed1984

[Redescription of Cercaria setifera F.S. Monticelli, 1914 (nec J. Müller) (Trematoda), a parasite of Conus ventricosus Hwass; comparison with various ophthalmotrichocercous cercariae from the western Mediterranean].

Cercaria setifera is a Digenean parasite of Conus ventricosus, the cercariae having been recovered from this mollusc on the French mediterranean coast. The cercaria is redescribed in this paper and various aspects of its behavior are noted. Several species of Lepocreadiid cercariae from the western Mediterranean Sea have been previously confused with Cercaria setifera. In this paper the synonyms of C. setifera are discussed. The metacercarial and adult stage are, as yet, unknown.

Animals↗
PubMed1995

alpha-Conotoxin ImI exhibits subtype-specific nicotinic acetylcholine receptor blockade: preferential inhibition of homomeric alpha 7 and alpha 9 receptors.

Through a study of cloned nicotinic receptors expressed in Xenopus oocytes, we provide evidence that alpha-conotoxin ImI, a peptide marine snail toxin that induces seizures in rodents, selectively blocks subtypes of nicotinic acetylcholine receptors. alpha-Conotoxin ImI blocks homomeric alpha 7 nicotinic receptors with the highest apparent affinity and homomeric alpha 9 receptors with 8-fold lower affinity. This toxin has no effect on receptors composed of alpha 2 beta 2, alpha 3 beta 2, alpha 4 beta 2, alpha 2 beta 4, alpha 3 beta 4, or alpha 4 beta 4 subunit combinations. In contrast to alpha-bungarotoxin, which has high affinity for alpha 7, alpha 9, and alpha 1 beta 1 gamma delta receptors, alpha-conotoxin ImI has low affinity for the muscle nAChR. Related Conus peptides, alpha-conotoxins MI and GI, exhibit a distinct specificity, strictly targeting the muscle subtype receptor but not alpha 7 or alpha 9 receptors. alpha-Conotoxins thus represent selective tools for the study of neuronal nicotinic acetylcholine receptors.

Amino Acid Sequence↗
PubMed2003

The synthesis of SO-3, a conopeptide with high analgesic activity derived from Conus striatus.

The synthesis and characterization of the conopeptide, SO-3, originally derived from Conus striatus is reported. It contains 25 amino acid residues and three disulfide bridges and manifests 72% sequence identity with MVIIA, an N-type Ca2+ channel inhibitor of high analgesic activity. We evaluated SO-3 in several mouse models of pain. The results indicate that SO-3 is a potent, nonaddictive, analgesic agent.

Amino Acid Sequence↗
PubMed1994

A new neurotoxin receptor site on sodium channels is identified by a conotoxin that affects sodium channel inactivation in molluscs and acts as an antagonist in rat brain.

The peptide conotoxin TxVIA is selectively toxic to molluscs and slows sodium current inactivation in mollusc neurons. Here we show that TxVIA binds with high affinity to new sites on sodium channels in both mollusc and rat central nervous systems, despite its lack of toxicity to vertebrates. Furthermore, TxVIA protects from the toxic effects of Conus striatus toxin in rat brain. The TxVIA binding site differs from other neurotoxin receptor sites affecting sodium channel inactivation in that binding is not voltage-dependent and undergoes negative allosteric modulation by veratridine. TxVIA therefore represents a novel category of sodium channel probes, designated delta-conotoxins. TxVIA is shown to discriminate between sodium channels in different phyla by activity but not by binding, thus providing a lead for the study of structural elements affecting gating modes of sodium channels.

Animals↗