PHAB toxins: a unique family of predatory sea anemone toxins evolving via intra-gene concerted evolution defines a new peptide fold

Cell Mol Life Sci. 2018 Dec;75(24):4511-4524. doi: 10.1007/s00018-018-2897-6. Epub 2018 Aug 14.


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.

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cnidarian Venoms / chemistry*
  • Cnidarian Venoms / genetics
  • Cnidarian Venoms / metabolism
  • Evolution, Molecular
  • Models, Molecular
  • Peptides / chemistry*
  • Peptides / genetics
  • Peptides / metabolism
  • Potassium Channels, Voltage-Gated / chemistry*
  • Potassium Channels, Voltage-Gated / genetics
  • Potassium Channels, Voltage-Gated / metabolism
  • Protein Conformation
  • Protein Folding
  • Sea Anemones / chemistry*
  • Sea Anemones / genetics
  • Sea Anemones / metabolism
  • Transcriptome


  • Cnidarian Venoms
  • Peptides
  • Potassium Channels, Voltage-Gated