Fig. 4.

The cyclic sequential attachment and regeneration model of Keap1-mediated degradation of Nrf2. In the basal state, newly translated Nrf2 (yellow) binds sequentially to a free Keap1 dimer (blue), first through the ETGE motif to form the open conformation (1) and then through the DLG motif, to form the closed conformation (2). Once in the closed conformation, Nrf2 can be targeted for ubiquitination by the Keap1-dependent E3-ubiquitin ligase (3). Ubiquitinated Nrf2 is released from Keap1 and degraded by the proteasome. The free Keap1 dimer is regenerated and able to bind to newly translated Nrf2 (4), and the cycle begins again. In the induced state, the formation of the closed conformation is uncoupled from ubiquitination (2). As a consequence, Nrf2 is not released from Keap1 (3), free Keap1 is not regenerated, and newly translated Nrf2 accumulates and turns on the expression of cytoprotective genes (4).