Kelch-like ECH-associated protein 1 (Keap1) BTB domain (Keap1 BTB)

Kelch-like ECH-associated protein 1 (Keap1) is a critical regulator of the cellular antioxidant response, acting as the primary sensor for oxidative and electrophilic stress [1]. It functions as an adaptor for the Cullin 3 (Cul3)-based E3 ubiquitin ligase complex, which targets the transcription factor Nrf2 for degradation under normal conditions [2]. The BTB (Broad-Complex, Tramtrack and Bric-à-brac) domain of Keap1 is essential for this process, as it facilitates Keap1 homodimerization and serves as the recruitment site for the Cul3-ROC1 ligase [3]. A key feature of the BTB domain is the presence of highly reactive cysteine residues, particularly Cys151, which serve as sensors for electrophilic compounds [4]. When these cysteines are modified by drugs or reactive species, Keap1 undergoes a conformational change that inhibits its ability to promote Nrf2 ubiquitination [5]. This leads to the stabilization and nuclear translocation of Nrf2, which then induces the expression of cytoprotective genes such as NQO1 and HMOX1 [6]. Consequently, the Keap1 BTB domain is a major therapeutic target for diseases characterized by oxidative stress and inflammation, including chronic kidney disease and neurodegenerative disorders [7]. However, therapeutic challenges include potential off-target reactivity and the risk of promoting survival in established cancer cells where Nrf2 is constitutively active [8].

Other names

Kelch-like protein 19KIAA0132KLHL19INRF2BTB domain of Keap1

Covalent modification of the Cys151 residue within the BTB domain, which prevents the Keap1-Cul3 complex from effectively ubiquitinating Nrf2, thereby allowing Nrf2 to accumulate and activate antioxidant gene expression [4, 6].