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. 2023 Mar 27;46(3):133–141. doi: 10.14348/molcells.2023.0028

Fig. 4. Updated Hinge-Latch model.

Fig. 4

Autophagy chaperone p62 accumulation disrupts the DLGex-Keap1 interaction and activates NRF2, and this mechanism conforms to the concept of the Hinge-Latch model. Similarly, pharmacological KEAP1-NRF2 PPI inhibitors disrupt the DLGex-KEAP1 interaction preferentially to the ETGE-KEAP1 interaction, and molecular basis for the efficacy of these chemicals is the utilization of the Hinge-Latch mechanism. In contrast, electrophilic NRF2-activating compounds activate NRF2 without disrupting the Neh2-KEAP1 interaction, implying that these KEAP1 thiol-modifying chemicals utilize mechanisms distinct from the Hinge-Latch mechanism. KEAP1, Kelch-like ECH-associated protein 1; NRF2, NF-E2-related factor 2; PPI, protein-protein interactions.