Münick Philipp, Strubel Alexander, Balourdas Dimitrios-Ilias, Funk Julianne S, Mernberger Marco, Osterburg Christian, Dreier Birgit, Schaefer Jonas V, Tuppi Marcel, Yüksel Büşra, Schäfer Birgit, Knapp Stefan, Plückthun Andreas, Stiewe Thorsten, Joerger Andreas C, Dötsch Volker
Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.
Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.
Nat Struct Mol Biol. 2025 May;32(5):790-801. doi: 10.1038/s41594-024-01456-7. Epub 2025 Jan 9.
Infection of cells with high-risk strains of the human papillomavirus (HPV) causes cancer in various types of epithelial tissue. HPV infections are responsible for ~4.5% of all cancers worldwide. Tumorigenesis is based on the inactivation of key cellular control mechanisms by the viral proteins E6 and E7. The HPV E6 protein interacts with the cellular E3 ligase E6AP, and this complex binds to the p53 DNA-binding domain, which results in degradation of p53. Inhibition of this interaction has the potential to reactivate p53, thus preventing oncogenic transformation. Here we describe the characterization of a designed ankyrin repeat protein that binds to the same site as the HPV E6 protein, thereby displacing the E3 ligase and stabilizing p53. Interaction with the designed ankyrin repeat protein does not affect p53 DNA binding or the crucial MDM2 negative feedback loop but reactivates a p53-dependent transcriptional program in HeLa (HPV18-positive) and SiHa (HPV16-positive) cells, suggesting a potential therapeutic use.
人乳头瘤病毒（HPV）高危型毒株感染细胞会在各类上皮组织中引发癌症。HPV感染导致了全球约4.5%的癌症发生。肿瘤发生是基于病毒蛋白E6和E7对关键细胞控制机制的失活作用。HPV E6蛋白与细胞E3连接酶E6AP相互作用，该复合物与p53的DNA结合结构域结合，导致p53降解。抑制这种相互作用有可能重新激活p53，从而防止致癌转化。在此，我们描述了一种设计的锚蛋白重复序列蛋白的特性，该蛋白与HPV E6蛋白结合于同一位点，从而取代E3连接酶并稳定p53。与设计的锚蛋白重复序列蛋白相互作用不会影响p53的DNA结合或关键的MDM2负反馈环，但能在HeLa（HPV18阳性）和SiHa（HPV16阳性）细胞中重新激活p53依赖的转录程序，提示其具有潜在的治疗用途。
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