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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Allosteric effects in the marginally stable von Hippel-Lindau tumor suppressor protein and allostery-based rescue mutant design
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Allosteric effects in the marginally stable von Hippel-Lindau tumor suppressor protein and allostery-based rescue mutant design

机译：边缘稳定的von Hippel-Lindau抑癌蛋白的变构作用和基于变构的抢救突变体设计

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摘要

Many multifunctional tumor suppressor proteins have low stability, a property linked to cancer development. The von Hippel-Lindau tumor suppressor protein (pVHL) is one of these proteins. pVHL forms part of the E3 ubiquitin ligase complex that regulates the degradation of the hypoxia-inducible factor (HIF). Under native conditions, free pVHL is a molten globule, but it is stabilized in the E3 complex. By using molecular dynamics simulations, we observed that the interface between the two pVHL domains is the least stable region in unbound pVHL. We designed five stable mutants: one with a mutation at the interdomain interface and the others in the α- or β-domains. Experimentally, type 2B pVHL disease mutant Y98N at the HIF binding site was shown to destabilize pVHL and decrease its binding affinity to HIF. Our simulations showed that the decrease in pVHL stability and binding affinity are allosterically regulated. The mutations designed to stabilize unbound wild-type pVHL, which are away from the elongin C and HIF binding sites, successfully stabilized the Y98N pVHL-elongin C complex and lowered the binding free energy of pVHL with HIF. Our results indicated both the enthalpic and dynamic allosteric components between the elongin C and HIF binding sites in pVHL, in the α- and β-domains, respectively, mediated by the interdomain interface and linker. Drugs mimicking the allosteric effects of these mutants may rescue pVHL function in von Hippel-Lindau disease.
机译：许多多功能肿瘤抑制蛋白的稳定性很低，这是与癌症发展有关的特性。 von Hippel-Lindau抑癌蛋白（pVHL）是这些蛋白之一。 pVHL形成E3泛素连接酶复合物的一部分，该复合物调节缺氧诱导因子（HIF）的降解。在自然条件下，游离的pVHL是一个熔融小球，但在E3复合物中稳定。通过使用分子动力学模拟，我们观察到两个pVHL域之间的界面是未结合的pVHL中最不稳定的区域。我们设计了五个稳定的突变体：一个突变体在域间界面处突变，另一个在α-或β-结构域中。实验表明，HIF结合位点的2B型pVHL疾病突变体Y98N会使pVHL不稳定并降低其对HIF的结合亲和力。我们的模拟表明pVHL稳定性和结合亲和力的下降是变构调节的。旨在稳定未结合的野生型pVHL的突变远离延伸蛋白C和HIF结合位点，成功稳定了Y98N pVHL-延伸蛋白C复合物，并降低了pVHL与HIF的结合自由能。我们的结果表明，pVHL中延伸蛋白C和HIF结合位点之间的焓变和动态变构成分，分别在域间界面和连接子介导的α域和β域中。模仿这些突变体的变构作用的药物可以挽救von Hippel-Lindau病的pVHL功能。

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