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Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling
Open accessAbstract
Keap1 is a BTB-Kelch substrate adaptor protein that regulates steady-state levels of Nrf2, a bZIP transcription factor, in response to oxidative stress. We have determined the structure of the Kelch domain of Keap1 bound to a 16-mer peptide from Nrf2 containing a highly conserved DxETGE motif. The Nrf2 peptide contains two short antiparallel beta-strands connected by two overlapping type I beta-turns stabilized by the aspartate and threonine residues. The beta-turn region fits into a binding pocket on the top face of the Kelch domain and the glutamate residues form multiple hydrogen bonds with highly conserved residues in Keap1. Mutagenesis experiments confirmed the role of individual amino acids for binding of Nrf2 to Keap1 and for Keap1-mediated repression of Nrf2-dependent gene expression. Our results provide a detailed picture of how a BTB-Kelch substrate adaptor protein binds to its cognate substrate and will enable the rational design of novel chemopreventive agents.
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“Crystal structures of peptide substrate complexes have been reported for four BTB-Kelch family members, including KEAP1, KLHL2, KLHL3 and KLHL20 (refs 80,81,82 ).”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [80]
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Ma, Q. (2013) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-011112-140320 · Cited by 4,903
“Neh2 interacts with Keap1 DC in a ratio of 1:2 through its ETGE and DLG motifs (43, 49, 50).”
BackgroundROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis
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“104) .”
BackgroundThe 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
“The loops which connect the -strands form a pocket on the bottom surface of the Kelch domain which provides the interface through which the ETGE motif (79Glu-Thr-Gly-Glu82) within the Neh2 domain of NRF2 binds to KEAP1 (95, 96).”
BackgroundUbiquitin ligases: structure, function, and regulation
Zheng, N., & Shabek, N. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014922 · Cited by 1,499
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The 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
“The BTB domain binds Cul3 and is required for Keap1 dimerization (Zipper and Mulcahy 2002; Lo et al. 2006).”
BackgroundSmall molecules, big targets: drug discovery faces the protein–protein interaction challenge
Scott, D. E., Bayly, A. R., Abell, C., & Skidmore, J. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.29 · Cited by 1,137
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
“In total, 13 intermolecular interactions are formed between Keap1 and Nrf2 (Padmanabhan et al. 2006; Lo et al. 2006).”
BackgroundMethodInfluentialLu, H., Zhou, Q., He, J., Jiang, Z., Peng, C., Tong, R., & Shi, J. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-00315-3 · Cited by 891
“In 2006, Hannink’s group analyzed the structure of a complex between the Kelch domain of Keap1 and Nrf2-derrived peptide, thus revealed the binding interface between Nrf2 and Keap1, and determined the key residues of Keap1, including Arg380, Arg415, Arg483, Ser363, Ser508, Ser555, and Ser602, which laid the foundation…”
BackgroundTargeted 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
NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer
Hayes, J. D., & McMahon, M. J. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.12.008 · Cited by 870
The eIF2α kinases: their structures and functions
Donnelly, N., Gorman, A. M., Gupta, S., & Samali, A. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1252-6 · Cited by 906
“In the context of the UPR, NRF2 undergoes PERK-mediated threonine phosphorylation at position 80 whereupon its binding to KEAP1 is disrupted [121] and NRF2 migrates to the nucleus where it induces the expression of its target genes.”
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
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
Surh, Y., Kundu, J. K., & Na, H. (2008) · Planta Medica · doi:10.1055/s-0028-1088302 · Cited by 758
“…to activation of Nrf2 through oxidation or chemical modification of Keap1 cysteine thiols, phosphorylation of specific serine [27] or threonine[26] residues of Nrf2 may facilitate the release of Nrf2 from the Keap1 repression and its subsequent nu-Fig.1 Proposed mechanisms for…”
Small 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
Shibata, 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
“Whereas T80 has both inter- and intramolecular interactions, Q75 has intramolecular contact (14, 21, 22).”
BackgroundMethodGenetic landscape of esophageal squamous cell carcinoma
Gao, Y., Chen, Z.-L., Li, J.-G., Hu, X.-D., Shi, X.-J., Sun, Z.-M., Zhang, F., Zhao, Z.-R., Li, Z.-T., Liu, Z.-Y., et al. (2014) · Nature Genetics · doi:10.1038/ng.3076 · Cited by 695
LAU, A., VILLENEUVE, N., Sun, Z., Wong, P. K., & Zhang, D. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.09.003 · Cited by 653
“[29] Lo SC, Li X, Henzl MT, Beamer LJ, Hannink M.”
BackgroundMutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities
Boyden, L. M., Choi, M., Choate, K. A., Nelson-Williams, C. J., Farhi, A., Toka, H. R., Tikhonova, I. R., Bjornson, R. D., Mane, S., Colussi, G., et al. (2012) · Nature · doi:10.1038/nature10814 · Cited by 651
“Dominant KLHL3 mutations are clustered in short segments within the kelch propeller and BTB domains implicated in substrat”
BackgroundTranscription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
Cuadrado, A., Manda, G., Hassan, A., Alcaraz, M. J., Barbas, C., Daiber, A., Ghezzi, P., León, R., López, M. G., Oliva, B., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014753 · Cited by 632
“The use of PPI inhibitors has been achieved by the prior elucidation of the X-ray crystal structure of KEAP1 (Padmanabhan et al., 2006) bound to a peptide containing the high-affinity binding ETGE motif of NRF2 (Lo et al., 2006).”
BackgroundActivators 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
“5- Å resolution in complex with the Kelch domain of human Keap1 [36].”
BackgroundPiantadosi, C. A., Carraway, M. S., Babiker, A., & Suliman, H. B. (2008) · Circulation Research · doi:10.1161/01.res.0000338597.71702.ad · Cited by 581
Basic 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 structure of the kelch/DGR domain of Keap1 has recently been resolved (297, 362), which sheds new light on the Keap1/Nrf2 interaction (484) (Fig.”
BackgroundThe integrated landscape of driver genomic alterations in glioblastoma
Frattini, V., Trifonov, V., Chan, J. M., Castano, A., Lia, M., Abate, F., Keir, S. T., Ji, A. X., Zoppoli, P., Niola, F., et al. (2013) · Nature Genetics · doi:10.1038/ng.2734 · Cited by 524
Cancer 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 BTB domain in Keap1 allows it to form a homodimer (355), and the Kelch-repeat domain, along with the CTR, forms a six-bladed b-propeller that serves as a protein-docking site (185, 199, 247).”
The Cullin-RING Ubiquitin-Protein Ligases
Hua, Z., & Vierstra, R. D. (2011) · Annual Review of Plant Biology · doi:10.1146/annurev-arplant-042809-112256 · Cited by 523
Nrf2/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
“Protein data bank (PDB) discloses several dozen of the Keap1 structures, in bound and unbound states [207,22,169,208].”
BackgroundZhuang, M., Calabrese, M. F., Liu, J., Waddell, M. B., Nourse, A., Hammel, M., Miller, D. J., Walden, H., Duda, D. M., Seyedin, S. N., et al. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.022 · Cited by 486
“The best-understood Cul3 adaptor is the BTB-Kelch protein Keap1, which mediates turnover of the Nrf2 transcription factor in oxidative stressresponse paths (Cullinan et al., 2004; McMahon et al., 2003; Zhang and Hannink, 2003; Zhang et al., 2004).”
Rada, P., Rojo, A. I., Evrard‐Todeschi, N., Innamorato, N. G., Cotte, A., Jaworski, T., Tobón-Velasco, J. C., Devijver, H., García‐Mayoral, M. F., LEUVEN, F. V., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00180-12 · Cited by 485
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“Asp-77 was suggested to participate in intramolecular bonding with Glu-79, Thr-80, and Gly-81 in the Keap1-bound form of the ETGE peptide (24, 33), and this residue also makes contacts with Keap1 via water molecules (24).”
BackgroundResultInfluentialSignal 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
Solis, L. M., Behrens, C., Dong, W., Suraokar, M. B., Ozburn, N. C., Moran, C. A., Corvalán, A. H., Biswal, S. S., Swisher, S. G., Bekele, B. N., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3352 · Cited by 430
Canonical 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
“In homeostatic conditions, the four-residue β-hairpin conformation of the ETGE motif in Nrf2, specifically, amino acid residues E78, E79, T80, E82 and F83, interacts with the bottom surface of the six-bladed-βpropeller structure of the Kelch domain of one protomer of a Keap1 homodimer (Y334, S363, R380, D382, R415, R4…”
A metabolite-derived protein modification integrates glycolysis with KEAP1–NRF2 signalling
Bollong, M. J., Lee, G., Coukos, J. S., Yun, H., Zambaldo, C., Chang, J. W., Chin, E. N., Ahmad, I., Chatterjee, A. K., Lairson, L. L., et al. (2018) · Nature · doi:10.1038/s41586-018-0622-0 · Cited by 344
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
“The ETGE motif folds into a b-turn and inserts into the substrate binding pocket of the Keap1 Kelch domain, forming specific electrostatic interactions between the sidechains of E79 and E82 of Nrf2 and several Keap1 residues lining the substrate binding [50,51].”
BackgroundThe 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
Abed, 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
“The crystal structures of human Keap1 Kelch domain bound with Nrf2 ETGE motif and mouse Keap1 DC domain bound with either ETGE or DLG revealed the interaction between Nrf2 and Keap1 at the binding interface in more details (Lo et al., 2006; Padmanabhan et al., 2006; Tong et al., 2007).”
PGAM5 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
“Taken together, these results indicate that PGAM5-L, Keap1 and Nrf2 form a ternary complex at mitochondria.”
BackgroundInfluentialSelf-citationPERK promotes cancer cell proliferation and tumor growth by limiting oxidative DNA damage
Bobrovnikova-Marjon, E. V., Grigoriadou, C., Pytel, D., Zhang, F., Ye, J., Koumenis, C., Cavener, D. R., & Diehl, J. A. (2010) · Oncogene · doi:10.1038/onc.2010.153 · Cited by 320
“The threonine 80 is essential for Keap1-Nrf2 binding (Lo et al., 2006), providing a biochemical basis for phosphorylation-dependent disruption of the Keap1-Nrf2 interaction.”
InfluentialStructural 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
“Finally, the Kelch domain and substrate from the KEAP1-Nrf2 complex (PDB 2FLU) (51) were modeled atop helix 14 of the BACK domain of KLHL11.”
BackgroundMethodInfluentialThe hallmarks of P arkinson's disease
Antony, P. M. A., Diederich, N. J., Krüger, R., & Balling, R. (2013) · FEBS Journal · doi:10.1111/febs.12335 · Cited by 317
Singh, S., Vrishni, S., Singh, B. K., Rahman, I., & Kakkar, P. (2010) · Free Radical Research · doi:10.3109/10715762.2010.507670 · Cited by 305
“that interact with Arginine, Serine, Asparagine residues of DGR regions of Keap1 dimer in a non-overlapping manner [34].”
BackgroundGenschik, P., Sumara, I., & Lechner, E. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.173 · Cited by 278
“For example, phosphorylation of the conserved threonine residue within the Nrf2 ETGE degron (see above) has the capability of disrupting its interaction with Keap1 and stabilising Nrf2 in cells (Lo et al , 2006).”
Crisman, 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
“NRF2‐ETGE‐motif‐containing peptides cocrystallized with KEAP1‐Kelch domain adopt a β‐hairpin conformation within the binding site that comprises residues Asp77, Glu78, Glu79, Thr80, Gly81, and Glu82.(59,61) This conformation is stabilized by an intramolecular hydrogen bonds network involving backbone atoms of residues”
BackgroundBeyond 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
“containing Nrf2 ETGE motif [107,111], or even 9 aa- (LDEETGEFL) or 7 aa-long (DEETGEF) sequences [105,106]).”
BackgroundJiang, Z., Lu, M., Xu, L., Yang, T., Xi, M., Xu, X., Guo, X., Zhang, X., You, Q., & Sun, H.-P. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm5000529 · Cited by 263
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).”
Giudice, A., Arra, C., & Turco, M. C. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-738-9_3 · Cited by 254
“They have also revealed that the IVR domain of Keap1 contains an NES between amino acids 272 and 312 with a conserved leucine-rich sequence (amino acids 301–310) similar to that seen in other proteins exported by Crm1/Exportin (93).”
BackgroundShibata, S., Zhang, J., Puthumana, J., Stone, K. L., & Lifton, R. P. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1304592110 · Cited by 253
“This inference is supported by data from the crystal structure of another Kelch-domain targeting molecule, Kelch-like ECH-associated protein 1 (KEAP1), and one of its targets, Nuclear factor erythroid 2-related factor 2 (NRF2).”
BackgroundInfluentialPiantadosi, C. A., Withers, C. M., Bartz, R. R., MacGarvey, N. C., Fu, P. P., Sweeney, T. E., Welty‐Wolf, K. E., & Suliman, H. B. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.207738 · Cited by 250
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
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
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
“Discussion The x-ray structure of the Keap1DC β-propeller domain has been solved both with and without substrate peptides (15, 30, 31, 40).”
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
Ohta, A., Schumacher, F., Mehellou, Y., Johnson, C., Knebel, A., Macartney, T., Wood, N. T., Alessi, D. R., & Kurz, T. (2013) · Biochemical Journal · doi:10.1042/bj20121903 · Cited by 225
Preparation and identification of antioxidant peptides from cottonseed proteins
Wang, L., Ma, M., Yu, Z., & Du, S. (2021) · Food Chemistry · doi:10.1016/j.foodchem.2021.129399 · Cited by 210
Oxidative Stress in Alzheimer’s Disease: Are We Connecting the Dots?
Rosini, M., Simoni, E., Milelli, A., Minarini, A., & Melchiorre, C. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400970m · Cited by 202
Lo, S.-C., & Hannink, M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606539200 · Cited by 199
Self-citationComprehensive analysis of loops at protein-protein interfaces for macrocycle design
Gavenonis, J., Sheneman, B. A., Siegert, T. R., Eshelman, M. R., & Kritzer, J. A. (2014) · Nature Chemical Biology · doi:10.1038/nchembio.1580 · Cited by 201
An Overview of the Nrf2/ARE Pathway and Its Role in Neurodegenerative Diseases
Zgórzyńska, E., Dziedzic, B., & Walczewska, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179592 · Cited by 215
“According to this “hinge and latch” model, the stoichiometric ratio of Keap1 to Nrf2 in the complex should be 2:1; however, studies did not confirm this ratio [50].”
ResultPALB2 Interacts with KEAP1 To Promote NRF2 Nuclear Accumulation and Function
Ma, J., Cai, H., Wu, T., Sobhian, B., Huo, Y., Alcivar, A. L., Mehta, M., Cheung, K. L., Ganesan, S., Kong, A. T., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06271-11 · Cited by 193
“Therefore, we conclude that the ETGE motif of PALB2 directly interacts with the kelch domain of KEAP1 in a fashion similar to the NRF2(ETGE)-KEAP1 interaction (12, 19).”
BackgroundDysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance
Raghunath, A., Sundarraj, K., Arfuso, F., Sethi, G., & Perumal, E. (2018) · Cancers · doi:10.3390/cancers10120481 · Cited by 187
“The Kelch domain of two Keap1 units binds to the Neh2 ETGE motif with high affinity and DLG motifs with low affinity separately [77].”
BackgroundCino, E. A., Choy, W., & Karttunen, M. (2012) · Journal of Chemical Theory and Computation · doi:10.1021/ct300323g · Cited by 191
Binding Mode and Structure–Activity Relationships around Direct Inhibitors of the Nrf2–Keap1 Complex
Jnoff, E., Albrecht, C., Barker, J. J., Barker, O., Beaumont, E., Bromidge, S. M., Brookfield, F. A., Brooks, M., Bubert, C., Ceska, T., et al. (2014) · ChemMedChem · doi:10.1002/cmdc.201300525 · Cited by 180
The Keap1–Nrf2 Cell Defense Pathway – A Promising Therapeutic Target?
Copple, I. M. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-398339-8.00002-1 · Cited by 174
Keap Calm, and Carry on Covalently
Wilson, A. J., Kerns, J. K., Callahan, J. F., & Moody, C. J. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400224q · Cited by 171
Targeting the Nrf2 pathway against cardiovascular disease
Li, J., Ichikawa, T., Janicki, J. S., & Cui, T. (2009) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220903025762 · Cited by 168
“Although the precise molecular mechanisms of Nrf2 activation are not fully understood, an increasing body of evidence has revealed that Keap1 plays a central role in the regulation of Nrf2 protein stability and Nrf2-driven transcriptional activity [24,41-45].”
BackgroundNrf2 Regulation by Curcumin: Molecular Aspects for Therapeutic Prospects
Shahcheraghi, S. H., Salemi, F., Peirovi, N., Ayatollahi, J., Alam, W., Khan, H. Z., & Saso, L. (2021) · Molecules · doi:10.3390/molecules27010167 · Cited by 169
Marrot, L., Jones, C., Perez, P., & Meunier, J. (2008) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2007.00424.x · Cited by 164
“In any case, the essential role of Keap1-Nrf2 status in modulation of endogenous antioxidant defenses is now well established (Lo et al., 2006 for review).”
BackgroundThe Role of NRF2/KEAP1 Signaling Pathway in Cancer Metabolism
Song, M.-Y., Lee, D.-Y., Chun, K., & Kim, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094376 · Cited by 170
“The BTB domain binds with Cul3 and mediates KEAP1 homodimerization that is critical for ubiquitination and the proteasomal degradation of NRF2 [44,45].”
BackgroundZhuang, C., Narayanapillai, S. C., Zhang, W., Sham, Y. Y., & Xing, C. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm4017174 · Cited by 159
Keap1/Cullin3 Modulates p62/SQSTM1 Activity via UBA Domain Ubiquitination
Lee, Y., Chou, T., Pittman, S. K., Keith, A. L., Razani, B., & Weihl, C. C. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.03.030 · Cited by 159
“This model is similar to alternative models of Keap1, which suggests that a homodimer can associate with two Nrf2 molecules or with Nrf2 and a second protein with a KIR motif, such as PGAM5, which then targets this complex to the mitochondria (Lo and Hannink, 2006; Lo et al., 2006).”
MethodCysteine-based regulation of the CUL3 adaptor protein Keap1
Sekhar, K. R., Rachakonda, G., & Freeman, M. L. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.06.016 · Cited by 156
“Cell-based studies suggest that Nrf2 binds to Keap1 with a 2:2 stoichiometry (Lo et al., 2006) whereas biophysical and biochemical studies support a 1:2 stoichiometry (Tong et al.”
Fujii, S., Sawa, T., Ihara, H., Tong, K. I., Ida, T., Okamoto, T., Ahmed, K. A., Ishima, Y., Motohashi, H., Yamamoto, M. P., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.145441 · Cited by 152
Peptide inhibitors of the Keap1–Nrf2 protein–protein interaction
Hancock, R., Bertrand, H. C., Tsujita, T., Naz, S., El-Bakry, A., Laoruchupong, J., Hayes, J. D., & Wells, G. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.10.486 · Cited by 151
Mészáros, B., Kumar, M., Gibson, T. J., Uyar, B., & Dosztányi, Z. (2017) · Science Signaling · doi:10.1126/scisignal.aak9982 · Cited by 147
Protein-structure-guided discovery of functional mutations across 19 cancer types
Niu, B., Scott, A. D., Sengupta, S., Bailey, M. H., Batra, P., Ning, J., Wyczalkowski, M. A., Liang, W.-W., Zhang, Q., McLellan, M. D., et al. (2016) · Nature Genetics · doi:10.1038/ng.3586 · Cited by 142
“Two of the residues for which variants were identified, Arg415 and Arg483 in KEAP1, have been experimentally validated, and both have been shown to be in the KEAP1 binding pocket and to have a major role in the stability of the KEAP1–NFE2L2 complex 22 .”
BackgroundMutant p53-Associated Molecular Mechanisms of ROS Regulation in Cancer Cells
Cordani, M., Butera, G., Pacchiana, R., Masetto, F., Mullappilly, N., Riganti, C., & Donadelli, M. (2020) · Biomolecules · doi:10.3390/biom10030361 · Cited by 145
“In normal conditions, Nrf2 is ubiquitinated and degraded by its association with Kelch-like ECH-associated protein-1 (Keap1) [44].”
BackgroundLuo, X., Weng, X., Bao, X., Bai, X., Lv, Y., Zhang, S., Chen, Y., Zhao, C., Zeng, M., Huang, J., et al. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102511 · Cited by 144
“reported that KEAP1-R483A mutant is unable to bind to NRF2 and repress NRF2 activity [50], which is contradictory to our finding.”
ResultInnamorato, N. G., Jaźwa, A., Rojo, A. I., García, C., Fernández‐Ruíz, J., Grochot‐Przeczek, A., Stachurska, A., Józkowicz, A., Dulak, J., & Cuadrado, A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011838 · Cited by 141
“Nrf2 has a very short half life due to its interaction with the BTB-Kelch protein Keap1 that promotes Nrf2 degradation by the proteasome [20].”
BackgroundCancer-Derived Mutations in KEAP1 Impair NRF2 Degradation but not Ubiquitination
Hast, B. E., Cloer, E. W., Goldfarb, D., Li, H., Siesser, P. F., Yan, F., Walter, V., Zheng, N., Hayes, D. N., & Major, M. B. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-1655 · Cited by 138
“One mutation, V155F occurred in two separate tumors, and interestingly, none of the mutations in KEAP1 were in residues that directly interface with NRF2 (20).”
Anuranjani, & Bala, M. (2014) · Redox Biology · doi:10.1016/j.redox.2014.02.008 · Cited by 138
Nrf2 activation through the inhibition of Keap1–Nrf2 protein–protein interaction
Lee, S., & Hu, L. (2020) · Medicinal Chemistry Research · doi:10.1007/s00044-020-02539-y · Cited by 140
Liu, P., Zhang, T., Chen, Q., Li, C., Chu, Y., Guo, Q., Zhang, Y., Zhou, W., Chen, H., Zhou, Z., et al. (2021) · Advanced Materials · doi:10.1002/adma.202100746 · Cited by 140
Self-citationCross-cancer profiling of molecular alterations within the human autophagy interaction network
Lebovitz, C. B., Robertson, A. G., Goya, R., Jones, S. J. M., Morin, R. D., Marra, M. A., & Gorski, S. M. (2015) · Autophagy · doi:10.1080/15548627.2015.1067362 · Cited by 136
Rojo, A. I., Rada, P., Egea, J., Rosa, A. O., López, M. G., & Cuadrado, A. (2008) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2008.06.007 · Cited by 133
Zhang, Y., & Xiang, Y. (2016) · Biochemical Journal · doi:10.1042/bj20151182 · Cited by 125
Camp, N. D., James, R. G., Dawson, D. W., Yan, F., Davison, J. M., Houck, S. A., Tang, X., Zheng, N., Major, M. B., & Moon, R. T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.316471 · Cited by 128
“Based on the crystal structure of the KELCH repeats and anNRF2 peptide (23, 29), we reasoned that mutation of serine 286 to an acidic residue would enhance the interaction between WTX and KEAP1.”
BackgroundInfluentialTonolo, F., Fiorese, F., Moretto, L., Folda, A., Scalcon, V., Grinzato, A., Ferro, S., Arrigoni, G., Bindoli, A., Feller, E., et al. (2020) · Antioxidants · doi:10.3390/antiox9020117 · Cited by 133
“Moreover, these residues are also implicated in the interaction between Kelch domain and Nrf2 [37] (Table 4).”
BackgroundKEAP1, a cysteine-based sensor and a drug target for the prevention and treatment of chronic disease
Naidu, S. D., & Dinkova‐Kostova, A. T. (2020) · Open Biology · doi:10.1098/rsob.200105 · Cited by 135
Luo, X., Wang, Y., Zhu, X., Chen, Y., Xu, B., Bai, X., Weng, X., Xu, J., Tao, Y., Yang, D., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102987 · Cited by 128
“Lo et al. reported that KEAP1-R483A mutant make KEAP1 unable to bind to NRF2 and repress NRF2 activity in 293T cell lines [82].”
BackgroundFarr, S. A., Ripley, J. L., Rukhsana Sultana, A., Zhang, Z., Niehoff, M. L., Platt, T. L., Murphy, M. P., Morley, J. E., Kumar, V. B., & Butterfield, D. A. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.11.014 · Cited by 130
“Nuclear factor erythroid-2-related factor 2 (Nrf2) is a transcription factor known to increase the level of many antioxidants, including glutathione-S transferase (GST), and is negatively regulated by the activity of GSK-3β.”
BackgroundJiang, Z., Lu, M., & You, Q. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b00586 · Cited by 128
Metadata
- Authors
- Lo, S., Li, X., Henzl, M. T., Beamer, L. J., & Hannink, M.
- Affiliations
- University of Missouri (US)
- Corresponding author
- Beamer, Lesa J
- Hannink, Mark
- Venue
- The EMBO Journal
- Published
- 2006-08-03
- Volume
- 25
- Issue
- 15
- Pages
- 3605-3617
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1538563
- OpenAlex
- W2141982524
- Cited by
- 604
- References
- 68
- Citations by year
- 2026: 66 · 2025: 66 · 2024: 44 · 2023: 48 · 2022: 47 · 2021: 36 · 2020: 35 · 2019: 23 · 2018: 22 · 2017: 21 · 2016: 25 · 2015: 25 · 2014: 22 · 2013: 34 · 2012: 22
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (P50CA103130)
- National Center for Complementary and Integrative Health (AT003899, R01AT003899)
- Lawrence Berkeley National Laboratory
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- Keap1, Nrf2, Kelch domain, protein-protein interaction, beta-turn, oxidative stress response, chemoprevention, protein structure
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Amino Acid Sequence, Animals, Binding Sites, Cells, Cultured, Chlorocebus aethiops, Humans, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Conformation, Signal Transduction, Conserved Sequence, Protein Structure, Tertiary, Dimerization, COS Cells, Amino Acid Motifs, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2
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