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Type: Journal article
Title: Novel venom proteins produced by differential domain-expression strategies in beaded lizards and gila monsters (genus Heloderma)
Author: Fry, B.
Roelants, K.
Winter, K.
Hodgson, W.
Griesman, L.
Kwok, H.
Scanlon, D.
Karas, J.
Shaw, C.
Wong, L.
Norman, J.
Citation: Molecular Biology and Evolution, 2010; 27(2):395-407
Publisher: Oxford Univ Press
Issue Date: 2010
ISSN: 0737-4038
Statement of
Bryan G. Fry, Kim Roelants, Kelly Winter, Wayne C. Hodgson, Laura Griesman, Hang Fai Kwok, Denis Scanlon, John Karas, Chris Shaw, Lily Wong and Janette A. Norman
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.
Keywords: Venom; adaptive evolution; molecular evolution; protein; toxin; Heloderma; byetta; exendin
Rights: © The Author 2009. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved.
RMID: 0020106193
DOI: 10.1093/molbev/msp251
Appears in Collections:Medical Sciences publications

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