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

Balasundaram Padmanabhan, Kit I. Tong, Tsutomu Ohta, Yoshihiro Nakamura, Maria Scharlock, Makiko Ohtsuji, Moon Il Kang, Akira Kobayashi, Shigeyuki Yokoyama, Masayuki Yamamoto

Research output: Contribution to journalArticlepeer-review

498 Citations (Scopus)

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 β 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 β 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.

Original languageEnglish
Pages (from-to)689-700
Number of pages12
JournalMolecular Cell
Volume21
Issue number5
DOIs
Publication statusPublished - 2006 Mar 3
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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