title: Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants.
abstract: The Kelch-like ECH associated protein 1 (Keap1) is a component of a Cullin3-based Cullin-RING E3 ubiquitin ligase (CRL) multisubunit protein complex. Within the CRL, homodimeric Keap1 functions as the Cullin3 adaptor, and importantly, it is also the critical component of the E3 ligase that performs the substrate recognition. The best-characterized substrate of Keap1 is transcription factor NF-E2 p45-related factor 2 (Nrf2), which orchestrates an elaborate transcriptional program in response to environmental challenges caused by oxidants, electrophiles and pro-inflammatory agents, allowing adaptation and survival under stress conditions. Keap1 is equipped with reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules (termed inducers), which have a characteristic chemical signature, reactivity with sulfhydryl groups. Inducers modify the cysteine sensors of Keap1 and impair its ability to target Nrf2 for ubiquitination and degradation. Consequently, Nrf2 accumulates, enters the nucleus and drives the transcription of its target genes, which encode a large network of cytoprotective proteins. Here we summarize the early studies leading to the prediction of the existence of Keap1, followed by the discovery of Keap1 as the main negative regulator of Nrf2. We then describe the available structural information on Keap1, its assembly with Cullin3, and its interaction with Nrf2. We also discuss the multiple cysteine sensors of Keap1 that allow for detection of a wide range of endogenous and environmental inducers, and provide fine-tuning and tight control of the Keap1/Nrf2 stress-sensing response.
authors: Division of Cancer Research, School of Medicine, University of Dundee, Scotland, UK; Department Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: a.dinkovakostova@dundee.ac.uk.
authors: Albena T
authors: AT
authors: Dinkova-Kostova
authors: Division of Cancer Research, School of Medicine, University of Dundee, Scotland, UK.
authors: Rumen V
authors: RV
authors: Kostov
authors: Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors: Peter
authors: P
authors: Canning
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007249:Inflammation; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000378:metabolism*; D008958:Models, Molecular; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016877:Oxidants / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C503645:CUL3 protein, human; D044842:Cullin Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016877:Oxidants; D044767:Ubiquitin-Protein Ligases; D003545:Cysteine; D010100:Oxygen
keywords: Cysteine sensor; Electrophiles; Keap1; Nrf2; Oxidants