title: Functional and structural diversification of the Anguimorpha lizard venom system.
abstract: Venom has only been recently discovered to be a basal trait of the Anguimorpha lizards. Consequently, very little is known about the timings of toxin recruitment events, venom protein molecular evolution, or even the relative physical diversifications of the venom system itself. A multidisciplinary approach was used to examine the evolution across the full taxonomical range of this ∼130 million-year-old clade. Analysis of cDNA libraries revealed complex venom transcriptomes. Most notably, three new cardioactive peptide toxin types were discovered (celestoxin, cholecystokinin, and YY peptides). The latter two represent additional examples of convergent use of genes in toxic arsenals, both having previously been documented as components of frog skin defensive chemical secretions. Two other novel venom gland-overexpressed modified versions of other protein frameworks were also recovered from the libraries (epididymal secretory protein and ribonuclease). Lectin, hyaluronidase, and veficolin toxin types were sequenced for the first time from lizard venoms and shown to be homologous to the snake venom forms. In contrast, phylogenetic analyses demonstrated that the lizard natriuretic peptide toxins were recruited independently of the form in snake venoms. The de novo evolution of helokinestatin peptide toxin encoding domains within the lizard venom natriuretic gene was revealed to be exclusive to the helodermatid/anguid subclade. New isoforms were sequenced for cysteine-rich secretory protein, kallikrein, and phospholipase A(2) toxins. Venom gland morphological analysis revealed extensive evolutionary tinkering. Anguid glands are characterized by thin capsules and mixed glands, serous at the bottom of the lobule and mucous toward the apex. Twice, independently this arrangement was segregated into specialized serous protein-secreting glands with thick capsules with the mucous lobules now distinct (Heloderma and the Lanthanotus/Varanus clade). The results obtained highlight the importance of utilizing evolution-based search strategies for biodiscovery and emphasize the largely untapped drug design and development potential of lizard venoms.
authors.affiliation: Venomics Research Laboratory, Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, Victoria, Australia. bgf@unimelb.edu.au
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Fry
authors.forename: Kelly
authors.initials: K
authors.lastname: Winter
authors.forename: Janette A
authors.initials: JA
authors.lastname: Norman
authors.forename: Kim
authors.initials: K
authors.lastname: Roelants
authors.forename: Rob J A
authors.initials: RJ
authors.lastname: Nabuurs
authors.forename: Matthias J P
authors.initials: MJ
authors.lastname: van Osch
authors.forename: Wouter M
authors.initials: WM
authors.lastname: Teeuwisse
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weerd
authors.forename: Judith E
authors.initials: JE
authors.lastname: McNaughtan
authors.forename: Hang Fai
authors.initials: HF
authors.lastname: Kwok
authors.forename: Holger
authors.initials: H
authors.lastname: Scheib
authors.forename: Laura
authors.initials: L
authors.lastname: Greisman
authors.forename: Elazar
authors.initials: E
authors.lastname: Kochva
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Miller
authors.forename: Fan
authors.initials: F
authors.lastname: Gao
authors.forename: John
authors.initials: J
authors.lastname: Karas
authors.forename: Denis
authors.initials: D
authors.lastname: Scanlon
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.forename: Sanjaya
authors.initials: S
authors.lastname: Kuruppu
authors.forename: Chris
authors.initials: C
authors.lastname: Shaw
authors.forename: Lily
authors.initials: L
authors.lastname: Wong
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Hodgson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019143:Evolution, Molecular; D015723:Gene Library; D006801:Humans; D008116:Lizards / Q000033:anatomy & histology / Q000145:classification / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D010802:Phylogeny; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016415:Sequence Alignment; D014688:Venoms / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D011498:Protein Precursors; D014688:Venoms; C527846:helokinestatin