Mapping the chemical and sequence space of the ShKT superfamily

Shafee, Thomas; Mitchell, Michela L.; Norton, Raymond S.

doi:10.1016/j.toxicon.2019.04.008

Cited by 16 publications

(19 citation statements)

References 52 publications

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“…All SA8 putative toxins in T. stephensoni had a cysteine spacing consistent with motif 3, described by Kozlov and Grishin [29], which has previously been observed in SA8 putative toxins from Anemonia viridis (P0DMZ3, P0DMZ4, P0DMZ5, P0DMZ6, P0DMZ7), sea anemone type 1 potassium channel toxins with a ShKT domain (P29187, P29186, P81897, Q9TW91) [29] and cysteine-rich domain (CRD) of snake venom cysteine-rich secretory proteins (CRISPs) [123]. Sequence space analysis [27] revealed that ShK-like proteins, CRISPs and SA8 putative toxins are clearly delineated into three groups ( Figure 8A ), reinforcing the unique sequence composition of SA8 putative toxins and indicating that they represent a single distinct protein family.…”

Section: Resultssupporting

confidence: 81%

“…An analogue of ShK (dalazatide, Shk-186) has shown remarkable efficacy in in preclinical animal models of autoimmune disease [15, [19][20][21] and entered phase 1 clinical trials for the treatment of plaque psoriasis [22]. Because of the therapeutic potential of ShK, sea anemone proteins containing ShK-like domains have received substantial research attention [23][24][25][26][27], but not all ShK-like peptides block ion channels. More recently, it was reported that multiple toxin-like peptides with the cysteine spacing characteristic of ShK are localised to neurons rather than venom-related structures in the starlet sea anemone, Nematostella vectensis [28].…”

Section: Introductionmentioning

confidence: 99%

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Genomic, Functional and Structural Analyses Reveal Mechanisms of Evolutionary Innovation within the Sea Anemone 8 Toxin Family

Ashwood

Elnahriry

Stewart

et al. 2022

Preprint

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ShK fromStichodactyla helianthushas established the therapeutic potential of sea anemone venom peptides, but many lineage-specific toxin families in actinarians remain uncharacterised. One such peptide family, sea anemone 8 (SA8), is present in all five sea anemone superfamilies. We explored the genomic arrangement and evolution of the SA8 gene family inActinia tenebrosaandTelmatactis stephensoni, characterised the expression patterns of SA8 sequences, and examined the structure and function of SA8 from the venom ofT. stephensoni. We identified ten SA8 genes in two clusters and six SA8 genes in five clusters forT. stephensoniandA. tenebrosa, respectively. Nine SA8T. stephensonigenes were found in a single cluster and an SA8 peptide encoded by an inverted SA8 gene from this cluster was recruited to venom. We show that SA8 genes in both species are expressed in a tissue-specific manner and the inverted SA8 gene has a unique tissue distribution. While functional activity of the SA8 putative toxin encoded by the inverted gene was inconclusive, its tissue localisation is similar to toxins used for predator deterrence. We demonstrate that, although mature SA8 putative toxins have similar cysteine spacing to ShK, SA8 peptides are distinct from ShK peptides based on structure and disulfide connectivity. Our results provide the first demonstration that SA8 is a unique gene family in actiniarians, evolving through a variety of structural changes including tandem and proximal gene duplication and an inversion event that together allowed SA8 to be recruited into the venom ofT. stephensoni.

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Section: Resultssupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Genomic, Functional and Structural Analyses Reveal Mechanisms of Evolutionary Innovation within the Sea Anemone 8 Toxin Family

Ashwood

Elnahriry

Stewart

et al. 2022

Preprint

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“…The vast majority of candidate toxins containing ShK domains did not have a close match to any toxin in the Tox-Prot database, but in 22 sequences we could confidently determine the six cysteine residue patterns characteristic of ShK domains ( Supplemental Figure S3 ). The exponential increase in ShK domain peptides found in anthozoans prompted a recent sequence-function study of the superfamily [ 134 ], and cerianthid ShK-domain toxins may represent additional structural scaffolds with novel function for further study.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis of Four Cerianthid (Cnidaria, Ceriantharia) Venoms

et al. 2020

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Tube anemones, or cerianthids, are a phylogenetically informative group of cnidarians with complex life histories, including a pelagic larval stage and tube-dwelling adult stage, both known to utilize venom in stinging-cell rich tentacles. Cnidarians are an entirely venomous group that utilize their proteinaceous-dominated toxins to capture prey and defend against predators, in addition to several other ecological functions, including intraspecific interactions. At present there are no studies describing the venom for any species within cerianthids. Given their unique development, ecology, and distinct phylogenetic-placement within Cnidaria, our objective is to evaluate the venom-like gene diversity of four species of cerianthids from newly collected transcriptomic data. We identified 525 venom-like genes between all four species. The venom-gene profile for each species was dominated by enzymatic protein and peptide families, which is consistent with previous findings in other cnidarian venoms. However, we found few toxins that are typical of sea anemones and corals, and furthermore, three of the four species express toxin-like genes closely related to potent pore-forming toxins in box jellyfish. Our study is the first to provide a survey of the putative venom composition of cerianthids and contributes to our general understanding of the diversity of cnidarian toxins.

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“…Short proteins with highly divergent sequences such as defensins cannot be analyzed with traditional phylogenetics (resulting trees have average bootstraps <20%). Specialized sequence space methods have therefore been developed to overcome these limitations [ 6 , 34 , 35 ]. When a sequence space of the plant defensin dataset is generated, the majority of HRDs fall into two main clusters ( Figure 1 B), one containing NbD2 and most of the Solanaceae HRDs, the other containing CrD26, AtD90, and AtD212 and the Brassicaceae HRDs.…”

Section: Resultsmentioning

confidence: 99%

Histidine-Rich Defensins from the Solanaceae and Brasicaceae Are Antifungal and Metal Binding Proteins

Bleackley

Vasa

Harvey

et al. 2020

JoF

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Plant defensins are best known for their antifungal activity and contribution to the plant immune system. The defining feature of plant defensins is their three-dimensional structure known as the cysteine stabilized alpha-beta motif. This protein fold is remarkably tolerant to sequence variation with only the eight cysteines that contribute to the stabilizing disulfide bonds absolutely conserved across the family. Mature defensins are typically 46–50 amino acids in length and are enriched in lysine and/or arginine residues. Examination of a database of approximately 1200 defensin sequences revealed a subset of defensin sequences that were extended in length and were enriched in histidine residues leading to their classification as histidine-rich defensins (HRDs). Using these initial HRD sequences as a query, a search of the available sequence databases identified over 750 HRDs in solanaceous plants and 20 in brassicas. Histidine residues are known to contribute to metal binding functions in proteins leading to the hypothesis that HRDs would have metal binding properties. A selection of the HRD sequences were recombinantly expressed and purified and their antifungal and metal binding activity was characterized. Of the four HRDs that were successfully expressed all displayed some level of metal binding and two of four had antifungal activity. Structural characterization of the other HRDs identified a novel pattern of disulfide linkages in one of the HRDs that is predicted to also occur in HRDs with similar cysteine spacing. Metal binding by HRDs represents a specialization of the plant defensin fold outside of antifungal activity.

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Mapping the chemical and sequence space of the ShKT superfamily

Cited by 16 publications

References 52 publications

Genomic, Functional and Structural Analyses Reveal Mechanisms of Evolutionary Innovation within the Sea Anemone 8 Toxin Family

Genomic, Functional and Structural Analyses Reveal Mechanisms of Evolutionary Innovation within the Sea Anemone 8 Toxin Family

Transcriptomic Analysis of Four Cerianthid (Cnidaria, Ceriantharia) Venoms

Histidine-Rich Defensins from the Solanaceae and Brasicaceae Are Antifungal and Metal Binding Proteins

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