Novel venom proteins produced by differential domain-expression strategies in beaded lizards and gila monsters (genus Heloderma)

  • Fry B
  • Roelants K
  • Winter K
 et al. 
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Abstract

The origin and evolution of venom proteins in helodermatid lizards were investigated by multidisciplinary techniques. Our analyses elucidated novel toxin types resultant from three unique domain-expression processes: 1) The first full-length sequences of lethal toxin isoforms (helofensins) revealed this toxin type to be constructed by an ancestral monodomain, monoproduct gene (beta-defensin) that underwent three tandem domain duplications to encode a tetradomain, monoproduct with a possible novel protein fold; 2) an ancestral monodomain gene (encoding a natriuretic peptide) was medially extended to become a pentadomain, pentaproduct through the additional encoding of four tandemly repeated proline-rich peptides (helokinestatins), with the five discrete peptides liberated from each other by posttranslational proteolysis; and 3) an ancestral multidomain, multiproduct gene belonging to the vasoactive intestinal peptide (VIP)/glucagon family being mutated to encode for a monodomain, monoproduct (exendins) followed by duplication and diversification into two variant classes (exendins 1 and 2 and exendins 3 and 4). Bioactivity characterization of exendin and helokinestatin elucidated variable cardioactivity between isoforms within each class. These results highlight the importance of utilizing evolutionary-based search strategies for biodiscovery and the virtually unexplored potential of lizard venoms in drug design and discovery.

Author-supplied keywords

  • Adaptive evolution
  • Byetta
  • Exendin
  • Heloderma
  • Molecular evolution
  • Protein
  • Toxin
  • Venom

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Authors

  • Hang Fai KwokUniversity of Macau

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  • Bryan G. Fry

  • Kim Roelants

  • Kelly Winter

  • Wayne C. Hodgson

  • Laura Griesman

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