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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BackgroundResultInfluential
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“Normally, the KELCH domain located in the C-terminus of KEAP1 interacts with the DLG and ETGE motifs in the NEH2 domain of NRF2 to mediate the ubiquitination and subsequent proteosome-mediated degradation of NRF2 in the cytosol (McMahon et al., 2006; Padmanabhan et al., 2008; Tong et al., 2006).”
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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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