DEG_Kelch_Keap1_2

Oxidative and xenobiotic stresses affect the cellular homeostasis and are responsible for the development of many diseases, including cancer, cardiovascular disease, diabetes, and neurodegeneration. The cellular defence mechanism against the oxidative stress and electrophilic attack referred to as “cytoprotective response” is obtained by the action of an array of genes encoding detoxifying and anti-oxidative stress enzymes. A Cap N’ Collar (CNC) family transcription factor Nrf2 and its homologues act as major regulators of cytoprotective gene expression (Kobayashi,2002). The level of Nrf2 (Q16236) in the cell is modulated mainly by its interaction with the KEAP1 protein (Q14145). One Nrf2 molecule interacts with two molecules of KEAP1 via two binding sites, the stronger binding motif and the weaker binding motif. Under unstressed conditions, KEAP1 Kelch domain (PF01344) binds to the degron motifs in Nrf2 and promote its ubiquitin dependent degradation. When cells are exposed to oxidative stress, the conformational changes in KEAP1 allow the high affinity motif to be attached to the KEAP1, acting as a hinge of the KEAP1 repression gate. On the other hand, the DLG motif acts as a latch, resulting in the detachment of low affinity motif from KEAP1 and escape protein degradation driving the expression of genes encoding detoxifying and anti-oxidative stress enzymes (24024136).
KEAP1 is a crucial hub in the oxidative stress responsive pathway and apoptosis (Hast,2013). It acts as a substrate adaptor protein for a Cul3 (Q13618)-dependent E3 ubiquitin ligase. Many of its interacting partners compete with Nrf2 for KEAP1 interaction. They all bind to the same bottom region of the propeller domain of KEAP1 with varying affinities (Padmanabhan,2006). Although there is no obvious sequence similarity between the high and low affinity binding motifs, the residues that are largely buried in the Kelch domain binding interface all have similar φ and ψ dihedral angles. The high affinity motif is present in a higher number of proteins. The low affinity motif, which have been so far identified in only Nrf2 (Q60795) and apoptotic protein Bcl2 (P10417).