Fig. 7.

Mechanism of regulation of the phase 2 response. Nrf2 (black) is retained in the cytoplasm by interaction with two molecules of Keap1, which are dimerized through their BTB domains (pink) and anchored to the actin cytoskeleton via the Kelch or DGR region (gray propeller). Inducers of the phase 2 response interact with cysteine thiol groups in the intervening region (IVR, yellow) of Keap1, causing the formation of disulfide bonds (most likely between C273 of one monomer and C288 of the other). This results in conformational change that renders Keap1 unable to bind to Nrf2, which then translocates to the nucleus. The Nrf2 in heterodimeric combination with other transcription factors such as small Maf binds to the ARE regulatory region of phase 2 genes and enhances their transcription.