Cited by 627Genomics, phytochemicals, and oxidative stressUbiquitin and proteasome pathwaysRedox biology and oxidative stress

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Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling

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Lo, Shih‐Ching, Li, Xuchu, Henzl, Michael T, Beamer, Lesa J, Hannink, Mark·2006·The EMBO Journal

DOI 10.1038/sj.emboj.7601243PMC PMC1538563

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Abstract

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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“4 G) [ 39 , 41 ].”
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“Other residues, such as Arg380, Arg415, and Arg483 were also reported to have a crucial role in Nrf2 binding (Lo et al., 2006).”
Background
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“As the master orchestrator of antioxidant defenses, NRF2 dissociates from KEAP1 under oxidative stress, translocates to the nucleus, and initiates antioxidant gene transcription 14,15 .”
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“C loops (Lo et al., 2006).”
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“In this study, the crystal structure of Keap1 protein (PDB ID: 2FLU) was obtained from the Protein Data Bank (https://www.rcsb.org/, accessed on 23 January 2025, Research Collab-oratory for Structural Bioinformatics, Rutgers University, Piscataway, NJ, USA) [26].”
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“The 32-kDa Kelch domain adopts a six-bladed β-propeller conformation and the structures in complex with peptides derived from Nrf2 that contain the binding motifs have been determined by X-ray crystallography (Lo et al. 2006; Padmanabhan et al. 2006; Tong et al. 2007).”
Background
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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
ORCID: Lo, Shih‐Ching
Beamer, Lesa J
Hannink, Mark
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2006-08-03
Volume: 25
Issue: 15
Pages: 3605-3617
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1038/sj.emboj.7601243
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: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
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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Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling

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