NDLI: Differential evolution and neofunctionalization of snake venom metalloprotease domains.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Brust, Andreas Sunagar, Kartik Undheim, Eivind A. B. Vetter, Irina Yang, Daryl C. Yang, Dary C. Casewell, Nicholas R. Jackson, Timothy N. W. Koludarov, Ivan Alewood, Paul F. Hodgson, Wayne C. Lewis, Richard J. King, Glenn F. Antunes, Agostinho Hendrikx, Iwan Fry, Bryan G.
Description	Author Affiliation: Brust A ( Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072 Australia)
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.
File Format	HTM / HTML
ISSN	15359476
e-ISSN	15359484
DOI	10.1074/mcp.M112.023135
Journal	Molecular & Cellular Proteomics
Issue Number	3
Volume Number	12
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2013-03-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Proteomics Evolution, Molecular Metalloproteases Genetics Protein Precursors Snake Venoms Amino Acid Sequence Animals Binding Sites Cell Line, Tumor Dose-response Relationship, Drug Classification Metabolism Models, Molecular Molecular Sequence Data Mutation Nicotinic Antagonists Pharmacology Peptides Phylogeny Chemistry Protein Structure, Tertiary Receptors, Nicotinic Selection, Genetic Sequence Homology, Amino Acid Enzymology Species Specificity Alpha7 Nicotinic Acetylcholine Receptor Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Medicine Analytical Chemistry Molecular Biology Biochemistry

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