Novel venom proteins produced by differential domain-expression strategies in beaded lizards and gila monsters (genus Heloderma).
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.
Fry
Bryan G
BG
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia. bgf@unimelb.edu.au
Roelants
Kim
K
Winter
Kelly
K
Hodgson
Wayne C
WC
Griesman
Laura
L
Kwok
Hang Fai
HF
Scanlon
Denis
D
Karas
John
J
Shaw
Chris
C
Wong
Lily
L
Norman
Janette A
JA
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
D065094:Bradykinin B2 Receptor Antagonists; D018076:DNA, Complementary; D010455:Peptides; D011506:Proteins; D014688:Venoms; C527846:helokinestatin