Kelch-like ECH-associated protein 1 (KEAP1, also known as KLHL19) is a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex that functions as a sensor for thiol-reactive chemopreventive compounds and oxidative stress. It targets NFE2L2/NRF2 (a transcription factor) for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression [, ]. Another KEAP1 substrate, PGAM5, a Bcl-XL-interacting protein, has also been identified [].The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding [], while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins []. In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins []. Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases [, ].
This entry includes the nucleosome-remodeling factor subunits BPTF (vertebrates) and NURF301 (Drosophila melanogaster), which are components of the NURF (nucleosome-remodeling factor) complex [, ]. The NURF complex catalyzes ATP-dependent nucleosome sliding and facilitates transcription of chromatin []. The HMGA/HMGI(Y)-like DNA-binding site of NURF301 facilitates nucleosome sliding []. BPTF binds histone H3K4me3 via its PHD zinc finger domain [], and interacts with the myc-associated zinc finger protein MAZ, altering its transcriptional activity, []and the Kelch-like Ech-associated protein KEAP1 [].
Nuclear factor erythroid 2-related factor 2 (Nrf2) belongs to the CNC-bZIP family, which is a group of transcription factors that are activated in response to cellular stress. It binds to antioxidant response (ARE) elements in the promoter regions of target genes []. It is constitutively and ubiquitously expressed in a number of tissues and cell lines. When exposed to oxidative stress, the expression of Nrf2 increases, further driving the transcriptional activation of genes that control cellular redox homeostasis []. Nrf2 is regulated by the repressor protein Keap1, which acts by directly interacting with Nrf2 and preventing its nuclear accumulation []. Keap1 not only acts to retain Nrf2 in the cytoplasm but also actively promotes its ubiquitylation and subsequent degradation by the proteasome.
