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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“There are two separate sites in Nrf2 that bind to Keap1, termed the ETGE and DLG motifs [111].”
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Clinically approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia
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“1A(2)) is Keap1, a hub protein that modifies its intrinsically disordered binding partner Nrf2 through a proposed ‘‘hinge and latch’’ process [41,42], leading to its polyubiquitination and subsequent degradation.”
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The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice
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New Insights into Oxidative and Reductive Stress Responses and Their Relation to the Anticancer Activity of Selenium-Containing Compounds as Hydrogen Selenide Donors
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“The stoichiometry of KEAP1 and NRF2 within the complex is 2:1, as demonstrated in an isothermal calorimetry study [42].”
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Interaction Energetics and Druggability of the Protein–Protein Interaction between Kelch-like ECH-Associated Protein 1 (KEAP1) and Nuclear Factor Erythroid 2 Like 2 (Nrf2)
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“Moreover, the insensitivity of the measured affinity to the presence of the DLG motif indicates that, for the longer construct in which both binding motifs are present, binding to KEAP1 is primarily through DxETGE, as expected given its higher affinity (33, 34).”
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Computational design of an epitope-specific Keap1 binding antibody using hotspot residues grafting and CDR loop swapping
Liu, X., Taylor, R. D., Griffin, L., Coker, S.-F., Adams, R., Ceska, T., Shi, J., Lawson, A. D. G., & Baker, T. (2017) · Scientific Reports · doi:10.1038/srep41306 · Cited by 39
“Two hairpin loop motifs from Nrf2 (the stronger binding ETGE motif and the weaker binding DLG motif) have been reported to bind at the same region of two Keap1 Kelch domains 21 .”
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The current status and future prospects for therapeutic targeting of KEAP1-NRF2 and β-TrCP-NRF2 interactions in cancer chemoresistance
Srivastava, R., Fernández-Ginés, R., Encinar, J. A., Cuadrado, A., & Wells, G. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.09.023 · Cited by 41
“It is well-known that under normal physiological conditions, the ETGE and DLG motifs in the NRF2-Neh2 regulatory domain, enable its binding to the Kelch domain of the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (KEAP1) [13,14].”
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Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds
Deng, Y., Meyer, S. A., Guan, X., Escalon, B. L., Ai, J., Wilbanks, M. S., Welti, R., García‐Reyero, N., & Perkins, E. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0014662 · Cited by 40
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Recent progress and applications of small molecule inhibitors of Keap1–Nrf2 axis for neurodegenerative diseases
Wang, J., Cao, Y., Yang, L., Zhu, H., Zhang, J., Che, J., Zhuang, R., & Shao, J. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115998 · Cited by 39
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“Keap1 serves as a linker protein for Cul3 based E3 ubiquitination of Nrf2, which leads to Nrf2’s proteosomal degradation.”
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Fuzzy Complex Formation between the Intrinsically Disordered Prothymosin α and the Kelch Domain of Keap1 Involved in the Oxidative Stress Response
Khan, H., Cino, E. A., Brickenden, A. M., Fan, J., Yang, D., & Choy, W. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.01.005 · Cited by 37
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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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