title: Novel venom proteins produced by differential domain-expression strategies in beaded lizards and gila monsters (genus Heloderma).
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia. bgf@unimelb.edu.au
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Fry
authors.forename: Kim
authors.initials: K
authors.lastname: Roelants
authors.forename: Kelly
authors.initials: K
authors.lastname: Winter
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Hodgson
authors.forename: Laura
authors.initials: L
authors.lastname: Griesman
authors.forename: Hang Fai
authors.initials: HF
authors.lastname: Kwok
authors.forename: Denis
authors.initials: D
authors.lastname: Scanlon
authors.forename: John
authors.initials: J
authors.lastname: Karas
authors.forename: Chris
authors.initials: C
authors.lastname: Shaw
authors.forename: Lily
authors.initials: L
authors.lastname: Wong
authors.forename: Janette A
authors.initials: JA
authors.lastname: Norman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001499:Bayes Theorem; D065094:Bradykinin B2 Receptor Antagonists; D018076:DNA, Complementary; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008116:Lizards / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000494:pharmacology; D010802:Phylogeny; D011506:Proteins / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017386:Sequence Homology, Amino Acid; D014688:Venoms / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000494:pharmacology
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D018076:DNA, Complementary; D010455:Peptides; D011506:Proteins; D014688:Venoms; C527846:helokinestatin