title: Evolution of an ancient venom: recognition of a novel family of cnidarian toxins and the common evolutionary origin of sodium and potassium neurotoxins in sea anemone.
abstract: Despite Cnidaria (sea anemones, corals, jellyfish, and hydroids) being the oldest venomous animal lineage, structure-function relationships, phyletic distributions, and the molecular evolutionary regimes of toxins encoded by these intriguing animals are poorly understood. Hence, we have comprehensively elucidated the phylogenetic and molecular evolutionary histories of pharmacologically characterized cnidarian toxin families, including peptide neurotoxins (voltage-gated Na(+) and K(+) channel-targeting toxins: NaTxs and KTxs, respectively), pore-forming toxins (actinoporins, aerolysin-related toxins, and jellyfish toxins), and the newly discovered small cysteine-rich peptides (SCRiPs). We show that despite long evolutionary histories, most cnidarian toxins remain conserved under the strong influence of negative selection-a finding that is in striking contrast to the rapid evolution of toxin families in evolutionarily younger lineages, such as cone snails and advanced snakes. In contrast to the previous suggestions that implicated SCRiPs in the biomineralization process in corals, we demonstrate that they are potent neurotoxins that are likely involved in the envenoming function, and thus represent the first family of neurotoxins from corals. We also demonstrate the common evolutionary origin of type III KTxs and NaTxs in sea anemones. We show that type III KTxs have evolved from NaTxs under the regime of positive selection, and likely represent a unique evolutionary innovation of the Actinioidea lineage. We report a correlation between the accumulation of episodically adaptive sites and the emergence of novel pharmacological activities in this rapidly evolving neurotoxic clade.
authors.affiliation: Venom Evolution Laboratory, School of Biological Sciences, The University of Queensland, St. Lucia, Queensland, Australia Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Mahdokht
authors.initials: M
authors.lastname: Jouiaei
authors.affiliation: Department of Ecology, Evolution and Behavior, The Alexander Silberman Institute for Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Kartik
authors.initials: K
authors.lastname: Sunagar
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Aya
authors.initials: A
authors.lastname: Federman Gross
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Holger
authors.initials: H
authors.lastname: Scheib
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
authors.affiliation: Department of Ecology, Evolution and Behavior, The Alexander Silberman Institute for Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel bgfry@uq.edu.au yehu.moran@mail.huji.ac.il.
authors.forename: Yehu
authors.initials: Y
authors.lastname: Moran
authors.affiliation: Venom Evolution Laboratory, School of Biological Sciences, The University of Queensland, St. Lucia, Queensland, Australia Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia bgfry@uq.edu.au yehu.moran@mail.huji.ac.il.
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Fry
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003001:Cloning, Molecular; D003064:Cnidarian Venoms / Q000737:chemistry / Q000235:genetics*; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry / Q000235:genetics*; D010802:Phylogeny; D011188:Potassium / Q000737:chemistry*; D011487:Protein Conformation; D012615:Sea Anemones / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D012964:Sodium / Q000737:chemistry*
chemical_list: D003064:Cnidarian Venoms; D009498:Neurotoxins; D012964:Sodium; D011188:Potassium
keywords: Cnidaria; disulfide-rich toxins; phylogeny; positive selection; potassium channel toxins; sodium channel toxins