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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.; Henriques, S.T.; Smith, J.J.; Cristofori-Armstrong, B.; Dekan, Z.; Boughton, B.A.; Alewood, P.F.; Tytgat, J.; King, G.F.; 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(24): 4511-4524.
In: Cellular and molecular life sciences. ISSN 1420-682X; e-ISSN 1420-9071
Peer reviewed article  

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Author keywords
    Neurotoxin; Ion channel; Mass spectrometry imaging; 3D structure;Concerted evolution; Extreme resolution mass spectrometry imaging;On-tissue reduction alkylation

Auteurs  Top 
  • Madio, B.
  • Peigneur, S.
  • Chin, Y.K.Y.
  • Hamilton, B.
  • Henriques, S.T.
  • Smith, J.J.
  • Cristofori-Armstrong, B.
  • Dekan, Z.
  • Boughton, B.A.
  • Alewood, P.F.
  • Tytgat, J.
  • King, G.F.
  • Undheim, E.A.B.

    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.

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