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

Bryan G Fry, Kim Roelants, Kelly Lee Winter, Wayne Clarence Hodgson, Laura Griesman, Hang Fai Kwok, Denis Scanlon, John Karas, Chris Shaw, Lily Wong, Janette A Norman

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59 Citations (Scopus)


The origin and evolution of venom proteins in helodermatid lizards was investigated by multidisciplinary techniques. Our analyses elucidated novel toxin types resultant from three unique domain-expression processes: i) the first full-length sequences of Lethal Toxin isoforms (helofensins) revealed this toxin type to be constructed by an ancestral mono-domain, mono-product gene (beta-defensin) which underwent three tandem domain duplications to encode a tetra-domain, mono-product with a possible novel protein fold; (ii) an ancestral mono-domain gene (encoding a natriuretic peptide) was medially extended to become a penta-domain, penta-product through the additional encoding of four tandemly repeated proline-rich peptides (helokinestatins), with the five discrete peptides liberated from each other by post-translational proteolysis; and iii) an ancestral multi-domain, multi-product gene belonging to the VIP/glucagon family being mutated to encode for a mono-domain, mono-product (exendins) followed by duplication and diversification into two variant classes (exendins 1 2 and exendins 3 4). Bioactivity characterization of exendin and helokinestatin elucidated variable cardioactivity between isofroms within each class. These results highlight the importance of utilising evolutionary-based search strategies for biodiscovery and the virtually unexplored potential of lizard venoms in drug design and discovery.
Original languageEnglish
Pages (from-to)395 - 407
Number of pages12
JournalMolecular Biology and Evolution
Publication statusPublished - 2010

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