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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
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
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-citationHayes, 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
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
Kay, L. E., Keifer, P. A., & Saarinen, T. (1992) · Journal of the American Chemical Society · doi:10.1021/ja00052a088 · Cited by 2,261
Research works printed but not linked: 1
- Garrett D. S., 1991, J. Magn. Reson., 95, 214
Cited by
Sorted by citations
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
The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968
Self-citationThe Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway
Baird, L., & Yamamoto, M. P. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00099-20 · Cited by 1,671
“reported for the shorter DLG motif (Table 3) (91, 98).”
BackgroundInfluentialSelf-citationJain, A., Lamark, T., Sjøttem, E., Bowitz Larsen, K., Atesoh Awuh, J., Øvervatn, A., McMahon, M., Hayes, J. D., & Johansen, T. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.118976 · Cited by 1,472
Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution
Taguchi, K., Motohashi, H., & Yamamoto, M. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01473.x · Cited by 1,478
“These observations contributed to the ‘hinge and latch model’ (Tong et al. 2006b).”
BackgroundMethodInfluentialSelf-citationThe emerging role of the Nrf2–Keap1 signaling pathway in cancerPreprint
Jaramillo, M. C., & Zhang, D. D. (2013) · Genes & Development · doi:10.1101/gad.225680.113 · Cited by 1,326
Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
Ngo, V., & Duennwald, M. L. (2022) · Antioxidants · doi:10.3390/antiox11122345 · Cited by 1,130
The cytoprotective role of the Keap1–Nrf2 pathway
Baird, L., & Dinkova‐Kostova, A. T. (2011) · Archives of Toxicology · doi:10.1007/s00204-011-0674-5 · Cited by 1,051
“4) (McMahon et al. 2006; Tong et al. 2006, 2007; Padmanabhan et al. 2008).”
BackgroundInfluentialOxidative pathways of chemical toxicity and oxidative stress biomarkers in marine organisms
Regoli, F., & Giuliani, M. E. (2013) · Marine Environmental Research · doi:10.1016/j.marenvres.2013.07.006 · Cited by 1,015
Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960
Landscape of genomic alterations in cervical carcinomas
Ojesina, A. I., Lichtenstein, L., Freeman, S. S., Pedamallu, C. S., Imaz-Rosshandler, I., Pugh, T. J., Cherniack, A. D., Ambrogio, L., Cibulskis, K., Bertelsen, B. I., et al. (2013) · Nature · doi:10.1038/nature12881 · Cited by 874
Kobayashi, M., & Yamamoto, M. P. (2006) · Advances in Enzyme Regulation · doi:10.1016/j.advenzreg.2006.01.007 · Cited by 862
Self-citationLau, A., Wang, X.-J., Zhao, F. L., Villeneuve, N. F., Wu, T., Jiang, T., Sun, Z., White, E., & Zhang, D. D. (2010) · Molecular and Cellular Biology · doi:10.1128/mcb.00248-10 · Cited by 852
“Binding of both the DLG and ETGE motifs of Nrf2 to the Kelch domain of a Keap1 homodimer is essential in presenting the lysine residues of Nrf2 in the correct orientation to accept ubiquitin (14, 22, 30).”
BackgroundTebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., & Hayes, J. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.021 · Cited by 837
“Hochmuth CE, Biteau B, Bohmann D, Jasper H. Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila.”
The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update
Lu, M., Ji, J., Jiang, Z., & You, Q. (2016) · Medicinal Research Reviews · doi:10.1002/med.21396 · Cited by 815
Calabrese, V., Cornelius, C., Dinkova‐Kostova, A. T., Calabrese, E. J., & Mattson, M. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.3074 · Cited by 817
“On the basis of a series of elegant studies, McMahon et al. (299, 450, 451) proposed that, first, the ETGE motif of Nrf2 binds to an arginine triad on one of the Keap1 subunits.”
Stress-activated cap’n’collar transcription factors in aging and human disease
Sykiotis, G. P., & Bohmann, D. (2010) · Science Signaling · doi:10.1126/scisignal.3112re3 · Cited by 776
Molecular mechanisms of Nrf2‐mediated antioxidant response
Li, W., & Kong, A. T. (2008) · Molecular Carcinogenesis · doi:10.1002/mc.20465 · Cited by 797
“It is very interesting to observe that in this nine-turns a-helix, six of seven lysine residues are located on the same side [55].”
BackgroundInfluentialSmall Molecule Modulators of Keap1‐ Nrf2‐ ARE Pathway as Potential Preventive and Therapeutic Agents
Magesh, S., Chen, Y., & Hu, L. (2012) · Medicinal Research Reviews · doi:10.1002/med.21257 · Cited by 760
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., & Yamamoto, M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.013 · Cited by 735
Self-citationActivation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis
Li, W., Khor, T. O., Xu, C., Shen, G., Jeong, W.-S., Yu, S., & Kong, A.-N. (2008) · Biochemical Pharmacology · doi:10.1016/j.bcp.2008.07.017 · Cited by 738
“, a high affinity phase I binding, mediated by the ETGE motif and a low affinity phase II binding mediated by the DLG motif, has been distinguished [8].”
BackgroundShibata, T., Ohta, T., Tong, K. I., Kokubu, A., Odogawa, R., Tsuta, K., Asamura, H., Yamamoto, M., & Hirohashi, S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806268105 · Cited by 728
“The double glycine repeat and the C-terminal region of Keap1 (hereafter refer as to Keap1-DC) recognize both the DLG and ETGE motifs of Nrf2 (20, 21).”
BackgroundSelf-citationDirect Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response
Chen, W., Sun, Z., Wang, X.-J., Jiang, T., Huang, Z., Fang, D., & Zhang, D. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.04.029 · Cited by 638
“It is believed that the Keap1 homodimer binds both the 29 DLG and 79 ETGE motifs in Nrf2 to align the seven ubiquitin-accepting lysine residues between these motifs into a conformation suitable for ubiquitin conjugation (McMahon et al., 2006; Tong et al., 2006, 2007; Zhang et al., 2004).”
BackgroundInfluentialLAU, A., VILLENEUVE, N., Sun, Z., Wong, P. K., & Zhang, D. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.09.003 · Cited by 653
“hat bind the Kelch domain of Keap1, which is the proposed hinge nd latch two-site binding model [54,55].”
Backgroundp62 links autophagy and Nrf2 signaling
Jiang, T., Harder, B. G., de la Vega, M. R., Wong, P. K., Chapman, E., & Zhang, D. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.014 · Cited by 657
“According to the hinge and latch model, the ETGE motif has a higher affinity for Keap1 than the DLG motif, which causes the latter to dynamically associate and dissociate from Keap1 to generate oscillating “closed” (associated) and “open” (dissociated) conformations [29–33].”
Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection
Zhang, M., An, C., Gao, Y., Leak, R. K., Chen, J., & Zhang, F. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.09.003 · Cited by 622
“The ETGF motif (KD ≈ 1000 nmol/L) has a higher affinity for Keap1 than the DLG motif (KD ≈ 5.3 nmol/L) (Tong et al., 2006).”
BackgroundInfluentialActivators and inhibitors of NRF2: a review of their potential for clinical development
Robledinos-Antón, N., Fernández-Ginés, R., Manda, G., & Cuadrado, A. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/9372182 · Cited by 413
Structural basis of Keap1 interactions with Nrf2
Canning, P., Sorrell, F. J., & Bullock, A. N. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.05.034 · Cited by 620
Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling
Lo, S., Li, X., Henzl, M. T., Beamer, L. J., & Hannink, M. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601243 · Cited by 604
“…Biology Organization The EMBO Journal VOL 25 | NO 15 | 2006 3613 second Keap1 binding site in Nrf2, containing the consensus sequence LxxQDxDLG and located at a distance of approximately 50 amino acids on the N-terminal side of the DxETGE motif, has recently been identified (Tong et al, 2006).”
BackgroundMethodInfluentialBasic Principles and Emerging Concepts in the Redox Control of Transcription Factors
Brigelius‐Flohé, R., & Flohé, L. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3534 · Cited by 590
“The Neh2 domain is locked in a position suitable for ubiquitination of the Lys residues (325, 485) which, hence, act as ubiquitin acceptors (532).”
BackgroundNrf2 signaling: An adaptive response pathway for protection against environmental toxic insults
Osburn, W. O., & Kensler, T. W. (2007) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2007.11.006 · Cited by 549
“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[3].”
BackgroundCancer Chemoprevention Mechanisms Mediated Through the Keap1–Nrf2 Pathway
Hayes, J. D., McMahon, M. J., Chowdhry, S., & Dinkova‐Kostova, A. T. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3221 · Cited by 549
The KEAP1–NRF2 System in Cancer
Taguchi, K., & Yamamoto, M. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00085 · Cited by 527
“Proc Natl Acad Sci U S A (2011) 108(4):1433–8.”
BackgroundInfluentialSelf-citationPhysiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity
Yamamoto, T., Suzuki, T., Kobayashi, A., Wakabayashi, J., Maher, J. M., Motohashi, H., & Yamamoto, M. P. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01704-07 · Cited by 515
“Although it was shown previously that the BTB domain mediates Keap1 dimerization (40) and that Keap1 remains as a homodimer in a solution (20, 32), the physiological contribution of the BTB domain to the function of Keap1 was still poorly understood.”
BackgroundInfluentialSelf-citationNrf2/Keap1/ARE signaling: Towards specific regulation
Ulasov, A. V., Rosenkranz, A. A., Georgiev, G. P., & Sobolev, A. S. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120111 · Cited by 534
“The Keap1 Kelch domain constitutes a sixbladed β-propeller structure, while the Neh2 domain is intrinsically disordered [206].”
BackgroundDiscovery of the Negative Regulator of Nrf2, Keap1: A Historical Overview
Itoh, K., Mimura, J., & Yamamoto, M. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3222 · Cited by 521
“While the N-terminal subdomain (residues 16–31) contains hydrophobic amino acid residues that can potentially form an amphipathic a -helix (47, 106), the central portion of the domain is rich in hydrophilic residues that may also adopt an a -helical structure (106) (Fig.”
Self-citationReactive Oxygen Species (ROS) Regulates Different Types of Cell Death by Acting as a Rheostat
Villalpando-Rodriguez, G. E., & Gibson, S. B. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/9912436 · Cited by 515
“Conversely, ROS-mediated signaling could activate procell death pathways such a JNK signaling [13, 43, 53].”
BackgroundMcMahon, M. J., Thomas, N., Itoh, K., Yamamoto, M. P., & Hayes, J. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601119200 · Cited by 495
Self-citationOrchestrating Redox Signaling Networks through Regulatory Cysteine Switches
Paulsen, C. E., & Carroll, K. S. (2009) · ACS Chemical Biology · doi:10.1021/cb900258z · Cited by 487
Nrf2 at the heart of oxidative stress and cardiac protection
Chen, Q. M., & Maltagliati, A. J. (2017) · Physiological Genomics · doi:10.1152/physiolgenomics.00041.2017 · Cited by 487
“Binding to both ETGE and DLG domains of Nrf2 is essential for Keap1-mediated ubiquitination, as such motion induces a conformation change of Nrf2 protein within the E3 ubiquitin ligase complex that allows Nrf2 to be polyubiquitinated (150, 215, 217).”
BackgroundNrf2 in cancers: A double‐edged sword
Wu, S., Lu, H., & Bai, Y. (2019) · Cancer Medicine · doi:10.1002/cam4.2101 · Cited by 479
Two-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism
Tong, K. I., Kobayashi, A., Katsuoka, F., & Yamamoto, M. (2006) · Biological Chemistry · doi:10.1515/bc.2006.164 · Cited by 473
“NMR structural analysis revealed that Neh2 is composed of a 33-aa central a-helix, followed by a small anti-parallel b-sheet (Tong et al., 2006).”
BackgroundInfluentialSelf-citationThe complexity of the Nrf2 pathway: beyond the antioxidant response
Huang, Y. S., Li, W., Su, Z., & Kong, A. T. (2015) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2015.08.001 · Cited by 460
“Nrf2 has two binding motifs in the Neh2 domain, the ETGE and DLG motifs, and recruits two molecules of Keap1 in the absence of stimuli [47, 48].”
BackgroundTong, K. I., Padmanabhan, B., Kobayashi, A., Shang, C., Hirotsu, Y., Yokoyama, S., & Yamamoto, M. P. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00753-07 · Cited by 459
“Our previous nuclear magnetic resonance chemical shift perturbation study suggested that both DLG and ETGE interact with an overlapping binding surface on Keap1-DC composed of conserved arginine residues (39).”
BackgroundMethodInfluentialSelf-citationSignal amplification in the KEAP1-NRF2-ARE antioxidant response pathway
Liu, S., Pi, J., & Zhang, Q. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102389 · Cited by 471
Villeneuve, N. F., Lau, A., & Zhang, D. D. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3211 · Cited by 423
Suzuki, T., & Yamamoto, M. P. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.800169 · Cited by 412
“This two-site recognition/binding mechanism of the Nrf2 Neh2 domain and Keap1 homodimer is essential for the efficient ubiquitination of Nrf2 (31, 33, 34).”
BackgroundMethodSelf-citationThe Keap1–Nrf2 system in cancers: stress response and anabolic metabolism
Mitsuishi, Y., Motohashi, H., & Yamamoto, M. P. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00200 · Cited by 411
“Two DC domains of the Keap1 homodimer associate with one molecule of Nrf2 (Tong et al., 2006).”
BackgroundSelf-citationCanonical and non-canonical mechanisms of Nrf2 activation
Silva‐Islas, C. A., & Maldonado, P. D. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.06.013 · Cited by 404
Activation of NRF2 by Nitrosative Agents and H2O2 Involves KEAP1 Disulfide Formation
Fourquet, S., Guérois, R., Biard, D. S. F., & Tolédano, M. B. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.051714 · Cited by 389
Proteasomal Degradation Is Transcriptionally Controlled by TCF11 via an ERAD-Dependent Feedback Loop
Steffen, J., Seeger, M., Koch, A., & Krüger, E. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.012 · Cited by 366
Keap1–Nrf2 Signaling: A Target for Cancer Prevention by Sulforaphane
Kensler, T. W., Egner, P. A., Agyeman, A. S., Visvanathan, K., Groopman, J. D., Chen, J., Chen, T.-Y., Fahey, J. W., & Talalay, P. (2012) · Topics in current chemistry · doi:10.1007/128_2012_339 · Cited by 363
Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin
Kim, Y. R., Oh, J. E., Kim, M. S., Kang, M. R., Park, S. W., Han, J. Y., Eom, H., Yoo, N. J., & Lee, S. H. (2009) · The Journal of Pathology · doi:10.1002/path.2653 · Cited by 357
“KEAP1 normally exists as a homodimer, and one NRF molecule interacts with two KEAP1 molecules via two binding sites, the stronger binding the ETGE motif and the weaker binding the DLG motif [16,17].”
BackgroundNatural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases
Kumar, H., Kim, I., More, S. V., Kim, B.-W., & Choi, D. (2013) · Natural Product Reports · doi:10.1039/c3np70065h · Cited by 338
Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants
Dinkova‐Kostova, A. T., Kostov, R. V., & Canning, P. (2016) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2016.08.005 · Cited by 340
“Nrf2 protein, known as the ETGE and DLG motifs [37].”
BackgroundSun, Z., Zhang, S., Chan, J. Y., & Zhang, D. D. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00630-07 · Cited by 332
“In accordance with our data, Zhang and colleagues have recently demonstrated that Keap1 does not regulate Nrf1, although the Keap1 binding motif is conserved in Nrf1(49).”
BackgroundInfluentialThe Nrf2–Keap1 defence pathway: Role in protection against drug-induced toxicity
Copple, I. M., Goldring, C. E., Kitteringham, N. R., & Park, B. K. (2007) · Toxicology · doi:10.1016/j.tox.2007.10.029 · Cited by 336
Nrf2—a therapeutic target for the treatment of neurodegenerative diseases
Johnson, D. A., & Johnson, J. A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.07.147 · Cited by 333
“When Keap1 senses oxidative or electrophilic stress, the low-affinity domain binding Nrf2 is abolished and proteosomal degradation of Nrf2 is disrupted [49].”
BackgroundAbed, D. A., Goldstein, M., Albanyan, H., Jin, H., & Hu, L. (2015) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2015.05.008 · Cited by 336
Davies, T. G., Wixted, W. E., Coyle, J. E., Griffiths-Jones, C., Hearn, K., McMenamin, R., Norton, D., Rich, S. J., Richardson, C., Saxty, G., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00228 · Cited by 322
Molecular Basis of Electrophilic and Oxidative Defense: Promises and Perils of Nrf2
Ma, Q., & He, X. (2012) · Pharmacological Reviews · doi:10.1124/pr.110.004333 · Cited by 317
“A series of peptide inhibitors were synthesized based on the Nrf2 Neh2 domain and the peptide sequences of p62 and prothymosin-α , which are known to bind Keap1 DC competitively with Nrf2 Neh2.”
InfluentialPGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria
Lo, S.-C., & Hannink, M. (2008) · Experimental Cell Research · doi:10.1016/j.yexcr.2008.02.014 · Cited by 300
“Biophysical studies have suggested the existence of a second motif in Nrf2 that also binds to the Kelch domain of Keap1, leading to a model in which the Keap1 dimer binds a single molecule of Nrf2, resulting in a Keap1–Nrf2 complex with a 2:1 stoichiometry [58–60].”
BackgroundRedox Control of Microglial Function: Molecular Mechanisms and Functional Significance
Rojo, A. I., McBean, G. J., Cindrić, M., Egea, J., López, M. G., Rada, P., Žarković, N., & Cuadrado, A. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5745 · Cited by 323
“It is thought that a single NRF2 polypeptide first binds one KEAP1 subunit through its high-affinity ETGE motif, and that this, in turn, enables the second low-affinity DLG motif to engage with the other Kelch-repeat domain of the remaining KEAP1 subunit (186, 313).”
Molecular Basis of the KEAP1-NRF2 Signaling Pathway
Suzuki, T., Takahashi, J. A., & Yamamoto, M. P. (2023) · Molecules and Cells · doi:10.14348/molcells.2023.0028 · Cited by 320
“The stoichiometry of KEAP1 and NRF2 within the KEAP1-NRF2 complex is 2:1, which is shown by means of isothermal calorimetry analysis (Tong et al., 2006a), nuclear magnetic resonance (NMR) titration analyses (Horie et al., 2021; Tong et al., 2006a), and an analytical centrifugation analysis (Iso et…”
BackgroundMethodInfluentialSelf-citationStructural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases
Canning, P., Cooper, C. D. O., Krojer, T., Murray, J. W., Pike, A. C. W., Chaikuad, A., Keates, T., Thangaratnarajah, C., Hojzan, V., Marsden, B. D., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.437996 · Cited by 284
The KEAP1-NRF2 pathway: Targets for therapy and role in cancer
Adinolfi, S., Patinen, T., Deen, A. J., Pitkänen, S., Härkönen, J., Kansanen, E., Küblbeck, J., & Levonen, A. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102726 · Cited by 326
“The interaction between NRF2 and KEAP1 is mediated via ETGE and DLG motifs at the Neh2 domain of NRF2 [14] (Fig.”
BackgroundThe Nrf2/HO‐1 Axis in Cancer Cell Growth and Chemoresistance
Furfaro, A. L., Traverso, N., Domenicotti, C., Piras, S., Moretta, L., Marinari, U. M., Pronzato, M. A., & Nitti, M. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1958174 · Cited by 303
Singh, S., Vrishni, S., Singh, B. K., Rahman, I., & Kakkar, P. (2010) · Free Radical Research · doi:10.3109/10715762.2010.507670 · Cited by 305
“Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto [35]”
BackgroundThe Role of Nrf2 in Cardiovascular Function and Disease
Satta, S., Mahmoud, A. M., Wilkinson, F. L., Alexander, M. Y., & White, S. J. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/9237263 · Cited by 306
“The Neh2 domain contains the Keap1 binding site (DLG and ETGE motifs), necessary for its cytoplasmic retention and degradation [55].”
BackgroundKEAP1 and done? Targeting the NRF2 pathway with sulforaphane
Dinkova-Kostova, A. T., Fahey, J. W., Kostov, R. V., & Kensler, T. W. (2017) · Trends in Food Science & Technology · doi:10.1016/j.tifs.2017.02.002 · Cited by 273
“As reviewed elsewhere, dozens of targets and pathways have been identi fi ed as potential mediators of the chemoprotective actions of sulforaphane (Brown & Hampton, 2011; Hayes et al., 2008; Zhang, 2012): few have undergone serious validation.”
BackgroundInfluentialPark, C. H., Lee, S. L., Okamoto, T., Tanaka, T., & Yokozawa, T. (2012) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2012/587902 · Cited by 282
“On the other hand, oxidative stress induces alterations in the Nrf2 complex, and its gene transcription, such as that of HO-1, is enhanced [25].”
BackgroundSelf-citationNRF2 addiction in cancer cells
Kitamura, H., & Motohashi, H. (2018) · Cancer Science · doi:10.1111/cas.13537 · Cited by 285
Protein S-guanylation by the biological signal 8-nitroguanosine 3′,5′-cyclic monophosphate
Sawa, T., Zaki, M. H., Okamoto, T., Akuta, T., Tokutomi, Y., Kim‐Mitsuyama, S., Ihara, H., Kobayashi, A., Yamamoto, M. P., Fujii, S., et al. (2007) · Nature Chemical Biology · doi:10.1038/nchembio.2007.33 · Cited by 274
“His-tagged mouse recombinant Keap1 was expressed in Escherichia coli and purified as described elsewher”
MethodSelf-citationChen, Y., Yang, Z., Meng, M., Zhao, Y., Dong, N., Yan, H., Liu, L., Ding, M., Peng, H. B., & Shao, F. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.004 · Cited by 270
“In the best-studied Cul3/Keap1/Nrf2 complex, a Keap1 homodimer recognizes both the DLG and ETGE motif within one Nrf2 molecule (Tong et al., 2006).”
BackgroundShaping the Nrf2-ARE-related pathways in Alzheimer’s and Parkinson’s diseases
Fão, L., Mota, S. I., & Rego, A. C. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100942 · Cited by 281
Role of Nrf2 and Its Activators in Respiratory Diseases
Liu, Q., Gao, Y., & Ci, X. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/7090534 · Cited by 280
“Several mechanisms for the activation of Nrf2 by Keap1 have been proposed as the following up to now [17, 19, 20].”
BackgroundCrisman, E., Duarte, P., Daudén, E., Cuadrado, A., Rodríguez-Franco, M. I., López, M. G., & Leon, R. M. (2022) · Medicinal Research Reviews · doi:10.1002/med.21925 · Cited by 289
“There are only KEAP1 binding data and crystallographic information, but there is a lack of competition experiments with NRF2.”
BackgroundInfluentialBeyond repression of Nrf2: An update on Keap1
Kopacz, A., Klóska, D., Forman, H. J., Józkowicz, A., & Grochot‐Przeczek, A. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.03.023 · Cited by 269
“Many methods were implemented to study this interaction and to establish the minimal interacting fragment, including surface plasmon resonance [105], fluorescence polarisation assay [106], FRET [107], and ITC [108].”
MethodFukutomi, T., Takagi, K., Mizushima, T., Ohuchi, N., & Yamamoto, M. P. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01191-13 · Cited by 267
“(B) A GST pulldown assay with 6 His-GST-tagged WT Neh2(1-56) or mutant forms thereof with purified recombinant Keap1-His.”
BackgroundMethodInfluentialSelf-citationStructure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO
Cleasby, A., Yon, J. R., Day, P. J., Richardson, C. J., Tickle, I. J., Williams, P. A., Callahan, J. F., Carr, R. A. E., Concha, N. O., Kerns, J. K., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098896 · Cited by 271
Cullin-RING Ubiquitin Ligase Regulatory Circuits: A Quarter Century Beyond the F-Box Hypothesis
Harper, J. W., & Schulman, B. A. (2021) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-090120-013613 · Cited by 262
Hast, B. E., Goldfarb, D., Mulvaney, K. M., Hast, M. A., Siesser, P. F., Yan, F., Hayes, D. N., & Major, M. B. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4400 · Cited by 259
“Crystallographic modeling revealed that NRF2 binds KEAP1 near the central pore of the KELCHβ-propeller (Figure 4E) (10, 13, 32).”
NRF2, a Superstar of Ferroptosis
Yan, R., Lin, B., Jin, W., Tang, L., Hu, S., & Cai, R. (2023) · Antioxidants · doi:10.3390/antiox12091739 · Cited by 292
“As mentioned above, under normal circumstances, two molecules of Keap1 bind to the ETGE and DLG motifs on the Neh2 domain of NRF2 via its Kelch repeat domain [44,59].”
Giudice, A., Arra, C., & Turco, M. C. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-738-9_3 · Cited by 254
“With regards to the importance of Nrf2 phosphorylation, two Nrf2 phosphorylation events have been recognized to modulate Nrf2 nuclear import/export in response to various chemopreventive agents (51).”
BackgroundInfluentialKeap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy
Fan, W., Tang, Z., Chen, D., Moughon, D., Ding, X., Chen, S., Zhu, M., & Zhong, Q. (2010) · Autophagy · doi:10.4161/auto.6.5.12189 · Cited by 251
Marcotte, D. J., Zeng, W., Hus, J., McKenzie, A., Hession, C., Jin, P., Bergeron, C., Lugovskoy, A. A., Enyedy, I. J., Cuervo, H., et al. (2013) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2013.04.019 · Cited by 251
Galea, C. A., Wang, Y., Sivakolundu, S. G., & Kriwacki, R. W. (2008) · Biochemistry · doi:10.1021/bi8006803 · Cited by 258
Rojo, A. I., de Sagarra, M. R., & Cuadrado, A. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05124.x · Cited by 246
Hammad, M., Raftari, M., Cesário, R., Salma, R., Godoy, P. R. D. V., Emami, S. N., & Haghdoost, S. (2023) · Antioxidants · doi:10.3390/antiox12071371 · Cited by 258
“One of the most-known hyper-reactive cysteines of Keap1 is Cys151, which is located at the BTB domain and is flanked by the basic residues His129, Lys131, Arg135, Lys150, and His154 [51].”
BackgroundEggler, A. L., Gay, K. A., & Mesecar, A. D. (2008) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.200700249 · Cited by 234
“2A) that mediate binding to the Keap1 Kelch repeats [20, 21].”
Ogura, T., Tong, K. I., Mio, K., Maruyama, Y., Kurokawa, H., Sato, C., & Yamamoto, M. P. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914036107 · Cited by 232
“The NMR analysis further revealed that the α-helix is mostly rigid, whereas the region from the N-terminal to the α-helix is rather flexible (27).”
BackgroundMethodInfluentialSelf-citationThe rise of antioxidant signaling—The evolution and hormetic actions of Nrf2
Maher, J. M., & Yamamoto, M. P. (2010) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2010.01.011 · Cited by 235
Self-citationThe Keap1-Nrf2 system and diabetes mellitus
Uruno, A., Yagishita, Y., & Yamamoto, M. (2015) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.12.012 · Cited by 231
Antioxidants in Translational Medicine
Schmidt, H. H. H. W., Stocker, R., Vollbracht, C., Paulsen, G., Riley, D. P., Daiber, A., & Cuadrado, A. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6393 · Cited by 232
“Adduct formation with electrophiles induces a conformational change in KEAP1 that prevents further degradation of NRF2 (145).”
BackgroundStructural assembly of cullin-RING ubiquitin ligase complexes
Zimmerman, E. S., Schulman, B. A., & Zheng, N. (2010) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2010.08.010 · Cited by 227
Mechanism of the Nrf2/Keap1/ARE signaling system
Tkachev, V., Брониславовна, М. Е., & Зенков, Н. К. (2011) · Biochemistry (Moscow) · doi:10.1134/s0006297911040031 · Cited by 229
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
