Journal
MOLECULAR BIOLOGY AND EVOLUTION
Volume 27, Issue 2, Pages 395-407Publisher
OXFORD UNIV PRESS
DOI: 10.1093/molbev/msp251
Keywords
venom; adaptive evolution; molecular evolution; protein; toxin; Heloderma; byetta; exendin
Funding
- Australian Academy of Science
- Australian French Association for Science and Technology
- Australia and Pacific Science Foundation
- CASS Foundation
- International Human Frontiers Science Program Organisation
- Netherlands Organisation for Scientific Research
- University of Melbourne
- Department of Innovation, Industry and Regional Development Victoria
- Australian Research Council
- Australian Government Department of Education, Science, and Training/EGIDE International Science Linkages
- FWO-Vlaanderen
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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.
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