The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
Keap1, the cysteine-based mammalian intracellular sensor for electrophiles and oxidants
Open accessAbstract
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.
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Self-citationStructure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex
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“Nrf2 protein, known as the ETGE and DLG motifs [37].”
BackgroundRada, P., Rojo, A. I., Chowdhry, S., McMahon, M., Hayes, J. D., & Cuadrado, A. (2011) · Molecular and Cellular Biology · doi:10.1128/mcb.01204-10 · Cited by 759 · cited 1×
“containing protein (b-TrCP), a substrate adaptor for Skp1-Cullin1based Cullin-RING E3 ubiquitin ligase [7,8], and the E3 ubiquitin ligase Hrd1 [9].”
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NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis
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Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1
Mills, E. L., Ryan, D. G., Prag, H. A., Dikovskaya, D., Menon, D., Zaslona, Z., Jedrychowski, M. P., Costa, A. S. H., Higgins, M., Hams, E., et al. (2018) · Nature · doi:10.1038/nature25986 · Cited by 1,885
Self-citationMolecular mechanisms of ferroptosis and their involvement in brain diseases
Costa, I., Barbosa, D. J., Benfeito, S., Silva, V., Chavarria, D., Borges, F., Remião, F., & Silva, R. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108373 · Cited by 402
Redox Signaling by Reactive Electrophiles and Oxidants
Parvez, S., Long, M. J. C., Poganik, J. R., & Aye, Y. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00698 · Cited by 359
The role of Nrf2 signaling in counteracting neurodegenerative diseases
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Metadata
- Authors
- Dinkova-Kostova, A. T., Kostov, R. V., & Canning, P.
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 617
- Pages
- 84-93
- ISSN
- 0003-9861 (ISSN-L)
- OpenAlex
- W2483469289
- Cited by
- 326
- References
- 21
- FWCI
- 10.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
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