Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered

Karunatilleke, Nadun C.; Fast, Courtney S.; Ngo, Vy; Brickenden, Anne; Duennwald, Martin L.; Konermann, Lars; Choy, Wing-Yiu

doi:10.3390/ijms22147434

Open AccessArticle

Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered

by

Nadun C. Karunatilleke

¹

,

Courtney S. Fast

²,

Vy Ngo

³

,

Anne Brickenden

¹,

Martin L. Duennwald

³,

Lars Konermann

^1,2,* and

Wing-Yiu Choy

^1,2,*

¹

Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada

²

Department of Chemistry, The University of Western Ontario, London, ON N6A 5B7, Canada

³

Department of Pathology and Laboratory Medicine, The University of Western Ontario, London, ON N6A 5C1, Canada

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2021, 22(14), 7434; https://doi.org/10.3390/ijms22147434

Submission received: 18 June 2021 / Revised: 6 July 2021 / Accepted: 8 July 2021 / Published: 11 July 2021

(This article belongs to the Special Issue Frontiers in Protein Structure Research)

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Abstract

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.

Keywords: oxidative stress; Nrf2; Keap1; nuclear magnetic resonance spectroscopy; hydrogen/deuterium exchange; mass spectrometry; circular dichroism; intrinsically disordered

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MDPI and ACS Style

Karunatilleke, N.C.; Fast, C.S.; Ngo, V.; Brickenden, A.; Duennwald, M.L.; Konermann, L.; Choy, W.-Y. Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered. Int. J. Mol. Sci. 2021, 22, 7434. https://doi.org/10.3390/ijms22147434

AMA Style

Karunatilleke NC, Fast CS, Ngo V, Brickenden A, Duennwald ML, Konermann L, Choy W-Y. Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered. International Journal of Molecular Sciences. 2021; 22(14):7434. https://doi.org/10.3390/ijms22147434

Chicago/Turabian Style

Karunatilleke, Nadun C., Courtney S. Fast, Vy Ngo, Anne Brickenden, Martin L. Duennwald, Lars Konermann, and Wing-Yiu Choy. 2021. "Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered" International Journal of Molecular Sciences 22, no. 14: 7434. https://doi.org/10.3390/ijms22147434

APA Style

Karunatilleke, N. C., Fast, C. S., Ngo, V., Brickenden, A., Duennwald, M. L., Konermann, L., & Choy, W.-Y. (2021). Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered. International Journal of Molecular Sciences, 22(14), 7434. https://doi.org/10.3390/ijms22147434

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Nrf2, the Major Regulator of the Cellular Oxidative Stress Response, is Partially Disordered

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