Two-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism

Tong, Kit I.; Kobayashi, Akira; Katsuoka, Fumiki; Yamamoto, Masayuki

doi:10.1515/bc.2006.164

Cited by 480Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressNF-κB Signaling Pathways

Two-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism

Tong, Kit I., Kobayashi, Akira, Katsuoka, Fumiki, Yamamoto, Masayuki·2006·Biological Chemistry

DOI 10.1515/bc.2006.164

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Abstract

Cells are equipped with a number of transcriptional factors that safeguard against various environmental insults. Proteasomal protein degradation plays an important role in the Keap1-Nrf2 cytoprotection system, with molecular machinery similar to that for other environmental defense systems such as inflammatory and hypoxic responses. While Nrf2 protein stabilization is known to be redox-sensitive, the transcription factors NF-kappaB and HIF-1alpha for inflammatory and hypoxic responses, respectively, are also influenced by the cellular redox conditions. In this review we present the recently proposed two-site substrate recognition model of the Keap1-Nrf2 system, which regulates the cellular responses against oxidative and xenobiotic stresses. The implications of two destructive motifs in Nrf2, the ETGE and DLG motifs, which appear to function as a hinge and latch attenuating Keap1 activity in different redox states, are discussed.

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The Neh2 domain is a redox-sensitive degron that negatively regulates Nrf2 activity and contains DLG and ETGE motifs to which Keap1 binds, as well as lysine residues targeted for ubiquitination.
“The N-terminal Neh2 domain is a redox-sensitive degron that negatively regulates Nrf2 activity and contains two highly conserved 29DLG31 and 79ETGE82 motifs to which Keap1 binds, as well as seven lysine residues that are targets for ubiquitination by the Cul3 E3 ubiquitin ligase [49,65].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [65]
Keap1 recruits Nrf2 first through binding of one Keap1 molecule to the high-affinity ETGE motif, and subsequent binding of the other Keap1 molecule at the low-affinity DLG motif locks Nrf2 in place for ubiquitination by Cul3 and degradation by the 26S proteasome.
“Keap1 recruits Nrf2 first through the binding of one Keap1 molecule to the high-affinity ETGE motif within the Nrf2’s Neh2 domain. Subsequent binding of the other Keap1 molecule at the low-affinity DLG motif locks Nrf2 in place by orienting the lysine residues within Neh2 in the correct position for ubiquitination by Cul3 and degradation by the 26S proteasome [58,65].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [65]

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Simon, M. C., Vaughn, D. J., Rathmell, W. K., & Ács, G. (2021) · PubMed · doi:10.17615/5j9w-fa07 · Cited by 28 · see citing works

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Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice.
Komatsu, M., Waguri, S., Koike, M., Sou, Y.-S., Ueno, T., Hara, T., Mizushima, N., Iwata, J.-I., Ezaki, J., Murata, S., et al. (2007) · Cell · doi:10.1016/j.cell.2007.10.035 · Cited by 2,124 · see citing works
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NRF2 and the Hallmarks of Cancer
Rojo de la Vega, M., Chapman, E., & Zhang, D. D. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.022 · Cited by 1,672 · see citing works
The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway
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Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution
Taguchi, K., Motohashi, H., & Yamamoto, M. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01473.x · Cited by 1,478 · see citing works
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The emerging role of the Nrf2–Keap1 signaling pathway in cancerPreprint
Jaramillo, M. C., & Zhang, D. D. (2013) · Genes & Development · doi:10.1101/gad.225680.113 · Cited by 1,304 · see citing works
Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
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Antioxidant responses and cellular adjustments to oxidative stress
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The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation
Bryan, H. K., Olayanju, A., Goldring, C. E., & Park, B. K. (2012) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.11.016 · Cited by 1,026 · see citing works
Molecular basis of the Keap1–Nrf2 system
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The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update
Lu, M., Ji, J., Jiang, Z., & You, Q. (2016) · Medicinal Research Reviews · doi:10.1002/med.21396 · Cited by 801 · see citing works
Oxidative stress response and Nrf2 signaling in aging
Zhang, H., Davies, K. J. A., & Forman, H. J. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.036 · Cited by 804 · see citing works
Cellular Stress Responses, The Hormesis Paradigm, and Vitagenes: Novel Targets for Therapeutic Intervention in Neurodegenerative Disorders
Calabrese, V., Cornelius, C., Dinkova‐Kostova, A. T., Calabrese, E. J., & Mattson, M. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.3074 · Cited by 803 · see citing works
Stress-activated cap’n’collar transcription factors in aging and human disease
Sykiotis, G. P., & Bohmann, D. (2010) · Science Signaling · doi:10.1126/scisignal.3112re3 · Cited by 776 · see citing works
Molecular mechanisms of Nrf2‐mediated antioxidant response
Li, W., & Kong, A. T. (2008) · Molecular Carcinogenesis · doi:10.1002/mc.20465 · Cited by 786 · see citing works
Redox-based regulation of signal transduction: principles, pitfalls, and promises
Janssen-Heininger, Y. M. W., Mossman, B. T., Heintz, N. H., Forman, H. J., Kalyanaraman, B., Finkel, T., Stamler, J. S., Rhee, S. G., & van der Vliet, A. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.03.011 · Cited by 784 · see citing works
Small Molecule Modulators of <scp>K</scp> eap1‐ <scp>N</scp> rf2‐ <scp>ARE</scp> Pathway as Potential Preventive and Therapeutic Agents
Magesh, S., Chen, Y., & Hu, L. (2012) · Medicinal Research Reviews · doi:10.1002/med.21257 · Cited by 760 · see citing works
Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis
Li, W., Khor, T. O., Xu, C., Shen, G., Jeong, W.-S., Yu, S., & Kong, A.-N. (2008) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.07.017 · Cited by 738 · see citing works
Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy
Shibata, T., Ohta, T., Tong, K. I., Kokubu, A., Odogawa, R., Tsuta, K., Asamura, H., Yamamoto, M., & Hirohashi, S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806268105 · Cited by 728 · see citing works
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Nrf2–ARE pathway: An emerging target against oxidative stress and neuroinflammation in neurodegenerative diseases
Buendía, I., Michalska, P., Navarro, E., Gameiro‐Ros, I., Egea, J., & Leon, R. M. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.11.003 · Cited by 683 · see citing works
Toward clinical application of the Keap1-Nrf2 pathway
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Focus on mammalian thioredoxin reductases — Important selenoproteins with versatile functions
Arnér, E. S. J. (2009) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2009.01.014 · Cited by 675 · see citing works
The Antioxidant Defense System Keap1-Nrf2 Comprises a Multiple Sensing Mechanism for Responding to a Wide Range of Chemical Compounds
Kobayashi, M., Li, L., Iwamoto, N., Nakajima‐Takagi, Y., Kaneko, H., Nakayama, Y., Eguchi, M., Wada, Y., Kumagai, Y., & Yamamoto, M. P. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01080-08 · Cited by 641 · see citing works
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p62 links autophagy and Nrf2 signaling
Jiang, T., Harder, B. G., de la Vega, M. R., Wong, P. K., Chapman, E., & Zhang, D. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.014 · Cited by 642 · see citing works
Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth
Ohta, T., Iijima, K., Miyamoto, M., Nakahara, I., Tanaka, H., Ohtsuji, M., Suzuki, T., Kobayashi, A., Yokota, J., Sakiyama, T., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5003 · Cited by 630 · see citing works
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Structural basis of Keap1 interactions with Nrf2
Canning, P., Sorrell, F. J., & Bullock, A. N. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.034 · Cited by 605 · see citing works
Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors
Brigelius-Flohé, R., & Flohé, L. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3534 · Cited by 577 · see citing works
NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8
Anandhan, A., Dodson, M. B., Shakya, A., Chen, J., Liu, P., Wei, Y., Tan, H., Wang, Q., Jiang, Z., Yang, K. B., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade9585 · Cited by 531 · see citing works
Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity
Yamamoto, T., Suzuki, T., Kobayashi, A., Wakabayashi, J., Maher, J. M., Motohashi, H., & Yamamoto, M. P. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01704-07 · Cited by 515 · see citing works
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Discovery of the Negative Regulator of Nrf2, Keap1: A Historical Overview
Itoh, K., Mimura, J., & Yamamoto, M. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3222 · Cited by 513 · see citing works
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Nrf2: friend or foe for chemoprevention?
Kensler, T. W., & Wakabayashi, N. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp231 · Cited by 487 · see citing works
Nrf2 at the heart of oxidative stress and cardiac protection
Chen, Q. M., & Maltagliati, A. J. (2017) · Physiological Genomics · doi:10.1152/physiolgenomics.00041.2017 · Cited by 474 · see citing works
The Nrf2 System as a Potential Target for the Development of Indirect Antioxidants
Jung, K.-A., & Kwak, M. (2010) · Molecules · doi:10.3390/molecules15107266 · Cited by 476 · see citing works
Structural and Functional Characterization of Nrf2 Degradation by the Glycogen Synthase Kinase 3/β-TrCP Axis
Rada, P., Rojo, A. I., Evrard‐Todeschi, N., Innamorato, N. G., Cotte, A., Jaworski, T., Tobón-Velasco, J. C., Devijver, H., García‐Mayoral, M. F., LEUVEN, F. V., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00180-12 · Cited by 474 · see citing works
Different Electrostatic Potentials Define ETGE and DLG Motifs as Hinge and Latch in Oxidative Stress Response
Tong, K. I., Padmanabhan, B., Kobayashi, A., Shang, C., Hirotsu, Y., Yokoyama, S., & Yamamoto, M. P. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00753-07 · Cited by 447 · see citing works
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Regulation of the Nrf2–Keap1 Antioxidant Response by the Ubiquitin Proteasome System: An Insight into Cullin-Ring Ubiquitin Ligases
Villeneuve, N. F., Lau, A., & Zhang, D. D. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3211 · Cited by 423 · see citing works
Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex
Baird, L., Llères, D., Swift, S., & Dinkova‐Kostova, A. T. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1305687110 · Cited by 386 · see citing works
Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosisPreprint
Wu, T., Zhao, F. L., Gao, B., Tan, C., Yagishita, N., Nakajima, T., Wong, P. K., Chapman, E., Fang, D., & Zhang, D. D. (2014) · Genes & Development · doi:10.1101/gad.238246.114 · Cited by 355 · see citing works
Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases
Kumar, H., Kim, I., More, S. V., Kim, B.-W., & Choi, D. (2013) · Natural Product Reports · doi:10.1039/c3np70065h · Cited by 334 · see citing works
Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants
Dinkova‐Kostova, A. T., Kostov, R. V., & Canning, P. (2016) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2016.08.005 · Cited by 332 · see citing works
The Nrf2–Keap1 defence pathway: Role in protection against drug-induced toxicity
Copple, I. M., Goldring, C. E., Kitteringham, N. R., & Park, B. K. (2007) · Toxicology · doi:10.1016/j.tox.2007.10.029 · Cited by 328 · see citing works
Dissecting the Crosstalk Between Nrf2 and NF-κB Response Pathways in Drug-Induced Toxicity
Gao, W., Guo, L., Yang, Y., Wang, Y., Xia, S., Gong, H., Zhang, B., & Yan, M. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.809952 · Cited by 328 · see citing works
Nrf2—a therapeutic target for the treatment of neurodegenerative diseases
Johnson, D. A., & Johnson, J. A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.07.147 · Cited by 328 · see citing works
Discovery of direct inhibitors of Keap1–Nrf2 protein–protein interaction as potential therapeutic and preventive agents
Abed, D. A., Goldstein, M., Albanyan, H., Jin, H., & Hu, L. (2015) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2015.05.008 · Cited by 330 · see citing works
Mechanisms of drug-induced liver injury
Yuan, L., & Kaplowitz, N. (2013) · Clinics in Liver Disease · doi:10.1016/j.cld.2013.07.002 · Cited by 322 · see citing works
Total antioxidant capacity: appraisal of a concept
Sies, H. (2007) · The Journal of Nutrition · doi:10.1093/jn/137.6.1493 · Cited by 308 · see citing works
Molecular Basis of the KEAP1-NRF2 Signaling Pathway
Suzuki, T., Takahashi, J. A., & Yamamoto, M. P. (2023) · Molecules and Cells · doi:10.14348/molcells.2023.0028 · Cited by 309 · see citing works
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Targeting NRF2 signaling for cancer chemoprevention
Kwak, M.-K., & Kensler, T. W. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.08.028 · Cited by 306 · see citing works
Nrf2-ARE stress response mechanism: A control point in oxidative stress-mediated dysfunctions and chronic inflammatory diseases
Singh, S., Vrishni, S., Singh, B. K., Rahman, I., & Kakkar, P. (2010) · Free Radical Research · doi:10.3109/10715762.2010.507670 · Cited by 294 · see citing works
Validation of the multiple sensor mechanism of the Keap1-Nrf2 system
Takaya, K., Suzuki, T., Motohashi, H., Onodera, K., Satomi, S., Kensler, T. W., & Yamamoto, M. P. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.06.023 · Cited by 277 · see citing works
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Mitochondria and Reactive Oxygen Species: Physiology and Pathophysiology
Bolisetty, S., & Jaimes, E. A. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14036306 · Cited by 274 · see citing works
Shaping the Nrf2-ARE-related pathways in Alzheimer’s and Parkinson’s diseases
Fão, L., Mota, S. I., & Rego, A. C. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100942 · Cited by 270 · see citing works
KEAP1‐NRF2 protein–protein interaction inhibitors: Design, pharmacological properties and therapeutic potential
Crisman, E., Duarte, P., Daudén, E., Cuadrado, A., Rodrı́guez-Franco, M. I., López, M. G., & Leon, R. M. (2022) · Medicinal Research Reviews · doi:10.1002/med.21925 · Cited by 273 · see citing works
Beyond repression of Nrf2: An update on Keap1
Kopacz, A., Klóska, D., Forman, H. J., Józkowicz, A., & Grochot‐Przeczek, A. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.03.023 · Cited by 262 · see citing works
Kinetic, Thermodynamic, and Structural Characterizations of the Association between Nrf2-DLGex Degron and Keap1
Fukutomi, T., Takagi, K., Mizushima, T., Ohuchi, N., & Yamamoto, M. P. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01191-13 · Cited by 265 · see citing works
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Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/β-TrCP
Cuadrado, A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.04.029 · Cited by 265 · see citing works
Structure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO
Cleasby, A., Yon, J. R., Day, P. J., Richardson, C. J., Tickle, I. J., Williams, P. A., Callahan, J. F., Carr, R. A. E., Concha, N. O., Kerns, J. K., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098896 · Cited by 263 · see citing works
Physical and functional interaction of sequestosome 1 with Keap1 regulates the Keap1-Nrf2 cell defense pathway
Copple, I. M., Lister, A., Obeng, A. D., Kitteringham, N. R., Jenkins, R. E., Layfield, R., Foster, B. J., Goldring, C. E., & Park, B. K. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.096545 · Cited by 260 · see citing works
Proteomic Analysis of Ubiquitin Ligase KEAP1 Reveals Associated Proteins That Inhibit NRF2 Ubiquitination
Hast, B. E., Goldfarb, D., Mulvaney, K. M., Hast, M. A., Siesser, P. F., Yan, F., Hayes, D. N., & Major, M. B. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4400 · Cited by 259 · see citing works
Review of Molecular Mechanisms Involved in the Activation of the Nrf2-ARE Signaling Pathway by Chemopreventive Agents
Giudice, A., Arra, C., & Turco, M. C. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-738-9_3 · Cited by 254 · see citing works
Thirty years of NRF2: advances and therapeutic challenges.
Zhang, D. D. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01145-0 · Cited by 282 · see citing works
SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity
Lee, D. H., Park, J. S., Lee, Y. S., Han, J., Lee, D., Kwon, S. W., Han, D. H., Lee, Y., & Bae, S. H. (2020) · Autophagy · doi:10.1080/15548627.2020.1712108 · Cited by 249 · see citing works
Nrf2, a Guardian of Healthspan and Gatekeeper of Species Longevity
Lewis, K. N., Mele, J., Hayes, J. D., & Buffenstein, R. (2010) · Integrative and Comparative Biology · doi:10.1093/icb/icq034 · Cited by 247 · see citing works
Nrf2—a Promising Therapeutic Target for Defensing Against Oxidative Stress in Stroke
Zhang, R., Xu, M., Wang, Y., Xie, F., Zhang, G., & Qin, X. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0111-0 · Cited by 243 · see citing works
Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy
Lister, A., Nedjadi, T., Kitteringham, N. R., Campbell, F., Costello, E., Lloyd, B. H., Copple, I. M., Williams, S. J., Owen, A., Neoptolemos, J. P., et al. (2011) · Molecular Cancer · doi:10.1186/1476-4598-10-37 · Cited by 243 · see citing works
Molecular mechanisms of natural products in chemoprevention: Induction of cytoprotective enzymes by Nrf2
Eggler, A. L., Gay, K. A., & Mesecar, A. D. (2008) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200700249 · Cited by 234 · see citing works
The rise of antioxidant signaling—The evolution and hormetic actions of Nrf2
Maher, J. M., & Yamamoto, M. P. (2010) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2010.01.011 · Cited by 231 · see citing works
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ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway
Deng, Z., Lim, J., Wang, Q., Purtell, K., Wu, S., Palomo, G. M., Tan, H., Manfredi, G., Zhao, Y., Peng, J., et al. (2019) · Autophagy · doi:10.1080/15548627.2019.1644076 · Cited by 232 · see citing works
NRF2 mutation confers malignant potential and resistance to chemoradiation therapy in advanced esophageal squamous cancer
Shibata, T., Kokubu, A., Saito, S., Narisawa-Saito, M., Sasaki, H., Aoyagi, K., Yoshimatsu, Y., Tachimori, Y., Kushima, R., Kiyono, T., et al. (2011) · Neoplasia · doi:10.1593/neo.11750 · Cited by 224 · see citing works
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Dietary Regulation of Keap1/Nrf2/ARE Pathway: Focus on Plant-Derived Compounds and Trace Minerals
Stefanson, A. L., & Bakovic, M. (2014) · Nutrients · doi:10.3390/nu6093777 · Cited by 226 · see citing works
Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1
Taguchi, K., Maher, J. M., Suzuki, T., Kawatani, Y., Motohashi, H., & Yamamoto, M. P. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.01591-09 · Cited by 225 · see citing works
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Molecular and Chemical Regulation of the Keap1-Nrf2 Signaling Pathway
Keum, Y., & Choi, B. Y. (2014) · Molecules · doi:10.3390/molecules190710074 · Cited by 224 · see citing works
Small molecule modulators of antioxidant response pathway
Hur, W., & Gray, N. S. (2010) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2010.12.009 · Cited by 213 · see citing works
Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids
Kansanen, E., Jyrkkänen, H.-K., & Levonen, A. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.11.038 · Cited by 208 · see citing works
KEAP1–NRF2 signalling and autophagy in protection against oxidative and reductive proteotoxicity
Dodson, M. B., Redmann, M., Rajasekaran, N. S., Darley-Usmar, V. M., & Zhang, J. (2015) · Biochemical Journal · doi:10.1042/bj20150568 · Cited by 203 · see citing works
Oncogenic potential of Nrf2 and its principal target protein heme oxygenase-1
Na, H., & Surh, Y. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.10.819 · Cited by 202 · see citing works
Role of Nrf2 in protection against acute kidney injury
Shelton, L. M., Park, B. K., & Copple, I. M. (2013) · Kidney International · doi:10.1038/ki.2013.248 · Cited by 201 · see citing works
Recurrent Loss of NFE2L2 Exon 2 Is a Mechanism for Nrf2 Pathway Activation in Human Cancers
Goldstein, L. D., Lee, J., Gnad, F., Klijn, C. N., Schaub, A., Reeder, J., Daemen, A., Bakalarski, C. E., Holcomb, T., Shames, D. S., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.08.010 · Cited by 200 · see citing works
The KEAP1–NRF2 System as a Molecular Target of Cancer Treatment
Taguchi, K., & Yamamoto, M. (2020) · Cancers · doi:10.3390/cancers13010046 · Cited by 195 · see citing works
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Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: Role of glycogen synthase kinase-3
Rojo, A. I., Medina‐Campos, O. N., Rada, P., Zúñiga-Toalá, A., López-Gazcón, A., Espada, S., Pedraza‐Chaverrí, J., & Cuadrado, A. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.11.003 · Cited by 195 · see citing works
Molecular basis for the disruption of Keap1–Nrf2 interaction via Hinge & Latch mechanism
Horie, Y., Suzuki, T., Inoue, J., Iso, T., Wells, G., Moore, T. W., Mizushima, T., Dinkova‐Kostova, A. T., Kasai, T., Kamei, T., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02100-6 · Cited by 195 · see citing works
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PALB2 Interacts with KEAP1 To Promote NRF2 Nuclear Accumulation and Function
Ma, J., Cai, H., Wu, T., Sobhian, B., Huo, Y., Alcivar, A. L., Mehta, M., Cheung, K. L., Ganesan, S., Kong, A. T., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06271-11 · Cited by 193 · see citing works
The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism
Chambel, S. S., Santos-Gonçalves, A., & Duarte, T. L. (2015) · BioMed Research International · doi:10.1155/2015/597134 · Cited by 192 · see citing works
Principles in Redox Signaling: From Chemistry to Functional Significance
Bindoli, A., & Rigobello, M. P. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4655 · Cited by 189 · see citing works
iASPP Is an Antioxidative Factor and Drives Cancer Growth and Drug Resistance by Competing with Nrf2 for Keap1 Binding
Ge, W., Zhao, K., Wang, X., Li, H., Yu, M., He, M., Xue, X., Zhu, Y., Zhang, C. L., Cheng, Y., et al. (2017) · Cancer Cell · doi:10.1016/j.ccell.2017.09.008 · Cited by 189 · see citing works
Regulation of NF-E2-Related Factor 2 Signaling for Cancer Chemoprevention: Antioxidant Coupled with Antiinflammatory
Hu, R., Saw, C. L. L., Yu, R., & Kong, A. T. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3276 · Cited by 187 · see citing works
Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance
Raghunath, A., Sundarraj, K., Arfuso, F., Sethi, G., & Perumal, E. (2018) · Cancers · doi:10.3390/cancers10120481 · Cited by 184 · see citing works
Comparison of Secondary Structure Formation Using 10 Different Force Fields in Microsecond Molecular Dynamics Simulations
Cino, E. A., Choy, W., & Karttunen, M. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct300323g · Cited by 184 · see citing works
Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processes
Reisman, S. A., Aleksunes, L. M., & Klaassen, C. D. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.12.028 · Cited by 184 · see citing works
The Keap1–Nrf2 Cell Defense Pathway – A Promising Therapeutic Target?
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Tong, K. I. (2007) · Terrestrial Environment Research Center (University of Tsukuba)
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Authors: Tong, K. I., Kobayashi, A., Katsuoka, F., & Yamamoto, M.
Affiliations: University of Tsukuba (JP)
ORCID: Kobayashi, Akira
Katsuoka, Fumiki
Yamamoto, Masayuki
Venue: Biological Chemistry
Publisher: Walter de Gruyter GmbH
Published: 2006-01-01
Volume: 387
Issue: 10/11
Pages: 1311-20
ISSN: 1431-6730 (ISSN-L)
1437-4315
DOI: 10.1515/bc.2006.164
OpenAlex: W2094661084
Cited by: 473
References: 78
Citations by year: 2026: 10 · 2025: 13 · 2024: 14 · 2023: 26 · 2022: 24 · 2021: 24 · 2020: 37 · 2019: 24 · 2018: 24 · 2017: 30 · 2016: 28 · 2015: 32 · 2014: 32 · 2013: 29 · 2012: 21
FWCI: 1.41
Type: journal article
Language: en
Open access: closed
Locations: Biological Chemistry (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords: Nrf2, Keap1, redox regulation, protein degradation, oxidative stress, xenobiotic stress, proteasome, transcriptional regulation, cytoprotection
MeSH terms: Animals, Humans, Models, Biological, Protein Binding, Substrate Specificity, Proteasome Endopeptidase Complex, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2

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Two-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism

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