Structural basis of Keap1 interactions with Nrf2

https://doi.org/10.1016/j.freeradbiomed.2015.05.034Get rights and content
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Highlights

  • Keap1 and Nrf2 are multidomain proteins that determine the antioxidant response.

  • Structural models suggest how Keap1 assembles into a Cullin–RING ligase.

  • Dimeric Keap1 supports a two-site tethering mechanism for Nrf2 ubiquitination.

  • Crystal structures reveal the mechanism of action of chemical inhibitors of Keap1.

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.

Keywords

Keap1
Nrf2
BTB
Kelch
Cullin
Ubiquitin
Free radicals

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1

Present address: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.