期刊
COMMUNICATIONS BIOLOGY
卷 4, 期 1, 页码 -出版社
NATURE RESEARCH
DOI: 10.1038/s42003-021-02100-6
关键词
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资金
- MEXT/JSPS KAKENHI [19H05649, 17K07298, 19K07340, 17KK0183]
- AMED [JP21am0101095, JP20cm0106101]
- Takeda Science Foundation
- Tohoku Medical Megabank Project [JP19km0105001, JP19km0105002]
- Project for Promoting Public Utilization of Advanced Research Infrastructure (MEXT)
- Sharing and administrative network for research equipment (MEXT)
- Grants-in-Aid for Scientific Research [17KK0183, 19K07340, 17K07298] Funding Source: KAKEN
This study reveals that the dissociation of Keap1 from Nrf2, known as the Hinge-Latch mechanism, is triggered by Keap1-Nrf2 inhibitors and occurs during p62-mediated Nrf2 activation, rather than by electrophilic Nrf2 inducers. Insights gained from this research can be used for the development of Nrf2 activators targeting the Keap1-Nrf2 interaction.
The Keap1-Nrf2 system is central for mammalian cytoprotection against various stresses and a drug target for disease prevention and treatment. One model for the molecular mechanisms leading to Nrf2 activation is the Hinge-Latch model, where the DLGex-binding motif of Nrf2 dissociates from Keap1 as a latch, while the ETGE motif remains attached to Keap1 as a hinge. To overcome the technical difficulties in examining the binding status of the two motifs during protein-protein interaction (PPI) simultaneously, we utilized NMR spectroscopy titration experiments. Our results revealed that latch dissociation is triggered by low-molecular-weight Keap1-Nrf2 PPI inhibitors and occurs during p62-mediated Nrf2 activation, but not by electrophilic Nrf2 inducers(.) This study demonstrates that Keap1 utilizes a unique Hinge-Latch mechanism for Nrf2 activation upon challenge by non-electrophilic PPI-inhibiting stimuli, and provides critical insight for the pharmacological development of next-generation Nrf2 activators targeting the Keap1-Nrf2 PPI. Using NMR spectroscopy, Horie, Suzuki, Inoue et al. show that the dissociation of Keap1 from Nrf2, or the Hinge-Latch mechanism, is triggered by Keap1-Nrf2 inhibitors and occurs during p62- mediated Nrf2 activation, but not by electrophilic Nrf2 inducers. This study provides insights into the design of Nrf2 activators targeting the Keap1-Nrf2 interaction.
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