scholarly journals δ-Conotoxin SuVIA suggests an evolutionary link between ancestral predator defence and the origin of fish-hunting behaviour in carnivorous cone snails

2015 ◽  
Vol 282 (1811) ◽  
pp. 20150817 ◽  
Author(s):  
Ai-Hua Jin ◽  
Mathilde R. Israel ◽  
Marco C. Inserra ◽  
Jennifer J. Smith ◽  
Richard J. Lewis ◽  
...  
Keyword(s):  
Voltage Dependence ◽  
Venom Gland ◽  
Underlying Mechanism ◽  
Cone Snail ◽  
Evolutionary Transition ◽  
Hunting Behaviour ◽  
Defensive Role ◽  
Cone Snails ◽  
Nanomolar Range ◽  
Predator Defence

Some venomous cone snails feed on small fishes using an immobilizing combination of synergistic venom peptides that target K v and Na v channels. As part of this envenomation strategy, δ-conotoxins are potent ichtyotoxins that enhance Na v channel function. δ-Conotoxins belong to an ancient and widely distributed gene superfamily, but any evolutionary link from ancestral worm-eating cone snails to modern piscivorous species has not been elucidated. Here, we report the discovery of SuVIA, a potent vertebrate-active δ-conotoxin characterized from a vermivorous cone snail ( Conus suturatus ). SuVIA is equipotent at hNa V 1.3, hNa V 1.4 and hNa V 1.6 with EC 50 s in the low nanomolar range. SuVIA also increased peak hNa V 1.7 current by approximately 75% and shifted the voltage-dependence of activation to more hyperpolarized potentials from –15 mV to –25 mV, with little effect on the voltage-dependence of inactivation. Interestingly, the proximal venom gland expression and pain-inducing effect of SuVIA in mammals suggest that δ-conotoxins in vermivorous cone snails play a defensive role against higher order vertebrates. We propose that δ-conotoxins originally evolved in ancestral vermivorous cones to defend against larger predators including fishes have been repurposed to facilitate a shift to piscivorous behaviour, suggesting an unexpected underlying mechanism for this remarkable evolutionary transition.

scholarly journals Ero1-Mediated Reoxidation of Protein Disulfide Isomerase Accelerates the Folding of Cone Snail Toxins

2018 ◽  
Vol 19 (11) ◽  
pp. 3418 ◽  
Author(s):  
Henrik O’Brien ◽  
Shingo Kanemura ◽  
Masaki Okumura ◽  
Robert Baskin ◽  
Pradip Bandyopadhyay ◽  
...  
Keyword(s):  
Protein Disulfide Isomerase ◽  
Venom Gland ◽  
Cone Snail ◽  
Disulfide Isomerase ◽  
Folding Rates ◽  
Cone Snails ◽  
And Function ◽  
Protein Disulfide ◽  
Insight Into

Disulfide-rich peptides are highly abundant in nature and their study has provided fascinating insight into protein folding, structure and function. Venomous cone snails belong to a group of organisms that express one of the largest sets of disulfide-rich peptides (conotoxins) found in nature. The diversity of structural scaffolds found for conotoxins suggests that specialized molecular adaptations have evolved to ensure their efficient folding and secretion. We recently showed that canonical protein disulfide isomerase (PDI) and a conotoxin-specific PDI (csPDI) are ubiquitously expressed in the venom gland of cone snails and play a major role in conotoxin folding. Here, we identify cone snail endoplasmic reticulum oxidoreductin-1 (Conus Ero1) and investigate its role in the oxidative folding of conotoxins through reoxidation of cone snail PDI and csPDI. We show that Conus Ero1 preferentially reoxidizes PDI over csPDI, suggesting that the reoxidation of csPDI may rely on an Ero1-independent molecular pathway. Despite the preferential reoxidation of PDI over csPDI, the combinatorial effect of Ero1 and csPDI provides higher folding yields than Ero1 and PDI. We further demonstrate that the highest in vitro folding rates of two model conotoxins are achieved when all three enzymes are present, indicating that these enzymes may act synergistically. Our findings provide new insight into the generation of one of the most diverse classes of disulfide-rich peptides and may improve current in vitro approaches for the production of venom peptides for pharmacological studies.

scholarly journals Transcriptomic-Proteomic Correlation in the Predation-Evoked Venom of the Cone Snail, Conus imperialis

Marine Drugs ◽  
2019 ◽  
Vol 17 (3) ◽  
pp. 177 ◽  
Author(s):  
Ai-Hua Jin ◽  
Sébastien Dutertre ◽  
Mriga Dutt ◽  
Vincent Lavergne ◽  
Alun Jones ◽  
...  
Keyword(s):  
Geographical Location ◽  
Venom Gland ◽  
Feeding Habit ◽  
Poor Correlation ◽  
Stabilizing Selection ◽  
Cone Snail ◽  
Venom Composition ◽  
Cone Snails ◽  
And Gender ◽  
Labelling Method

Individual variation in animal venom has been linked to geographical location, feeding habit, season, size, and gender. Uniquely, cone snails possess the remarkable ability to change venom composition in response to predatory or defensive stimuli. To date, correlations between the venom gland transcriptome and proteome within and between individual cone snails have not been reported. In this study, we use 454 pyrosequencing and mass spectrometry to decipher the transcriptomes and proteomes of the venom gland and corresponding predation-evoked venom of two specimens of Conus imperialis. Transcriptomic analyses revealed 17 conotoxin gene superfamilies common to both animals, including 5 novel superfamilies and two novel cysteine frameworks. While highly expressed transcripts were common to both specimens, variation of moderately and weakly expressed precursor sequences was surprisingly diverse, with one specimen expressing two unique gene superfamilies and consistently producing more paralogs within each conotoxin gene superfamily. Using a quantitative labelling method, conotoxin variability was compared quantitatively, with highly expressed peptides showing a strong correlation between transcription and translation, whereas peptides expressed at lower levels showed a poor correlation. These results suggest that major transcripts are subject to stabilizing selection, while minor transcripts are subject to diversifying selection.

scholarly journals Combined Proteotranscriptomic-Based Strategy to Discover Novel Antimicrobial Peptides from Cone Snails

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 344
Author(s):  
Anicet Ebou ◽  
Dominique Koua ◽  
Audrey Addablah ◽  
Solange Kakou-Ngazoa ◽  
Sébastien Dutertre
Keyword(s):  
Antimicrobial Peptides ◽  
Marine Invertebrates ◽  
Current Knowledge ◽  
Venom Gland ◽  
Biologically Active ◽  
Cone Snail ◽  
Active Peptides ◽  
Speed Up ◽  
Cone Snails ◽  
Conventional Antibiotics

Despite their impressive diversity and already broad therapeutic applications, cone snail venoms have received less attention as a natural source in the investigation of antimicrobial peptides than other venomous animals such as scorpions, spiders, or snakes. Cone snails are among the largest genera (Conus sp.) of marine invertebrates, with more than seven hundred species described to date. These predatory mollusks use their sophisticated venom apparatus to capture prey or defend themselves. In-depth studies of these venoms have unraveled many biologically active peptides with pharmacological properties of interest in the field of pain management, the treatment of epilepsy, neurodegenerative diseases, and cardiac ischemia. Considering sequencing efficiency and affordability, cone snail venom gland transcriptome analyses could allow the discovery of new, promising antimicrobial peptides. We first present here the need for novel compounds like antimicrobial peptides as a viable alternative to conventional antibiotics. Secondly, we review the current knowledge on cone snails as a source of antimicrobial peptides. Then, we present the current state of the art in analytical methods applied to crude or milked venom followed by how antibacterial activity assay can be implemented for fostering cone snail antimicrobial peptides studies. We also propose a new innovative profile Hidden Markov model-based approach to annotate full venom gland transcriptomes and speed up the discovery of potentially active peptides from cone snails.

scholarly journals Developmental modularity and phenotypic novelty within a biphasic life cycle: morphogenesis of a cone snail venom gland

2011 ◽  
Vol 279 (1726) ◽  
pp. 77-83 ◽  
Author(s):  
Louise R. Page
Keyword(s):  
Feeding Behaviour ◽  
Venom Gland ◽  
Cone Snail ◽  
Evolutionary Transition ◽  
Metamorphic Stage ◽  
Oesophageal Gland ◽  
Key Innovation ◽  
Biphasic Life Cycle ◽  
Epithelial Sheet ◽  
Phenotypic Novelty

The venom gland of predatory cone snails ( Conus spp.), which secretes neurotoxic peptides that rapidly immobilize prey, is a proposed key innovation for facilitating the extraordinary feeding behaviour of these gastropod molluscs. Nevertheless, the unusual morphology of this gland has generated controversy about its evolutionary origin and possible homologues in other gastropods. I cultured feeding larvae of Conus lividus and cut serial histological sections through the developing foregut during larval and metamorphic stages to examine the development of the venom gland. Results support the hypothesis of homology between the venom gland and the mid-oesophageal gland of other gastropods. They also suggest that the mid-region of the gastropod foregut, like the anterior region, is divisible into dorsal and ventral developmental modules that have different morphological, functional and ontogenetic fates. In larvae of C. lividus , the ventral module of the middle foregut transformed into the anatomically novel venom gland of the post-metamorphic stage by rapidly pinching-off from the main dorsal channel of the mid-oesophagus, an epithelial remodelling process that may be similar to other cases where epithelial tubes and vesicles arise from a pre-existing epithelial sheet. The developmental remodelling mechanism could have facilitated an abrupt evolutionary transition to the derived morphology of this important gastropod feeding innovation.

scholarly journals Variation of Two S3b Residues in KV4.1–4.3 Channels Underlies Their Different Modulations by Spider Toxin κ-LhTx-1

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhen Xiao ◽  
Piao Zhao ◽  
Xiangyue Wu ◽  
Xiangjin Kong ◽  
Ruiwen Wang ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Voltage Dependence ◽  
Underlying Mechanism ◽  
Voltage Sensor ◽  
Action Mode ◽  
Gating Modifier ◽  
Peptide Toxin ◽  
Peptide Toxins ◽  
Key Residues ◽  
Animal Venoms

The naturally occurred peptide toxins from animal venoms are valuable pharmacological tools in exploring the structure-function relationships of ion channels. Herein we have identified the peptide toxin κ-LhTx-1 from the venom of spider Pandercetes sp (the Lichen huntsman spider) as a novel selective antagonist of the KV4 family potassium channels. κ-LhTx-1 is a gating-modifier toxin impeded KV4 channels’ voltage sensor activation, and mutation analysis has confirmed its binding site on channels’ S3b region. Interestingly, κ-LhTx-1 differently modulated the gating of KV4 channels, as revealed by toxin inhibiting KV4.2/4.3 with much more stronger voltage-dependence than that for KV4.1. We proposed that κ-LhTx-1 trapped the voltage sensor of KV4.1 in a much more stable resting state than that for KV4.2/4.3 and further explored the underlying mechanism. Swapping the non-conserved S3b segments between KV4.1(280FVPK283) and KV4.3(275VMTN278) fully reversed their voltage-dependence phenotypes in inhibition by κ-LhTx-1, and intensive mutation analysis has identified P282 in KV4.1, D281 in KV4.2 and N278 in KV4.3 being the key residues. Furthermore, the last two residues in this segment of each KV4 channel (P282/K283 in KV4.1, T280/D281 in KV4.2 and T277/N278 in KV4.3) likely worked synergistically as revealed by our combinatorial mutations analysis. The present study has clarified the molecular basis in KV4 channels for their different modulations by κ-LhTx-1, which have advanced our understanding on KV4 channels’ structure features. Moreover, κ-LhTx-1 might be useful in developing anti-arrhythmic drugs given its high affinity, high selectivity and unique action mode in interacting with the KV4.2/4.3 channels.

scholarly journals Australian funnel-web spiders evolved human-lethal δ-hexatoxins for defense against vertebrate predators

2020 ◽  
Vol 117 (40) ◽  
pp. 24920-24928 ◽  
Author(s):  
Volker Herzig ◽  
Kartik Sunagar ◽  
David T. R. Wilson ◽  
Sandy S. Pineda ◽  
Mathilde R. Israel ◽  
...  
Keyword(s):  
Molecular Evolution ◽  
Venom Gland ◽  
Sequence Conservation ◽  
Mating Season ◽  
Lethal Effects ◽  
Voltage Gated ◽  
Web Spider ◽  
Self Defense ◽  
Defensive Role ◽  
Vertebrate Predators

Australian funnel-web spiders are infamous for causing human fatalities, which are induced by venom peptides known as δ-hexatoxins (δ-HXTXs). Humans and other primates did not feature in the prey or predator spectrum during evolution of these spiders, and consequently the primate lethality of δ-HXTXs remains enigmatic. Funnel-web envenomations are mostly inflicted by male spiders that wander from their burrow in search of females during the mating season, which suggests a role for δ-HXTXs in self-defense since male spiders rarely feed during this period. Although 35 species of Australian funnel-web spiders have been described, only nine δ-HXTXs from four species have been characterized, resulting in a lack of understanding of the ecological roles and molecular evolution of δ-HXTXs. Here, by profiling venom-gland transcriptomes of 10 funnel-web species, we report 22 δ-HXTXs. Phylogenetic and evolutionary assessments reveal a remarkable sequence conservation of δ-HXTXs despite their deep evolutionary origin within funnel-web spiders, consistent with a defensive role. We demonstrate that δ-HXTX-Ar1a, the lethal toxin from the Sydney funnel-web spider Atrax robustus, induces pain in mice by inhibiting inactivation of voltage-gated sodium (NaV) channels involved in nociceptive signaling. δ-HXTX-Ar1a also inhibited inactivation of cockroach NaV channels and was insecticidal to sheep blowflies. Considering their algogenic effects in mice, potent insecticidal effects, and high levels of sequence conservation, we propose that the δ-HXTXs were repurposed from an initial insecticidal predatory function to a role in defending against nonhuman vertebrate predators by male spiders, with their lethal effects on humans being an unfortunate evolutionary coincidence.

scholarly journals Voltage- and NADPH-dependence of electron currents generated by the phagocytic NADPH oxidase

2005 ◽  
Vol 388 (2) ◽  
pp. 485-491 ◽  
Author(s):  
Gábor L. PETHEŐ ◽  
Nicolas DEMAUREX
Keyword(s):  
Membrane Potential ◽  
Nadph Oxidase ◽  
Voltage Dependence ◽  
Intrinsic Property ◽  
Maximal Activity ◽  
Underlying Mechanism ◽  
Potential Range ◽  
Electron Current ◽  
Steady State Current ◽  
Voltage Dependent

The phagocytic NADPH oxidase generates superoxide by transferring electrons from cytosolic NADPH to extracellular O2. The activity of the oxidase at the plasma membrane can be measured as electron current (Ie), and the voltage dependence of Ie was recently reported to exhibit a strong rectification in human eosinophils, with the currents being nearly voltage independent at negative potentials. To investigate the underlying mechanism, we performed voltage-clamp experiments on inside-out patches from human eosinophils activated with PMA. Electron current was evoked by bath application of different concentrations of NADPH, whereas slow voltage ramps (0.8 mV/ms), ranging from −120 to 200 mV, were applied to obtain ‘steady-state’ current–voltage relationships (I–V). The amplitude of Ie recorded at −40 mV was minimal at 8 μM NADPH and saturated above 1 mM, with half-maximal activity (Km) observed at approx. 110 μM NADPH. Comparison of I–V values obtained at different NADPH concentrations revealed that the voltage-dependence of Ie is strongly influenced by the substrate concentration. Above 0.1 mM NADPH, Ie was markedly voltage-dependent and steeply decreased with depolarization within the physiological membrane potential range (−60 to 60 mV), the I–V curve strongly rectifying only below −100 mV. At lower NADPH concentrations the I–V curve was progressively shifted to more positive potentials and Ie became voltage-independent also within the physiological range. Consequently, the Km of the oxidase decreased by approx. 40% (from 100 to 60 μM) when the membrane potential increased from −60 to 60 mV. We concluded that the oxidase activity depends on both membrane potential and [NADPH], and that the shape of the Ie–V curve is influenced by the concentration of NADPH in the submillimolar range. The surprising voltage-independence of Ie reported in whole-cell perforated patch recordings was most likely due to substrate limitation and is not an intrinsic property of the oxidase.

scholarly journals Vexitoxins: a novel class of conotoxin-like venom peptides from predatory gastropods of the genus Vexillum

2022 ◽  
Author(s):  
Ksenia G Kuznetsova ◽  
Sofia S Zvonareva ◽  
Rustam Ziganshin ◽  
Elena S Mekhova ◽  
Polina Yu Dgebuadze ◽  
...  
Keyword(s):  
Sequence Similarity ◽  
Venom Gland ◽  
Data Sets ◽  
Rna Seq ◽  
Proteomic Profiling ◽  
Post Translational Modifications ◽  
Origin And Evolution ◽  
The Family ◽  
Venom Evolution ◽  
Cone Snails

Venoms of predatory marine cone snails (the family Conidae, order Neogastropoda) are intensely studied because of the broad range of biomedical applications of the neuropeptides that they contain, conotoxins. Meanwhile anatomy in some other neogastropod lineages strongly suggests that they have evolved similar venoms independently of cone snails, nevertheless their venom composition remains unstudied. Here we focus on the most diversified of these lineages, the genus Vexillum (the family Costellariidae). We have generated comprehensive multi-specimen, multi-tissue RNA-Seq data sets for three Vexillum species, and supported our findings in two species by proteomic profiling. We show that venoms of Vexillum are dominated by highly diversified short cysteine-rich peptides that in many aspects are very similar to conotoxins. Vexitoxins possess the same precursor organization, display overlapping cysteine frameworks and share several common post-translational modifications with conotoxins. Some vexitoxins show detectable sequence similarity to conotoxins, and are predicted to adopt similar domain conformations, including a pharmacologically relevant inhibitory cysteine-know motif (ICK). The tubular gL of Vexillum is a notably more recent evolutionary novelty than the conoidean venom gland. Thus, we hypothesize lower divergence between the toxin genes, and their somatic counterparts compared to that in conotoxins, and we find support for this hypothesis in the molecular evolution of the vexitoxin cluster V027. We use this example to discuss how future studies on vexitoxins can inform origin and evolution of conotoxins, and how they may help addressing standing questions in venom evolution.

scholarly journals Venom Diversity and Evolution in the Most Divergent Cone Snail Genus Profundiconus

Toxins ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 623 ◽  
Author(s):  
Giulia Fassio ◽  
Maria Vittoria Modica ◽  
Lou Mary ◽  
Paul Zaharias ◽  
Alexander E. Fedosov ◽  
...  
Keyword(s):  
De Novo ◽  
Venom Gland ◽  
Phylogenetic Position ◽  
Cone Snail ◽  
Dietary Breadth ◽  
The Family ◽  
New Gene ◽  
Peptide Toxins ◽  
Transcript Diversity ◽  
Venom Evolution

Profundiconus is the most divergent cone snail genus and its unique phylogenetic position, sister to the rest of the family Conidae, makes it a key taxon for examining venom evolution and diversity. Venom gland and foot transcriptomes of Profundiconus cf. vaubani and Profundiconus neocaledonicus were de novo assembled, annotated, and analyzed for differential expression. One hundred and thirty-seven venom components were identified from P. cf. vaubani and 82 from P. neocaledonicus, with only four shared by both species. The majority of the transcript diversity was composed of putative peptides, including conotoxins, profunditoxins, turripeptides, insulin, and prohormone-4. However, there were also a significant percentage of other putative venom components such as chymotrypsin and L-rhamnose-binding lectin. The large majority of conotoxins appeared to be from new gene superfamilies, three of which are highly different from previously reported venom peptide toxins. Their low conotoxin diversity and the type of insulin found suggested that these species, for which no ecological information are available, have a worm or molluscan diet associated with a narrow dietary breadth. Our results indicate that Profundiconus venom is highly distinct from that of other cone snails, and therefore important for examining venom evolution in the Conidae family.

scholarly journals Rapid sensitive analysis of cysteine rich peptide venom components

2009 ◽  
Vol 106 (17) ◽  
pp. 6910-6915 ◽  
Author(s):  
Beatrix M. Ueberheide ◽  
David Fenyö ◽  
Paul F. Alewood ◽  
Brian T. Chait
Keyword(s):  
Charge State ◽  
Disulfide Bonds ◽  
Electron Transfer Dissociation ◽  
Venom Gland ◽  
Bioactive Molecules ◽  
Sequence Information ◽  
Cone Snail ◽  
Sequence Coverage ◽  
Crude Venom ◽  
Peptide Toxins

Disulfide-rich peptide venoms from animals such as snakes, spiders, scorpions, and certain marine snails represent one of nature's great diversity libraries of bioactive molecules. The various species of marine cone shells have alone been estimated to produce >50,000 distinct peptide venoms. These peptides have stimulated considerable interest because of their ability to potently alter the function of specific ion channels. To date, only a small fraction of this immense resource has been characterized because of the difficulty in elucidating their primary structures, which range in size between 10 and 80 aa, include up to 5 disulfide bonds, and can contain extensive posttranslational modifications. The extraordinary complexity of crude venoms and the lack of DNA databases for many of the organisms of interest present major analytical challenges. Here, we describe a strategy that uses mass spectrometry for the elucidation of the mature peptide toxin components of crude venom samples. Key to this strategy is our use of electron transfer dissociation (ETD), a mass spectrometric fragmentation technique that can produce sequence information across the entire peptide backbone. However, because ETD only yields comprehensive sequence coverage when the charge state of the precursor peptide ion is sufficiently high and the m/z ratio is low, we combined ETD with a targeted chemical derivatization strategy to increase the charge state of cysteine-containing peptide toxins. Using this strategy, we obtained full sequences for 31 peptide toxins, using just 7% of the crude venom from the venom gland of a single cone snail (Conus textile).

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