title: Computational and experimental characterization of dVHL establish a Drosophila model of VHL syndrome.
abstract: The von Hippel-Lindau (VHL) cancer syndrome is associated with mutations in the VHL gene. The pVHL protein is involved in response to changes in oxygen availability as part of an E3-ligase that targets the Hypoxia-Inducible Factor for degradation. pVHL has a molten globule configuration with marginal thermodynamic stability. The cancer-associated mutations further destabilize it. The Drosophila homolog, dVHL, has relatively low sequence similarity to pVHL, and is also involved in regulating HIF1-α. Using in silico, in vitro and in vivo approaches we demonstrate high similarity between the structure and function of dVHL and pVHL. These proteins have a similar fold, secondary and tertiary structures, as well as thermodynamic stability. Key functional residues in dVHL are evolutionary conserved. This structural homology underlies functional similarity of both proteins, evident by their ability to bind their reciprocal partner proteins, and by the observation that transgenic pVHL can fully maintain normal dVHL-HIF1-α downstream pathways in flies. This novel transgenic Drosophila model is thus useful for studying the VHL syndrome, and for testing drug candidates to treat it.
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Merav D
authors.initials: MD
authors.lastname: Shmueli
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Lee
authors.initials: L
authors.lastname: Schnaider
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Herzog
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Gazit
authors.affiliation: Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Segal
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D017124:Conserved Sequence; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D019143:Evolution, Molecular; D005123:Eye / Q000473:pathology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013347:Subcellular Fractions / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000737:chemistry; D006623:von Hippel-Lindau Disease / Q000378:metabolism* / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; C000601277:Vhl protein, Drosophila; D049452:Green Fluorescent Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human