title: Differential evolution and neofunctionalization of snake venom metalloprotease domains.
abstract: Snake venom metalloproteases (SVMP) are composed of five domains: signal peptide, propeptide, metalloprotease, disintegrin, and cysteine-rich. Secreted toxins are typically combinatorial variations of the latter three domains. The SVMP-encoding genes of Psammophis mossambicus venom are unique in containing only the signal and propeptide domains. We show that the Psammophis SVMP propeptide evolves rapidly and is subject to a high degree of positive selection. Unlike Psammophis, some species of Echis express both the typical multidomain and the unusual monodomain (propeptide only) SVMP, with the result that a lower level of variation is exerted upon the latter. We showed that most mutations in the multidomain Echis SVMP occurred in the protease domain responsible for proteolytic and hemorrhagic activities. The cysteine-rich and disintegrin-like domains, which are putatively responsible for making the P-III SVMPs more potent than the P-I and P-II forms, accumulate the remaining variation. Thus, the binding sites on the molecule's surface are evolving rapidly whereas the core remains relatively conserved. Bioassays conducted on two post-translationally cleaved novel proline-rich peptides from the P. mossambicus propeptide domain showed them to have been neofunctionalized for specific inhibition of mammalian a7 neuronal nicotinic acetylcholine receptors. We show that the proline rich postsynaptic specific neurotoxic peptides from Azemiops feae are the result of convergent evolution within the precursor region of the C-type natriuretic peptide instead of the SVMP. The results of this study reinforce the value of studying obscure venoms for biodiscovery of novel investigational ligands.
authors.affiliation: ‡Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072 Australia;
authors.forename: Andreas
authors.initials: A
authors.lastname: Brust
authors.forename: Kartik
authors.initials: K
authors.lastname: Sunagar
authors.forename: Eivind A B
authors.initials: EA
authors.lastname: Undheim
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
authors.forename: Daryl C
authors.initials: DC
authors.lastname: Yang
authors.forename: Dary C
authors.initials: DC
authors.lastname: Yang
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Casewell
authors.forename: Timothy N W
authors.initials: TN
authors.lastname: Jackson
authors.forename: Ivan
authors.initials: I
authors.lastname: Koludarov
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Hodgson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Glenn F
authors.initials: GF
authors.lastname: King
authors.forename: Agostinho
authors.initials: A
authors.lastname: Antunes
authors.forename: Iwan
authors.initials: I
authors.lastname: Hendrikx
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Fry
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019143:Evolution, Molecular; D006801:Humans; D045726:Metalloproteases / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010802:Phylogeny; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011978:Receptors, Nicotinic / Q000378:metabolism; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D012910:Snake Venoms / Q000145:classification / Q000201:enzymology / Q000235:genetics*; D013045:Species Specificity; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D018733:Nicotinic Antagonists; D010455:Peptides; D011498:Protein Precursors; D011978:Receptors, Nicotinic; D012910:Snake Venoms; D064569:alpha7 Nicotinic Acetylcholine Receptor; D045726:Metalloproteases