Structural basis of Keap1 interactions with Nrf2

Abstract

Keap1 is a highly redox-sensitive member of the BTB-Kelch family that assembles with the Cul3 protein to form a Cullin–RING E3 ligase complex for the degradation of Nrf2. Oxidative stress disables Keap1, allowing Nrf2 protein levels to accumulate for the transactivation of critical stress response genes. Consequently, the Keap1–Nrf2 system is extensively pursued for the development of protein–protein interaction inhibitors that will stabilize Nrf2 for therapeutic effect in conditions of neurodegeneration, inflammation, and cancer. Here we review current progress toward the structure determination of Keap1 and its protein complexes with Cul3, Nrf2 substrate, and small-molecule antagonists. Together the available structures establish a rational three-dimensional model to explain the two-site binding of Nrf2 as well as its efficient ubiquitination.

miR-214 protects erythroid cells against oxidative stress by targeting ATF4 and EZH2

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“…Oxidative stress increases in models of PRC degeneration (36), and antioxidant treatment delays PRC death (4). Oxidative stress leads to increased levels of the transcription factor nuclear factor erythroid-derived 2-like 2 (NRF2), which translocates to the nucleus to up-regulate the expression of detoxifying and antioxidant genes (37,38). Compelling data from Cepko's laboratory (39) showed that subretinal delivery of Nrf2 using adeno-associated viral vectors in neonatal mice promoted the survival of PRC in retinal degeneration models.…”

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“…24,25 In response to oxidative stress, Nrf2 moves to the nucleus and binds to the antioxidant response element (ARE), which serves as a promoter sequence. 21,25 Furthermore, Nrf2 has been a new therapeutic target for demyelination in multiple sclerosis (MS).…”