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.
Highlights
The von Hippel-Lindau (VHL) syndrome is a rare hereditary cancer, associated with mutations in the VHL tumor suppressor gene
The structure of human pVHL has already been elucidated by crystallographic methods, this has yet to be achieved for Drosophila Drosophila VHL (dVHL)
Flies have greatly facilitated drug screening [64]. Such studies have shown that the Drosophila VHL can interact with Drosophila Elongin C in vitro [40,41] and form a complex with the human Elongin CB complex and mouse Rbx-1, but not with the human Elongin A
Summary
The von Hippel-Lindau (VHL) syndrome is a rare hereditary cancer, associated with mutations in the VHL tumor suppressor gene. The pVHL tumor suppressor protein is the substrate recognition subunit of a complex, comprising pVHL as well as Elongin C and B, termed VCB complex [4,5,6]. This complex functions as part of an SCFlike ubiquitin-ligase that promotes the degradation of target proteins required for growth and vascularization of solid tumors [7,8,9]. The best known target genes of HIF encode proteins involved in glycolysis, glucose transport (Glut-1), angiogenesis (vascular endothelial growth factor (VEGF)) and erythropoiesis (erythropoietin), i.e., proteins that mediate the cellular response and adaptation to hypoxic conditions [21,22,23,24]. The short isoform of pVHL is localized primarily to the nucleus whereas the long isoform is more frequently associated tightly with microtubules in the cytoplasm [32,33]
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