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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NMRPipe: A multidimensional spectral processing system based on UNIX pipes
Delaglio, F., Grzesiek, S., Vuister, G. W., Zhu, G., Pfeifer, J., & Bax, A. (1995) · Journal of Biomolecular NMR · doi:10.1007/bf00197809 · Cited by 15,961
NMR with Proteins and Nucleic Acids
Wüthrich, K. (1986) · Europhysics news · doi:10.1051/epn/19861701011 · Cited by 8,028
NMR of Proteins and Nucleic Acids
(2006) · Royal Society of Chemistry eBooks · doi:10.1039/9781847555236-00336 · Cited by 5,874
Investigation of exchange processes by two-dimensional NMR spectroscopy
Jeener, J., Meier, B. H., Bachmann, P., & Ernst, R. R. (1979) · The Journal of Chemical Physics · doi:10.1063/1.438208 · Cited by 4,750
Mitochondria, Oxidants, and Aging
Balaban, R. S., Nemoto, S., & Finkel, T. (2005) · Cell · doi:10.1016/j.cell.2005.02.001 · Cited by 4,388
Intrinsically unstructured proteins and their functions
Dyson, H. J., & Wright, P. E. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1589 · Cited by 3,871
Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634
Self-citation
GLUTATHIONE TRANSFERASES
Hayes, J. D., Flanagan, J. U., & Jowsey, I. R. (2004) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.45.120403.095857 · Cited by 3,565
Attenuated T 2 relaxation by mutual cancellation of dipole–dipole coupling and chemical shift anisotropy indicates an avenue to NMR structures of very large biological macromolecules in solution
Pervushin, K. V., Riek, R., Wider, G., & Kurt Wüthrich, A. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.23.12366 · Cited by 2,450
Pure absorption gradient enhanced heteronuclear single quantum correlation spectroscopy with improved sensitivity
Kay, L. E., Keifer, P. A., & Saarinen, T. (1992) · Journal of the American Chemical Society · doi:10.1021/ja00052a088 · Cited by 2,261

Show all 71 references

Research works printed but not linked: 1

Garrett D. S., 1991, J. Magn. Reson., 95, 214

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Background
Mechanisms Underlying Chemopreventive Effects of Flavonoids via Multiple Signaling Nodes within Nrf2-ARE and AhR-XRE Gene Regulatory Networks
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Background
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Background
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“Keap1 promotes the ubiquitination of NRF2 in the cytoplasm and keeps it at a low level in the cytoplasm.(9) When exposed to oxidative stress or using an NRF2 activator, NRF2 is dissociated from Keap1 binding and then translocated to the nucleus, where it transcribes with sMaf protein polymer and ARE gene to activate t…”
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“Constitutive activation of Nrf2 is evident in several human cancer cell lines as well as in tumors (35-38).”
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“The amino acid sequence present in the C-terminal of Neh3 domain is a determining factor for activation of ARE.”
BackgroundInfluential
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“The DGR domain of Keap1, which mediates interaction with Nrf2 (25), was important for HBx-binding (Fig.”
Background
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“The interaction between Keap1 and Nrf2 requires the Nrf2 DLG and ETGE domains: ETGE engages Nrf2 with Keap1, while the DLG motif acts as latch to (un)lock the Nrf2 Neh2 domain in an appropriate spatial orientation, and thus regulates Nrf2 stability and ubiquitination [4,5].”
Background
Dietary Phytochemicals Targeting Nrf2 to Enhance the Radiosensitivity of Cancer
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“Among these functional domains, Neh2 was located in the N-terminal, which contains ETGE and DLG motifs for binding the inhibitory protein Kelch-like ECH-associated protein 1 (Keap1) [19 – 21].”

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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