Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism

Biol Chem. 2006 Oct-Nov;387(10-11):1311-20. doi: 10.1515/BC.2006.164.


Cells are equipped with a number of transcriptional factors that safeguard against various environmental insults. Proteasomal protein degradation plays an important role in the Keap1-Nrf2 cytoprotection system, with molecular machinery similar to that for other environmental defense systems such as inflammatory and hypoxic responses. While Nrf2 protein stabilization is known to be redox-sensitive, the transcription factors NF-kappaB and HIF-1alpha for inflammatory and hypoxic responses, respectively, are also influenced by the cellular redox conditions. In this review we present the recently proposed two-site substrate recognition model of the Keap1-Nrf2 system, which regulates the cellular responses against oxidative and xenobiotic stresses. The implications of two destructive motifs in Nrf2, the ETGE and DLG motifs, which appear to function as a hinge and latch attenuating Keap1 activity in different redox states, are discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Models, Biological*
  • NF-E2-Related Factor 2 / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding
  • Substrate Specificity


  • Intracellular Signaling Peptides and Proteins
  • NF-E2-Related Factor 2
  • Proteasome Endopeptidase Complex