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Cited by 749Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressGlutathione Transferases and Polymorphisms

Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer

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Padmanabhan, Balasundaram, Tong, Kit I., Ohta, Tsutomu, Nakamura, Yoshihiro, Scharlock, Maria, Ohtsuji, Makiko, Kang, Moon-Il, Kobayashi, Akira +2 more·2006·Molecular Cell
DOI 10.1016/j.molcel.2006.01.013
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Abstract

Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction. To elucidate the molecular mechanism of the Keap1 and Nrf2 interaction, we resolved the six-bladed beta propeller crystal structure of the Kelch/DGR and CTR domains of mouse Keap1 and revealed that extensive inter- and intrablade hydrogen bonds maintain the structural integrity and proper association of Keap1 with Nrf2. A peptide containing the ETGE motif of Nrf2 binds the beta propeller of Keap1 at the entrance of the central cavity on the bottom side via electrostatic interactions with conserved arginine residues. We found a somatic mutation and a gene variation in human lung cancer cells that change glycine to cysteine in the DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2. These results provide a structural basis for the loss of Keap1 function and gain of Nrf2 function.

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  • Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance.

    “Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, thereby leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance (e.g., chemoresistance) (Figure 8) [161,162,163,164,165,166,167,168,169,170,171].”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [163]

  • Mutations in KEAP1 were first discovered in human lung adenocarcinoma cell lines, wherein a glycine-to-cysteine substitution within the Nrf2-binding domain of Keap1 reduces its affinity for Nrf2, resulting in loss of canonical Nrf2 regulation and constitutive Nrf2 hyperactivation.

    “Mutations in KEAP1 were first discovered in human lung adenocarcinoma cell lines, wherein a glycine-to-cysteine substitution within the Nrf2-binding domain of Keap1 reduces its affinity for Nrf2, resulting in loss of canonical Nrf2 regulation and constitutive Nrf2 hyperactivation [163].”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [163]

  • Most of these cancers' aberrant Nrf2 expression and poor prognosis have been attributed to loss-of-function mutations in KEAP1 and/or gain-of-function mutations in NFE2L2.

    “most of which have been attributed to loss-of-function mutations in the KEAP1 gene and/or gain-of-function mutations in the NFE2L2 gene encoding Nrf2 [162,163,164,166,167].”

    From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [163]

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Authors
Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., & Yamamoto, M.
Affiliations
  • RIKEN (JP)
  • University of Tsukuba (JP)
  • National Cancer Center Research Institute (JP)
  • SPring-8 (JP)
Corresponding author
  • Yokoyama, Shigeyuki
  • Yamamoto, Masayuki
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2006-03
Volume
21
Issue
5
Pages
689-700
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2006.01.013
OpenAlex
W1974546855
Cited by
735
References
37
Citations by year
2026: 27 · 2025: 29 · 2024: 32 · 2023: 43 · 2022: 39 · 2021: 36 · 2020: 41 · 2019: 32 · 2018: 33 · 2017: 31 · 2016: 44 · 2015: 43 · 2014: 28 · 2013: 57 · 2012: 36
FWCI
12.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (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 › Redox biology and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
Keywords
Keap1, Nrf2, Kelch domain, six-bladed β-propeller, crystal structure, point mutations, lung cancer, oxidative stress response, cysteine substitution, protein-protein interaction, conformational change, arginine residues
MeSH terms
Kelch-Like ECH-Associated Protein 1, Amino Acid Sequence, Animals, Binding Sites, Cytoskeletal Proteins, Humans, Lung Neoplasms, Molecular Sequence Data, Peptide Fragments, Proteins, Structure-Activity Relationship, Gene Expression Regulation, Neoplastic, Point Mutation, Protein Structure, Tertiary, Crystallography, X-Ray, DNA-(Apurinic or Apyrimidinic Site) Lyase, DNA Glycosylases, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, NF-E2-Related Factor 2, Mice

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