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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, B., Peigneur, S., Chin, Y.K.Y., Hamilton, B.R., Henriques, S.T., Smith, J.J., Cristofori-Armstrong, B., Dekan, Z., Boughton, B.A.ORCID: 0000-0001-6342-9814, Alewood, P.F., Tytgat, J., King, G.F. and Undheim, E.A.B. (2018) PHAB toxins: A unique family of predatory sea anemone toxins evolving via intra-gene concerted evolution defines a new peptide fold. Cellular and Molecular Life Sciences, 75 . pp. 4511-4524.

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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.

Item Type: Journal Article
Publisher: Springer
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