Novel Venom Proteins Produced by Differential Domain-Expression Strategies in Beaded Lizards and Gila Monsters (genus Heloderma)

• Published in: Molecular biology and evolution 2010-02, Vol.27 (2), p.395-407
• Main Authors: Fry, Bryan G., Roelants, Kim, Winter, Kelly, Hodgson, Wayne C., Griesman, Laura, Kwok, Hang Fai, Scanlon, Denis, Karas, John, Shaw, Chris, Wong, Lily, Norman, Janette A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Aorta, Thoracic - drug effects; Bayes Theorem; Bradykinin B2 Receptor Antagonists; DNA, Complementary; Evolution; Female; Gene expression; Guinea Pigs; Ileum - drug effects; In Vitro Techniques; Lizards; Lizards - metabolism; Male; Molecular biology; Molecular Sequence Data; Mutation; Peptides; Peptides - chemistry; Peptides - classification; Peptides - genetics; Peptides - pharmacology; Phylogeny; Proteins; Proteins - chemistry; Proteins - classification; Proteins - genetics; Proteins - pharmacology; Rats; Rats, Sprague-Dawley; Reptiles & amphibians; Sequence Homology, Amino Acid; Toxins; Venoms - chemistry; Venoms - classification; Venoms - genetics; Venoms - pharmacology
• ISSN: 0737-4038; 1537-1719
• DOI: 10.1093/molbev/msp251

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.