Related Experiment Video
Updated: Jan 15, 2026

Use of Label-free Optical Biosensors to Detect Modulation of Potassium Channels by G-protein Coupled Receptors
Published on: February 10, 2014
Bidirectional regulation of KEAP1 BTB domain-based sensor activity
Takafumi Suzuki1, Kenji Takagi2, Tatsuro Iso3
1Department of Biochemistry & Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan; Advanced Research Center for Innovations in Next-Generation Medicine (INGEM), Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai, 980-8573, Japan.
Abstract:
The KEAP1-CUL3 ubiquitin ligase regulates protein stability of transcriptional factor NRF2 and plays critical roles in cellular stress response. The BTB domain of KEAP1 functions as a sensor for electrophilic chemicals. However, the precise mechanisms by which electrophiles are recognized and inhibit BTB activity remain unclear. Here, we show that electrophilic modification alters the spatial arrangement of the BTB homodimer, regulating its ligase activity. Co-crystal structural analyses and functional studies using potent NRF2-inducing CDDO-derivatives, synthetic electrophilic compounds structurally related to clinically approved molecules such as Omaveloxolone, revealed that the key sensor residue, Cys151, resides in a structurally elaborate environment within the BTB domain. Modification of Cys151 by NRF2 inducers changes the spatial configuration of the CUL3-binding sites in the BTB homodimer, reducing KEAP1-CUL3 complex affinity. In contrast, a Cys151-targeting NRF2 inhibitor induces an opposite rearrangement of the BTB homodimer. This study elucidates the molecular mechanism by which the BTB domain finely regulates KEAP1-CUL3 ubiquitin ligase activity.
More Related Videos
Related Concept Videos
Calmodulin-dependent Signaling
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
Amplifying Signals via Enzymatic Cascade
Covalently Linked Protein Regulators
These groups modify specific amino acids in a protein....
GPCRs Regulate Adenylyl Cylase Activity
Regulated Protein Degradation
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
The JAK-STAT Signaling Pathway

