KEAP1是抑癌基因，编码蛋白是一种E3泛素连接酶复合物的底物衔接蛋白。E3泛素连接酶复合物由蛋白质CUL3和RBX1形成，并且靶向NRF2进行泛素化和随后的蛋白酶体降解。KEAP1的BTB结构域结合CUL3，并且Kelch重复结构域通过KEAP1同源二聚化结合NRF2。IVR区含有关键的半胱氨酸残基，其硫醇侧链响应于氧化应激而被修饰。IVR中半胱氨酸残基的修饰破坏了KEAP1与NRF2和CUL3的结合，导致NRF2释放以用于靶基因的转录激活。KEAP1的突变倾向于在整个基因内发生，并且通常被认为破坏了对NRF2的KEAP1依赖性调节。这种破坏激活了NRF2依赖性途径，包括那些在氧化应激反应中受到调节的途径。

KEAP1 encodes a substrate adaptor protein for the E3 ubiquitin ligase complex. This complex is formed by the proteins CUL3 and RBX1 and targets NRF2 for ubiquitination and subsequent proteasomal degradation. NRF2 (encoded by the gene NFE2L2) is a master transcriptional regulator of the cellular antioxidant response. Activation of NRF2 can provide a fitness advantage for cells by upregulating pathways for handling xenobiotic stress and detoxification. The BTB domain of KEAP1 binds CUL3, and the Kelch-repeat domain binds NRF2 via KEAP1 homodimerization. The IVR region contains critical cysteine residues whose thiol side chains are modified in response to oxidative stress. Modification of cysteine residues in the IVR disrupts binding of KEAP1 to NRF2 and CUL3, resulting in the release of NRF2 for transcriptional activation of target genes. Mutations in KEAP1 tend to occur throughout the body of the gene, and are commonly thought to disrupt KEAP1-dependent regulation of NRF2. This disruption activates NRF2-dependent pathways, including those regulated in the oxidative stress response.

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