The DOI matches its Crossref record; 70 of the 71 references it cites were found in a registry or an index.
Keap1 Recruits Neh2 through Binding to ETGE and DLG Motifs: Characterization of the Two-Site Molecular Recognition Model
Open accessAbstract
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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“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 [58]
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Role of nrf2 in oxidative stress and toxicity
Ma, Q. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140320 · Cited by 4,903
“In this two-site-binding, or hinge-and-latch, model (49) (Figure 2c), Keap1 recruits newly synthesized Nrf2 by binding to Neh2.”
BackgroundROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis
D'Autréaux, B., & Toledano, M. B. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2256 · Cited by 3,642
“Zinc coordination by Cys residues in KeaP1 is reminiscent of Hsp33 and Rsra, suggesting that, in a similar way to 103,131 .”
BackgroundKomatsu, M., Kurokawa, H., Waguri, S., Taguchi, K., Kobayashi, A., Ichimura, Y., Sou, Y.-S., Ueno, I., Sakamoto, A., Tong, K. I., et al. (2010) · Nature Cell Biology · doi:10.1038/ncb2021 · Cited by 2,288
Self-citationTranscriptional Regulation by Nrf2
Tonelli, C., Chio, I. I. C., & Tuveson, D. A. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7342 · Cited by 2,280
“The Neh2 domain contains two highly conserved amino acid stretches, the DLG and ETGE motifs, which mediate the interaction with Nrf2 negative regulator Kelch-like ECH-associated protein 1 (Keap1) and seven lysine residues targeted for ubiquitylation and subsequent proteasomal degradation of Nrf2 (60, 102, 166).”
BackgroundThe Nrf2 regulatory network provides an interface between redox and intermediary metabolism
Hayes, J. D., & Dinkova‐Kostova, A. T. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.02.002 · Cited by 2,210
Metadata
- 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
- 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
- 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
- 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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