fig2

Figure 2. Structural and functional domains of NRF2. A Schematic representation of the human/mammalian NRF2 structure and function domains. There are 7 highly conserved regions in NRF2 that are referred to as NEH domains. From the N-terminal to the C-terminal of NRF2, the NEH2 domain contains the DLG/ETGE motifs that facilitate NRF2 interaction with KEAP1 and for KEAP1-dependent NRF2 proteasomal degradation. The NEH2 domain also contain a lysine residues rich site that is directly ubiquitylated by the Cul3/Rbx1/E3 cullin-based E3 ubiquitin ligase substrate adaptor complex, as well as a first NLS sequence between the amino acids 42 and 53. The NEH4-5 domains facilitate the interaction of NRF2 with Hdr1 and other proteins like p300 and CBP to activate NRF2-dependent transcription; also, a NES is located between amino acids 191-202 in the NEH5 region. The NEH7 domain contains sites for interaction with the RARs (RXR-α and RAR-α) that facilitates NRF2 transcriptional repression. The NEH6 domain contains two specific sites of interaction with the β-transducing repeat-containing protein (βTrCP ubiquitin ligase; the binding by βTrCP to the DSGIS motif requires the prior phosphorylation of NRF2 in Ser344 and Ser347 by Gsk-3β, but the interaction of βTrCP with the DSPAGS motif of NRF2 is direct. The association of NRF2 with βTrCP leads to Cul1-mediated ubiquitination, followed by NRF2 proteasome degradation. The NEH1 domain contains the CNC bZIP region, which is required for DNA binding and dimerization with small Maf proteins and other TFs; also, there is a second NES sequence between amino acids 553 and 562. Finally, the NEH3 region is another transactivation domain that contains a second NLS sequence between amino acids 595 and 601. NRF2: nuclear factor E2-related factor 2; NLS: nuclear localisation signal; NES: nuclear export signal; CNC bZIP: Cap'n'Collar basic leucine zipper; TFs: transcription factors; Maf: musculoaponeurotic fibrosarcoma