Conotoxin Gene Superfamilies

Robinson, Samuel D.; Norton, Raymond S.

doi:10.3390/md12126058

Cited by 150 publications

(222 citation statements)

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“…Characterizing the functional aspects of conotoxins is critical to understanding the relationship between diet specificity and conotoxin evolution because prey specialization exists at the level of protein function. However, it is known that conotoxin gene superfamilies are poor predictors of protein function and conotoxins with similar functions can convergently evolve in different gene superfamilies (Kaas et al 2010;Puillandre et al 2012;Robinson and Norton 2014). Therefore, if the functional aspects of cone snail venom repertoires are examined, a correlation between diet specificity and conotoxin composition may appear, such as in the case with cone snail insulins (Safavi-Hemami et al 2016).…”

Section: Diet and Venom Evolutionmentioning

confidence: 99%

“…that capture their prey using a cocktail of venomous neurotoxins (Puillandre et al 2014). Cone snail venom precursor peptides (conotoxins) are typically composed of three regions: the signal region that directs the protein into the secretory pathway, the prepro region that is cleaved during protein maturation, and the mature region that ultimately becomes the mature peptide (Robinson and Norton 2014). In some instances, there exists a "post" region of the peptide following the mature region that is also cleaved during protein processing (Robinson and Norton 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Cone snail venom precursor peptides (conotoxins) are typically composed of three regions: the signal region that directs the protein into the secretory pathway, the prepro region that is cleaved during protein maturation, and the mature region that ultimately becomes the mature peptide (Robinson and Norton 2014). In some instances, there exists a "post" region of the peptide following the mature region that is also cleaved during protein processing (Robinson and Norton 2014). Conotoxins are classified into > 40 gene superfamilies (e.g., A superfamily and O1 superfamily) based on signal sequence identity, though some gene superfamilies were identified based on domain similarities to proteins from other venomous taxa (Robinson and Norton 2014).…”

Section: Introductionmentioning

confidence: 99%

“…In some instances, there exists a "post" region of the peptide following the mature region that is also cleaved during protein processing (Robinson and Norton 2014). Conotoxins are classified into > 40 gene superfamilies (e.g., A superfamily and O1 superfamily) based on signal sequence identity, though some gene superfamilies were identified based on domain similarities to proteins from other venomous taxa (Robinson and Norton 2014). To examine the evolution of conotoxin gene superfamilies from genomic DNA, we designed probes targeting over 800 nonconotoxin genes for phylogenetic analyses and conotoxins from 12 previously sequenced Conidae transcriptomes (Phuong et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Targeted Sequencing of Venom Genes from Cone Snail Genomes Improves Understanding of Conotoxin Molecular Evolution

Phuong

Mahardika

2018

Molecular Biology and Evolution

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To expand our capacity to discover venom sequences from the genomes of venomous organisms, we applied targeted sequencing techniques to selectively recover venom gene superfamilies and nontoxin loci from the genomes of 32 cone snail species (family, Conidae), a diverse group of marine gastropods that capture their prey using a cocktail of neurotoxic peptides (conotoxins). We were able to successfully recover conotoxin gene superfamilies across all species with high confidence (> 100Â coverage) and used these data to provide new insights into conotoxin evolution. First, we found that conotoxin gene superfamilies are composed of one to six exons and are typically short in length (mean ¼ $85 bp). Second, we expanded our understanding of the following genetic features of conotoxin evolution: 1) positive selection, where exons coding the mature toxin region were often three times more divergent than their adjacent noncoding regions, 2) expression regulation, with comparisons to transcriptome data showing that cone snails only express a fraction of the genes available in their genome (24-63%), and 3) extensive gene turnover, where Conidae species varied from 120 to 859 conotoxin gene copies. Finally, using comparative phylogenetic methods, we found that while diet specificity did not predict patterns of conotoxin evolution, dietary breadth was positively correlated with total conotoxin gene diversity. Overall, the targeted sequencing technique demonstrated here has the potential to radically increase the pace at which venom gene families are sequenced and studied, reshaping our ability to understand the impact of genetic changes on ecologically relevant phenotypes and subsequent diversification.

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Section: Diet and Venom Evolutionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeted Sequencing of Venom Genes from Cone Snail Genomes Improves Understanding of Conotoxin Molecular Evolution

Phuong

Mahardika

2018

Molecular Biology and Evolution

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“…The active venoms contain an array of peptides that bind to and modulate the properties of ion channels, G-protein-coupled receptors, and neurotransmitter receptors (1). Several peptides modulate the activities of voltage-gated sodium channels (VGSCs), 4 which are implicated in numerous neurological disorders, as well as neuropathic pain.…”

mentioning

confidence: 99%

Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin μO§-GVIIJ

Green

Gajewiak

Chhabra

et al. 2016

Journal of Biological Chemistry

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Cone snail toxins are well known blockers of voltage-gated sodium channels, a property that is of broad interest in biology and therapeutically in treating neuropathic pain and neurological disorders. Although most conotoxin channel blockers function by direct binding to a channel and disrupting its normal ion movement, conotoxin O §-GVIIJ channel blocking is unique, using both favorable binding interactions with the channel and a direct tether via an intermolecular disulfide bond. Disulfide exchange is possible because conotoxin O §-GVIIJ contains an S-cysteinylated Cys-24 residue that is capable of exchanging with a free cysteine thiol on the channel surface. Here, we present the solution structure of an analog of O §-GVIIJ (GVIIJ[C24S]) and the results of structure-activity studies with synthetic O §-GVIIJ variants. GVIIJ[C24S] adopts an inhibitor cystine knot structure, with two antiparallel ␤-strands stabilized by three disulfide bridges. The loop region linking the ␤-strands (loop 4) presents residue 24 in a configuration where it could bind to the proposed free cysteine of the channel (Cys-910, rat Na V 1.2 numbering; at site 8). The structure-activity study shows that three residues (Lys-12, Arg-14, and Tyr-16) located in loop 2 and spatially close to residue 24 were also important for functional activity. We propose that the interaction of O §-GVIIJ with the channel depends on not only disulfide tethering via Cys-24 to a free cysteine at site 8 on the channel but also the participation of key residues of O §-GVIIJ on a distinct surface of the peptide.Marine snails of the genus Conus employ a complex venom mixture to subdue prey and as an effective means of defending against predation. The active venoms contain an array of peptides that bind to and modulate the properties of ion channels, G-protein-coupled receptors, and neurotransmitter receptors (1). Several peptides modulate the activities of voltage-gated sodium channels (VGSCs), 4 which are implicated in numerous neurological disorders, as well as neuropathic pain. Four classes of conopeptides have been shown to affect VGSC activity. Peptides belonging to the -and ␦-families promote activation and inhibit inactivation, respectively, whereas the -and O-conotoxins inhibit VGSCs by either blocking the Na ϩ conductance pore or preventing channel activation, respectively (2, 3). Recently, the founding member of a fifth class of VGSC inhibitors was identified that blocks the channel through interaction with a previously unidentified neurotoxin binding site, site 8 (Fig. 1A) (4).O §-GVIIJ is a 35-residue peptide isolated from the venom of the piscivorous snail Conus geographus (Fig. 1B). In vitro folding of linear O §-GVIIJ with thiol-reactive oxidants (i.e. glutathione, L-cystine, or cystamine) resulted in adducts where Cys-24 was disulfide-bonded with glutathione, cysteine, or cysteamine, respectively (abbreviated as GVIIJ SSG , GVIIJ SSC , and GVIIJ SSEA , respectively; see Fig. 1C for structures). Of these, the GVIIJ SSC variant most closely resembled ...

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Recent Developments and Chemical Diversity of Cone Snails with Special Reference to Indian Cone Snails

Palanisamy

Dhanabalan²,

Sundaresan

2018

Blue Biotechnology

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Conotoxin Gene Superfamilies

Cited by 150 publications

References 183 publications

Targeted Sequencing of Venom Genes from Cone Snail Genomes Improves Understanding of Conotoxin Molecular Evolution

Targeted Sequencing of Venom Genes from Cone Snail Genomes Improves Understanding of Conotoxin Molecular Evolution

Structural Basis for the Inhibition of Voltage-gated Sodium Channels by Conotoxin μO§-GVIIJ

Recent Developments and Chemical Diversity of Cone Snails with Special Reference to Indian Cone Snails

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