KEAP1
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Kelch-like ECH-associated protein 1 is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''Keap1''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.


Structure

Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 residue, which is one of the important cysteines in stress sensing. The intervening region (IVR) domain contains two critical cysteine residues, Cys273 and Cys288, which are a second group of cysteines important for stress sensing. A double glycine repeat (DGR) and C-terminal region (CTR) domains collaborate to form a β-propeller structure, which is where Keap1 interacts with Nrf2.


Interactions

Keap1 has been shown to
interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with Nrf2, a master regulator of the antioxidant response, which is important for the amelioration of
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
. Under quiescent conditions, Nrf2 is anchored in the cytoplasm through binding to Keap1, which, in turn, facilitates the
ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
and subsequent
proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
of Nrf2. Such sequestration and further degradation of Nrf2 in the cytoplasm are mechanisms for the repressive effects of Keap1 on Nrf2. Keap1 is not only a
tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or re ...
gene, but also a metastasis suppressor gene. Recently, several interesting studies have also identified a hidden circuit in NRF2 regulations. In the mouse Keap1 (INrf2) gene, Lee and colleagues found that an AREs located on a negative strand can subtly connect Nrf2 activation to Keap1 transcription. When examining NRF2 occupancies in human lymphocytes, Chorley and colleagues identified an approximately 700 bp locus within the KEAP1 promoter region was consistently top rank enriched, even at the whole-genome scale. These basic findings have depicted a mutually influenced pattern between NRF2 and KEAP1. NRF2-driven KEAP1 expression characterized in human cancer contexts, especially in human squamous cell cancers, depicted a new perspective in understanding NRF2 signaling regulation.


As a drug target

Because Nrf2 activation leads to a coordinated
antioxidant Antioxidants are compounds that inhibit oxidation, a chemical reaction that can produce free radicals. This can lead to polymerization and other chain reactions. They are frequently added to industrial products, such as fuels and lubrica ...
and
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
response, and Keap1 represses Nrf2 activation, Keap1 has become a very attractive drug target. A series of synthetic oleane
triterpenoid Triterpenes are a class of chemical compounds composed of three terpene units with the molecular formula C30H48; they may also be thought of as consisting of six isoprene units. Animals, plants and fungi all produce triterpenes, including squal ...
compounds, known as antioxidant inflammation modulators (AIMs), are being developed by Reata Pharmaceuticals, Inc. and are potent inducers of the Keap1- Nrf2 pathway, blocking Keap1-dependent Nrf2 ubiquitination and leading to the stabilization and nuclear translocation of Nrf2 and subsequent induction of Nrf2 target genes. The lead compound in this series,
bardoxolone methyl Bardoxolone methyl (also known as “RTA 402”, “CDDO-methyl ester”, CDDO-Me, and more formally methyl bardoxolonate) is an experimental and orally-bioavailable semi-synthetic triterpenoid, based on the scaffold of the natural product olean ...
(also known as CDDO-Me or RTA 402), was in late-stage clinical trials for the treatment of
chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
(CKD) in patients with type 2
diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
and showed an ability to improve markers of renal function in these patients. However, the Phase 3 trial was halted due to safety concerns.


Human health

Mutations in ''KEAP1'' that result in loss-of-function are not linked to familial cancers, though they do predispose individuals to multinodular goiters. The proposed mechanism leading to goiter formation is that the
redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
stress experienced when the thyroid produces hormones selects for
loss of heterozygosity Loss of heterozygosity (LOH) is a type of genetic abnormality in diploid organisms in which one copy of an entire gene and its surrounding chromosomal region are lost. Since diploid cells have two copies of their genes, one from each parent, a sing ...
of ''KEAP1'', leading to the goiters.


Gallery

File:KEAP1 NRF2 signaling pathway.jpg, (a) NRF2 and KEAP1 protein domains; (b) KEAP1 homodimerizes through the BTB domain, and through the Kelch domains KEAP1 interacts with NRF2 at the ETGE and DLG motifs File:KEAP1 and NRF2 interacting with cellular metabolism.jpg, The relationship of the NRF2/KEAP1 pathway with cellular metabolism


References


Further reading

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