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

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

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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Crossref · 10.1038/sj.emboj.7601243

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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.

    “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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  1. Hooft RW, Sander C, Vriend G (1996) Positioning hydrogen atoms by optimizing hydrogen-bond networks in protein structures. Proteins 26: 363–376 [DOI] [PubMed] [Google Scholar]

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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
Venue
The EMBO Journal
Published
2006-08-03
Volume
25
Issue
15
Pages
3605-3617
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
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
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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