Karunatilleke Nadun C, Fast Courtney S, Ngo Vy, Brickenden Anne, Duennwald Martin L, Konermann Lars, Choy Wing-Yiu
Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
Department of Chemistry, The University of Western Ontario, London, ON N6A 5B7, Canada.
Int J Mol Sci. 2021 Jul 11;22(14):7434. doi: 10.3390/ijms22147434.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription regulator that plays a pivotal role in coordinating the cellular response to oxidative stress. Through interactions with other proteins, such as Kelch-like ECH-associated protein 1 (Keap1), CREB-binding protein (CBP), and retinoid X receptor alpha (RXRα), Nrf2 mediates the transcription of cytoprotective genes critical for removing toxicants and preventing DNA damage, thereby playing a significant role in chemoprevention. Dysregulation of Nrf2 is linked to tumorigenesis and chemoresistance, making Nrf2 a promising target for anticancer therapeutics. However, despite the physiological importance of Nrf2, the molecular details of this protein and its interactions with most of its targets remain unknown, hindering the rational design of Nrf2-targeted therapeutics. With this in mind, we used a combined bioinformatics and experimental approach to characterize the structure of full-length Nrf2 and its interaction with Keap1. Our results show that Nrf2 is partially disordered, with transiently structured elements in its Neh2, Neh7, and Neh1 domains. Moreover, interaction with the Kelch domain of Keap1 leads to protection of the binding motifs in the Neh2 domain of Nrf2, while the rest of the protein remains highly dynamic. This work represents the first detailed structural characterization of full-length Nrf2 and provides valuable insights into the molecular basis of Nrf2 activity modulation in oxidative stress response.
核因子红细胞2相关因子2（Nrf2）是一种转录调节因子，在协调细胞对氧化应激的反应中起关键作用。通过与其他蛋白质相互作用，如 Kelch样ECH相关蛋白1（Keap1）、CREB结合蛋白（CBP）和视黄酸X受体α（RXRα），Nrf2介导对清除毒物和预防DNA损伤至关重要的细胞保护基因的转录，从而在化学预防中发挥重要作用。Nrf2的失调与肿瘤发生和化疗耐药性有关，使Nrf2成为抗癌治疗的一个有前景的靶点。然而，尽管Nrf2具有重要的生理意义，但其分子细节及其与大多数靶点的相互作用仍不清楚，这阻碍了针对Nrf2的治疗药物的合理设计。考虑到这一点，我们采用生物信息学和实验相结合的方法来表征全长Nrf2及其与Keap1的相互作用结构。我们的结果表明，Nrf2部分无序，在其Neh2、Neh7和Neh1结构域中有短暂的结构化元件。此外，与Keap1的Kelch结构域相互作用可保护Nrf2的Neh2结构域中的结合基序，而蛋白质的其余部分仍保持高度动态。这项工作代表了全长Nrf2的首次详细结构表征，并为氧化应激反应中Nrf2活性调节的分子基础提供了有价值的见解。
