Kelch-like ECH-associated protein 1–Nuclear factor erythroid 2-related factor 2 protein-protein interaction (Keap1–Nrf2 PPI)

The Keap1–Nrf2 protein-protein interaction is a cytoplasmic regulatory complex in which Kelch-like ECH-associated protein 1 (Keap1) binds to the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). Under normal (unstressed) conditions, Keap1 acts as a substrate adaptor in a Cullin3 (Cul3)-based E3 ubiquitin ligase complex, targeting Nrf2 for ubiquitination and subsequent proteasomal degradation[2][3][4][6][7]. Upon exposure to oxidative or electrophilic stress, specific cysteine residues in Keap1 undergo covalent modifications, triggering conformational changes that prevent Nrf2 ubiquitination. Stabilized Nrf2 translocates to the nucleus, where it dimerizes with small Maf proteins and binds to antioxidant response elements (AREs) to activate the expression of cytoprotective and detoxifying genes[4][6][7]. Pharmacological disruption of the Keap1–Nrf2 interaction—either through direct protein-protein interaction inhibitors or electrophilic compounds—elevates Nrf2 activity and offers a promising therapeutic strategy for conditions involving oxidative, inflammatory, and metabolic stress, though persistent activation may contribute to cancer progression[1][6][7].

Other names

Keap1–Nrf2 interactionKeap1–Nrf2 complexKeap1–Nrf2 pathwayKeap1–Nrf2 signalingKeap1–Nrf2 axis

Disruptors of Keap1–Nrf2 interaction: Block binding of Keap1 to Nrf2, preventing Nrf2 ubiquitination and degradation. Electrophilic modifiers: Covalently modify Keap1 cysteine residues, inducing conformational change that impairs ubiquitin ligase activity and stabilizes Nrf2[1][2][5].