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Pore-forming toxins (PFT) are water-soluble proteins that possess the remarkable ability to self-assemble on the membrane of target cells, where they form pores causing cell damage. Here, we elucidate the mechanism of action of the haemolytic protein fragaceatoxin C (FraC), a α-barrel PFT, by determining the crystal structures of FraC at four different stages of the lytic mechanism, namely the water-soluble state, the monomeric lipid-bound form, an assembly intermediate and the fully assembled transmembrane pore. The structure of the transmembrane pore exhibits a unique architecture composed of both protein and lipids, with some of the lipids lining the pore wall, acting as assembly cofactors. The pore also exhibits lateral fenestrations that expose the hydrophobic core of the membrane to the aqueous environment. The incorporation of lipids from the target membrane within the structure of the pore provides a membrane-specific trigger for the activation of a haemolytic toxin. Actinoporins are water-soluble pore-forming toxins that self-assemble in the membranes of target cells. Here, the authors provide insight into the mechanism of membrane pore formation by solving the structures of several states of the hemolytic protein fragaceatoxin C, including the fully assembled pore.

Sea anemones produce venoms of exceptional molecular diversity, with at least 17 different molecular scaffolds reported to date. These venom components have traditionally been classified according to pharmacological activity and amino acid sequence. However, this classification system suffers from vulnerabilities due to functional convergence and functional promiscuity. Furthermore, for most known sea anemone toxins, the exact receptors they target are either unknown, or at best incomplete. In this review, we first provide an overview of the sea anemone venom system and then focus on the venom components. We have organised the venom components by distinguishing firstly between proteins and non-proteinaceous compounds, secondly between enzymes and other proteins without enzymatic activity, then according to the structural scaffold, and finally according to molecular target.

Mitogenome diversity is staggering among early branching animals with respect to size, gene density, content and order, and number of tRNA genes, especially in cnidarians. This last point is of special interest as tRNA cleavage drives the maturation of mitochondrial mRNAs and is a primary mechanism for mt-RNA processing in animals. Mitochondrial RNA processing in non-bilaterian metazoans, some of which possess a single tRNA gene in their mitogenomes, is essentially unstudied despite its importance in understanding the evolution of mitochondrial transcription in animals. We characterized the mature mitochondrial mRNA transcripts in a species of the octocoral genus Sinularia (Alcyoniidae: Octocorallia), and defined precise boundaries of transcription units using different molecular methods. Most mt-mRNAs were polycistronic units containing two or three genes and 5' and/or 3' untranslated regions of varied length. The octocoral specific, mtDNA-encoded mismatch repair gene, the mtMutS, was found to undergo alternative polyadenylation, and exhibited differential expression of alternate transcripts suggesting a unique regulatory mechanism for this gene. In addition, a long noncoding RNA complementary to the ATP6 gene (lncATP6) potentially involved in antisense regulation was detected. Mt-mRNA processing in octocorals possessing a single mt-tRNA is complex. Considering the variety of mitogenome arrangements known in cnidarians, and in general among non-bilaterian metazoans, our findings provide a first glimpse into the complex mtDNA transcription, mt-mRNA processing, and regulation among early branching animals and represent a first step towards understanding its functional and evolutionary implications.

Sea anemone venoms have long been recognized as a rich source of peptides with interesting pharmacological and structural properties, but they still contain many uncharacterized bioactive compounds. Here we report the discovery, three-dimensional structure, activity, tissue localization, and putative function of a novel sea anemone peptide toxin that constitutes a new, sixth type of voltage-gated potassium channel (K V ) toxin from sea anemones. Comprised of just 17 residues, κ-actitoxin-Ate1a (Ate1a) is the shortest sea anemone toxin reported to date, and it adopts a novel three-dimensional structure that we have named the Proline-Hinged Asymmetric β-hairpin (PHAB) fold. Mass spectrometry imaging and bioassays suggest that Ate1a serves a primarily predatory function by immobilising prey, and we show this is achieved through inhibition of Shaker-type K V channels. Ate1a is encoded as a multi-domain precursor protein that yields multiple identical mature peptides, which likely evolved by multiple domain duplication events in an actinioidean ancestor. Despite this ancient evolutionary history, the PHAB-encoding gene family exhibits remarkable sequence conservation in the mature peptide domains. We demonstrate that this conservation is likely due to intra-gene concerted evolution, which has to our knowledge not previously been reported for toxin genes. We propose that the concerted evolution of toxin domains provides a hitherto unrecognised way to circumvent the effects of the costly evolutionary arms race considered to drive toxin gene evolution by ensuring efficient secretion of ecologically important predatory toxins.

Cnidaria constitute an important phylum of venomous animals, several of which have a significant impact on human health and activities. Cnidarian venoms are included in a special capsule called nematocyst, and are known to consist of peptides, proteins, phospholipids, glycoproteins, sterols, bioactive amines and carbohydrates. Cnidarian venoms are used for hunting and defence, and have paralytic, neurotoxic, cytotoxic, dermotoxic and hemolytic effects on other living organisms. In this study, the neurological and behavioural effects of different doses of venom obtained from the nematocysts of Alicia mirabilis and Aurelia aurita were observed on blue crabs (Callinectes sapidus) individuals. For this purpose, various doses of venoms were injected on the linkage between merus and carpus parts of the cheliped of blue crab individuals. The most common effects of A. mirabilis and A. aurita venoms were observed to be stiffness and trembling behavior in the legs. These symptoms indicate that venom causes neural paralytic syndrome. It has been observed that the effect of venom increases with time and paralysis occurs before death.

Sea anemone venoms contain diverse toxins that have significant pharmacological potential, including anticancer, ecticidal, and immunotherapeutic properties. However, critically, the extraction methodology influences venom composition and bioactivity. This study characterized venom from Stichodactyla haddoni obtained via homogenization, electrical stimulation, and milking. Extraction yields varied significantly between methods: the homogenization, electrical stimulation, and milking of healthy sea anemones yielded crude venoms at rates of 17.8%, 3.4%, and 1.5%, respectively. SDS-PAGE revealed distinct protein banding patterns and concentrations, while RP-HPLC demonstrated method-dependent compositional differences. Comprehensive proteomic profiling identified 2370 proteins, encompassing both unique and shared components across extraction techniques. Label-free quantitative analysis confirmed significant variations in protein abundance that was attributable to the extraction method. Cytotoxicity assays against cancer cell lines revealed concentration-dependent inhibition, with milking-derived venom exhibiting the highest potency. Insecticidal activity against Tenebrio molitor was also method-dependent, with milking venom inducing the highest mortality rate. These findings elucidate the profound impact of extraction methodology on the protein composition and functional activities of S. haddoni venom, providing crucial insights for its optimized exploitation in pharmacological development.