Cited by 780Genomics, phytochemicals, and oxidative stressProtein Structure and DynamicsGlutathione Transferases and Polymorphisms

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Keap1 Recruits Neh2 through Binding to ETGE and DLG Motifs: Characterization of the Two-Site Molecular Recognition Model

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Tong, Kit I., Katoh, Yasutake, Kusunoki, Hideki, Itoh, Ken, Tanaka, Toshiyuki, Yamamoto, Masayuki·2006·Molecular and Cellular Biology

DOI 10.1128/mcb.26.8.2887-2900.2006PMC PMC1446969

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Abstract

The expression of the phase 2 detoxification enzymes and antioxidant proteins is induced at the transcriptional level by Nrf2 and negatively regulated at the posttranslational level by Keap1 through protein-protein interactions with and subsequent proteolysis of Nrf2. We found that the Neh2 domain of Nrf2 is an intrinsically disordered but biologically active regulatory domain containing a 33-residue central alpha-helix followed by a mini antiparallel beta-sheet. Isothermal calorimetry analysis indicated that one Neh2 molecule interacts with two molecules of Keap1 via two binding sites, the stronger binding ETGE motif and the weaker binding DLG motif. Nuclear magnetic resonance titration study showed that these two motifs of the Neh2 domain bind to an overlapping site on the bottom surface of the beta-propeller structure of Keap1. In contrast, the central alpha-helix of the Neh2 domain does not have any observable affinity to Keap1, suggesting that this region may serve as a bridge connecting the two motifs for the association with the two beta-propeller structures of a dimer of Keap1. Based on these observations, we propose that Keap1 recruits Nrf2 by the ETGE motif and that the DLG motif of the Neh2 domain locks its lysine-rich central alpha-helix in a correct position to benefit ubiquitin signaling.

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Background
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“org 7 Kelch domains of the E3 ubiquitin ligase Kelch-like ECHassociated protein 1 (KEAP1), which is the most notable negative regulator of NRF2 and contains a number of cysteine residues (including C151, C273, and C288) that act as electrophilic attack centers (130).”
Background
Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches – Pulmonary Disease/Asthma
Audousset, C., McGovern, T. K., & Martin, J. G. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.727806 · Cited by 80
“PI3K, PKC, c-Jun, N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) have all been shown to positively regulate Nrf2 (Tong et al., 2006), whereas p38 MAPK regulates the Nrf2 pathway both positively and negatively (Yu et al.”
Background
Fragment-based drug discovery and its application to challenging drug targets
Price, A. J., Howard, S., & Cons, B. D. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170029 · Cited by 79
KEAP1-Mutant NSCLC: The Catastrophic Failure of a Cell-Protecting Hub
Scalera, S., Mazzotta, M., Cortile, C., Krasniqi, E., Maria, R. D., Cappuzzo, F., Ciliberto, G., & Maugeri‐Saccà, M. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.03.011 · Cited by 80
Protective actions of nuclear factor erythroid 2-related factor 2 (NRF2) and downstream pathways against environmental stressors
Jiménez, M. T. B., Frenis, K., Hahad, O., Steven, S., Cohen, G., Cuadrado, A., Münzel, T. F., & Daiber, A. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.05.016 · Cited by 77
The Role of Organosulfur Compounds as Nrf2 Activators and Their Antioxidant Effects
Egbujor, M. C., Petrosino, M., Zuhra, K., & Saso, L. (2022) · Antioxidants · doi:10.3390/antiox11071255 · Cited by 76
“Indeed, Neh2 is stretched between two Kelch domains in the Keap1 homodimer and binds Kelch via two different binding motifs, one with low affinity (the DLG domain) and one with high affinity (the ETGE domain) (Figures 1 and 2A), which is composed of an evolutionarily conserved amino acid sequence motif [57,58].”
Background
Dual Roles of Oxidative Stress in Metal Carcinogenesis
Xu, J., Wise, J. T. F., Wang, L., Schumann, K., Zhang, Z., & Shi, X. (2017) · Journal of Environmental Pathology Toxicology and Oncology · doi:10.1615/jenvironpatholtoxicoloncol.2017025229 · Cited by 78
Cis-element architecture of Nrf2–sMaf heterodimer binding sites and its relation to diseases
Otsuki, A., & Yamamoto, M. P. (2019) · Archives of Pharmacal Research · doi:10.1007/s12272-019-01193-2 · Cited by 74
Self-citation
OTUD1 deubiquitinase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways
Oikawa, D., Gi, M., Kosako, H., Shimizu, K., Takahashi, H., Shiota, M., Hosomi, S., Komakura, K., Wanibuchi, H., Tsuruta, D., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-05145-5 · Cited by 75
“KEAP1 regulates the proteasomal degradation of the NRF2 transcription factor, as a component of the Cullin 3 (CUL3)–E3 complex [24].”
BackgroundMethodInfluential
The Regulation of NFE2L2 (NRF2) Signalling and Epithelial-to-Mesenchymal Transition in Age-Related Macular Degeneration Pathology
Hyttinen, J. M. T., Kannan, R., Felszeghy, S., Niittykoski, M., Salminen, A., & Kaarniranta, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20225800 · Cited by 70
“This modification occurs at seven Lys residues which are situated between the KEAP1 binding sites of NFE2L2 and it leads to the rapid degradation of NFE2L2 by the 26S proteasome machinery [75,81].”
Background
Nuclear Factor Erythroid 2 - Related Factor 2 Signaling in Parkinson Disease: A Promising Multi Therapeutic Target Against Oxidative Stress, Neuroinflammation and Cell Death
Kumar, H., Koppula, S., Kim, I., More, S. V., Kim, B.-W., & Choi, D. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527311211080012 · Cited by 70
Current strategies and progress for targeting the “undruggable” transcription factors
Zhuang, J., Liu, Q., Wu, D., & Tie, L. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-021-00852-9 · Cited by 77
“Under normal conditions, Nrf2 is in the cytoplasm and interacts with Keap1 to maintain a low protein level [71].”
Background
CR6-interacting Factor 1 (CRIF1) Regulates NF-E2-related Factor 2 (NRF2) Protein Stability by Proteasome-mediated Degradation
Kang, H. J., Hong, Y. B., Kim, H. J., & Bae, I. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.084590 · Cited by 71
Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner
Tao, S., Rojo de la Vega, M., Quijada, H., Wondrak, G. T., Wang, T., Garcia, J. G. N., & Zhang, D. D. (2016) · Scientific Reports · doi:10.1038/srep18760 · Cited by 68
Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls
Aranda‐Rivera, A. K., Cruz‐Gregorio, A., Pedraza‐Chaverrí, J., & Scholze, A. (2022) · Antioxidants · doi:10.3390/antiox11061112 · Cited by 74
“Indeed, the downregulation of Nrf2 promotes NF-κB activation because both transcription factors compete by the binding DNA site of cyclic-adenosine-monophosphate (cAMP)response-element-binding-protein (CREB)-binding protein (CBP), causing the upregulation of NF-κB [42].”
BackgroundInfluential
Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2
Bathish, B., Robertson, H., Dillon, J. F., Dinkova‐Kostova, A. T., & Hayes, J. D. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.06.226 · Cited by 70
The NRF-2/HO-1 Signaling Pathway: A Promising Therapeutic Target for Metabolic Dysfunction-Associated Steatotic Liver Disease
Li, N., Hao, L., Li, S., Deng, J., Yu, F., Zhang, J., Nie, A., & Hu, X. (2024) · Journal of Inflammation Research · doi:10.2147/jir.s490418 · Cited by 74
Natural Nrf2 Modulators for Skin Protection
Boo, Y. C. (2020) · Antioxidants · doi:10.3390/antiox9090812 · Cited by 69
“Under the basal, unstressed condition, the Cul3 complex ubiquitylates Nrf2 at a lysine (Lys, K) residing between the 29DLG31 and 79ETGE82 motifs [42].”
Background
Regulation of Keap1-Nrf2 signaling in health and diseases
Xiao, J.-L., Liu, H.-Y., Sun, C., & Tang, C. (2024) · Molecular Biology Reports · doi:10.1007/s11033-024-09771-4 · Cited by 73
“The Keap1 protein forms a dimer through the BTB structural domain and binds to the Nrf2 protein, The specific structural domains in the Nrf2 protein, DLG, and ETGE are two binding motifs for Keap2 [43, 44 ].”
Targeting the NF-E2-Related Factor 2 Pathway: a Novel Strategy for Traumatic Brain Injury
Zhang, L., & Wang, H. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0456-z · Cited by 67
S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis
Mead, R. J., Higginbottom, A., Allen, S. P., Kirby, J., Bennett, E., Barber, S. C., Heath, P. R., Coluccia, A., Patel, N., Gardner, I. B., et al. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.04.018 · Cited by 66
“This complex associates with NRF2 via a “hinge and latch mechanism” [18,19] where a Keap1 homodimer binds two distinct motifs within the Neh2 domain of Nrf2, one of which forms a strong interaction (hinge) and the second a weak interaction (latch).”
Background
Nrf2: bane or blessing in cancer?
Xiang, M., Namani, A., Wu, S., & Wang, X. (2014) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-014-1627-1 · Cited by 70
Role of Nuclear Factor Erythroid 2-Related Factor 2 in Diabetic Nephropathy
Cui, W., Min, X., Xu, X., Du, B., & Luo, P. (2017) · Journal of Diabetes Research · doi:10.1155/2017/3797802 · Cited by 68
“Neh2 domain is highly conserved between species [23] and enables Nrf2 to combine with Kelch-like ECH-associated protein 1 (Keap1) [24, 25].”
Background
Emerging Substrate Proteins of Kelch-like ECH Associated Protein 1 (Keap1) and Potential Challenges for the Development of Small-Molecule Inhibitors of the Keap1-Nuclear Factor Erythroid 2‑Related Factor 2 (Nrf2) Protein–Protein Interaction
Zhang, Y., Shi, Z., Zhou, Y., Xiao, Q., Wang, H., & Peng, Y. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01865 · Cited by 67
Role of Nrf2 dysfunction in the pathogenesis of diabetic nephropathy: Therapeutic prospect of epigallocatechin-3-gallate
Mohan, T., Narasimhan, K. K. S., Ravi, D. B., Velusamy, P., Chandrasekar, N., Chakrapani, L. N., Srinivasan, A., Karthikeyan, P., Kannan, P., Tamilarasan, B., et al. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.07.037 · Cited by 66
Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
Pallesen, J. S., Narayanan, D., Tran, K. T., Solbak, S. M. Ø., Marseglia, G., Sørensen, L. M. E., Høj, L. J., Munafò, F., Carmona, R. M., Garcia, A. D., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c02094 · Cited by 66
Overlooked and valuable facts to know in the NRF2/KEAP1 field
Kopacz, A., Rojo, A. I., Patibandla, C., Lastra, D., Piechota-Polańczyk, A., Klóska, D., Józkowicz, A., Sutherland, C. D., Cuadrado, A., & Grochot‐Przeczek, A. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.08.044 · Cited by 67
p62-Dependent Phase Separation of Patient-Derived KEAP1 Mutations and NRF2
Cloer, E. W., Siesser, P. F., Cousins, E. M., Goldfarb, D., Mowrey, D. D., Harrison, J. S., Weir, S., Dokholyan, N. V., & Major, M. B. (2018) · Molecular and Cellular Biology · doi:10.1128/mcb.00644-17 · Cited by 69
Pharmacological Applications of Nrf2 Inhibitors as Potential Antineoplastic Drugs
Telkoparan‐Akillilar, P., Süzen, S., & Saso, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20082025 · Cited by 69
“The characterization of the crystal structure of Keap1 in complex with the Neh2 domain of Nrf2 may deliver chances to design molecules that specially and selectively interfere with the binding of Keap1 and Nrf2 [141].”
Background
Nrf2 in early vascular ageing: Calcification, senescence and therapy
Arefin, S., Buchanan, S. J., Hobson, S., Steinmetz, J. L., Alsalhi, S., Shiels, P. G., Kublickiene, K. R., & Stenvinkel, P. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2020.02.026 · Cited by 67
Targeting NRF2–KEAP1 axis by Omega-3 fatty acids and their derivatives: Emerging opportunities against aging and diseases
Davinelli, S., Medoro, A., Intrieri, M., Saso, L., Scapagnini, G., & Kang, J. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.11.017 · Cited by 72
Intrinsically disordered proteins may escape unwanted interactions via functional misfolding
Uversky, V. N. (2011) · Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics · doi:10.1016/j.bbapap.2011.03.010 · Cited by 68
Updated Research and Applications of Small Molecule Inhibitors of Keap1-Nrf2 Protein-Protein Interaction: a Review
Zhuang, C., Miao, Z., Sheng, C., & Zhang, W. (2014) · Current Medicinal Chemistry · doi:10.2174/0929867321666140217104648 · Cited by 67
“These findings confirmed the conclusion that the glutamic acids played a crucial role in interacting with Arg380, 415 and 483 by forming electrostatic binding [51].”
BackgroundResult
An overview of the mechanisms and novel roles of Nrf2 in cardiovascular diseases
Jiang, S., Yang, Y., Li, T. X., Ma, Z., Hu, W., Deng, C., Fan, C., Lv, J., Sun, Y., & Yi, W. (2016) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2016.1250887 · Cited by 66
“The DLG motif, located in the N-terminal region, is important for the ubiquitination and degradation of Nrf2, while the ETGE motif is essential for interacting with Keap1 [12].”
Background
Nrf2 and antioxidant defense against CYP2E1 toxicity
Cederbaum, A. I. (2009) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425250903143769 · Cited by 63
“Normally, under basal conditions, Nrf2 is bound to Keap1 in the cytoplasm due to an interaction between a single Nrf2 protein and a Keap1 dimer [112].”
Background
Resveratrol derivatives as promising chemopreventive agents with improved potency and selectivity
Kondratyuk, T. P., Park, E., Marler, L. E., Ahn, S., Yuan, Y., Choi, Y., Yu, R., van Breemen, R. B., Sun, B., Hoshino, J., et al. (2011) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201100122 · Cited by 63
A simple method for amino acid selective isotope labeling of recombinant proteins in E. coli
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MethodInfluentialSelf-citation
The Role of Glucosinolate Hydrolysis Products from Brassica Vegetable Consumption in Inducing Antioxidant Activity and Reducing Cancer Incidence
Becker, T. M., & Juvik, J. A. (2016) · Diseases · doi:10.3390/diseases4020022 · Cited by 62
“This, in turn, causes the Keap1 dimer to release the DLG motif of Nrf2, which is suggested to prevent Nrf2 polyubiquitination and degradation [111–113].”
New developments in mechanisms of prostate cancer progression
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Targeting Nrf2 may reverse the drug resistance in ovarian cancer
Li, D., Hong, X., Zhao, F., Ci, X., & Zhang, S. (2021) · Cancer Cell International · doi:10.1186/s12935-021-01822-1 · Cited by 63
“The Neh2 domain contains two sites, namely DLG and ETGE, which combine with the cytoplasmic protein Keap1, a negative regulator of Nrf2 transcriptional activity [26].”
Background
Research progress on pharmacological effects and new dosage forms of baicalin
Bao, M., Ma, Y., Liang, M., Sun, X., Ju, X., Yong, Y., & Liu, X. (2022) · Veterinary Medicine and Science · doi:10.1002/vms3.960 · Cited by 60
Redox-regulating role of insulin: The essence of insulin effect
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Authors: Tong, K. I., Katoh, Y., Kusunoki, H., Itoh, K., Tanaka, T., & Yamamoto, M.
Affiliations: University of Tsukuba (JP)
Corresponding author: Tanaka, Toshiyuki
Yamamoto, Masayuki
ORCID: Kusunoki, Hideki
Itoh, Ken
Tanaka, Toshiyuki
Yamamoto, Masayuki
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2006-04-01
Volume: 26
Issue: 8
Pages: 2887-2900
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.26.8.2887-2900.2006
PMC: PMC1446969
OpenAlex: W2171218310
Cited by: 759
References: 71
Citations by year: 2026: 44 · 2025: 44 · 2024: 42 · 2023: 56 · 2022: 58 · 2021: 46 · 2020: 59 · 2019: 41 · 2018: 38 · 2017: 51 · 2016: 31 · 2015: 34 · 2014: 36 · 2013: 35 · 2012: 30
FWCI: 7.06
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (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 › Protein Structure and Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Keywords: Keap1, Nrf2, protein-protein interaction, two-site model, beta-propeller, intrinsically disordered proteins, ubiquitin ligase, post-translational regulation, antioxidant proteins
MeSH terms: Kelch-Like ECH-Associated Protein 1, Amino Acid Sequence, Animals, Binding Sites, Calorimetry, Cytoskeletal Proteins, Escherichia coli, Models, Chemical, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Processing, Post-Translational, Recombinant Fusion Proteins, Thermodynamics, Ultracentrifugation, Conserved Sequence, Point Mutation, Sequence Homology, Amino Acid, Protein Structure, Secondary, Protein Structure, Tertiary, Nuclear Magnetic Resonance, Biomolecular, Amino Acid Motifs, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice

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Keap1 Recruits Neh2 through Binding to ETGE and DLG Motifs: Characterization of the Two-Site Molecular Recognition Model

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