Two-site substrate recognition model for the Keap1-Nrf2 system: a hinge and latch mechanism.
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.
Tong
Kit I
KI
Graduate School of Comprehensive Human Sciences, Center for Tsukuba Advanced Research Alliance and JST-ERATO Environmental Response Project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
Kobayashi
Akira
A
Katsuoka
Fumiki
F
Yamamoto
Masayuki
M
D000818:Animals; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D013379:Substrate Specificity
D047908:Intracellular Signaling Peptides and Proteins; D051267:NF-E2-Related Factor 2; D046988:Proteasome Endopeptidase Complex