Data from: Computational and experimental characterization of dVHL establish a Drosophila model of VHL syndrome

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.希佩尔-林道（von Hippel-Lindau, VHL）癌症综合征与VHL基因的突变密切相关。pVHL蛋白作为靶向缺氧诱导因子（Hypoxia-Inducible Factor, HIF）使其降解的E3泛素连接酶（E3-ligase）复合物的组分之一，参与氧浓度变化的感知与应答过程。pVHL蛋白呈现熔球态构象，热力学稳定性较低；癌症相关突变会进一步削弱其稳定性。果蝇同源蛋白dVHL与pVHL的序列相似性相对较低，但同样参与调控HIF1-α。本研究通过计算机模拟实验（in silico）、体外实验（in vitro）与体内实验（in vivo）三种方法，证实dVHL与pVHL在结构与功能上具有高度相似性：二者具有相似的折叠模式、二级与三级结构，且热力学稳定性相近。dVHL中的关键功能残基在进化上具有保守性。这种结构同源性是二者功能相似的基础，具体体现为二者均可结合各自的互作伴侣蛋白，且转基因pVHL能够完全维持果蝇体内正常的dVHL-HIF1-α下游通路。因此，该新型转基因果蝇模型可用于VHL综合征的相关研究，同时也可用于筛选治疗该疾病的候选药物。