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.冯·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）并介导其降解的E3泛素连接酶复合物的组成部分，参与氧浓度变化的应答调控过程。pVHL具有熔球态构象，热力学稳定性有限，癌症相关突变会进一步降低其稳定性。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的相关通路。本研究通过计算机模拟（in silico）、体外（in vitro）及体内（in vivo）实验方法，证实dVHL与pVHL在结构与功能上具有高度相似性：二者拥有相似的折叠模式、二级与三级结构，且热力学稳定性相近。dVHL中的关键功能残基具有进化保守性。这种结构同源性是二者功能相似的分子基础，具体体现为二者能够结合各自的相互作用伴侣蛋白，且转基因表达的pVHL可完全维持果蝇体内正常的dVHL-HIF1-α下游信号通路。因此，该新型转基因果蝇模型可用于VHL综合征的相关研究，以及该疾病治疗候选药物的筛选与验证。