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PHAB toxins: a unique family of predatory sea anemone toxins evolving via intra-gene concerted evolution defines a new peptide fold
- Madio, Bruno, Peigneur, Steve, Chin, Yanni K. Y., Hamilton, Brett R., Henriques, Sónia Troeira, Smith, Jennifer J., Cristofori-Armstrong, Ben, Dekan, Zoltan, Boughton, Berin A., Alewood, Paul F., Tytgat, Jan, King, Glenn F., Undheim, Eivind A. B.
- Cellular and molecular life sciences 2018 v.75 no.24 pp. 4511-4524
- Anthozoa, ancestry, bioactive compounds, bioassays, concerted evolution, genes, germplasm conservation, image analysis, mass spectrometry, peptides, potassium channels, secretion, toxins, venoms
- 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 (KV) 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 KV 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.