In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis, and metabolism of the organism.
Nuclear receptors bind directly to DNA regulating the expression of adjacent genes; hence these receptors are classified as transcription factors. [2] [3] The regulation of gene expression by nuclear receptors often occurs in the presence of a ligand—a molecule that affects the receptor's behavior. Ligand binding to a nuclear receptor results in a conformational change activating the receptor. The result is up- or down-regulation of gene expression.
A unique property of nuclear receptors that differentiates them from other classes of receptors is their direct control of genomic DNA. Nuclear receptors play key roles in both embryonic development and adult homeostasis. As discussed below, nuclear receptors are classified according to mechanism [4] [5] or homology. [6] [7]
Nuclear receptors are specific to metazoans (animals) and are not found in protists, algae, fungi, or plants. [8] Amongst the early-branching animal lineages with sequenced genomes, two have been reported from the sponge Amphimedon queenslandica , two from the comb jelly Mnemiopsis leidyi [9] four from the placozoan Trichoplax adhaerens and 17 from the cnidarian Nematostella vectensis . [10] There are 270 nuclear receptors in the roundworm Caenorhabditis elegans alone, [11] 21 in the fruit fly and other insects, [12] 73 in zebrafish. [13] Humans, mice, and rats have respectively 48, 49, and 47 nuclear receptors each. [14]
Ligands that bind to and activate nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, and xenobiotic hormones. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that activate these receptors can have profound effects on the organism. Many of these regulated genes are associated with various diseases, which explains why the molecular targets of approximately 13% of U.S. Food and Drug Administration (FDA) approved drugs target nuclear receptors. [15]
A number of nuclear receptors, referred to as orphan receptors, [16] have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR bind a number of metabolic intermediates such as fatty acids, bile acids and/or sterols with relatively low affinity. These receptors hence may function as metabolic sensors. Other nuclear receptors, such as CAR and PXR appear to function as xenobiotic sensors up-regulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics. [17]
Most nuclear receptors have molecular masses between 50,000 and 100,000 daltons.
Nuclear receptors are modular in structure and contain the following domains: [18] [19]
The DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the N-terminal (A/B), hinge region (D) and optional C-terminal (F) domains may be conformationally flexible and disordered. [22] Domains relative orientations are very different by comparing three known multi-domain crystal structures, two of them binding on DR1 (DBDs separated by 1 bp), [1] [23] one binding on DR4 (by 4 bp). [24]
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Nuclear receptors are multifunctional proteins that transduce signals of their cognate ligands. Nuclear receptors (NRs) may be classified into two broad classes according to their mechanism of action and subcellular distribution in the absence of ligand.[ citation needed ]
Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to nuclear receptors located in the cytosol (type I NR) or nucleus (type II NR) of the cell. Binding causes a conformational change in the receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the NRs to DNA transcription regulation sites which result in up or down-regulation of gene expression. They generally function as homo/heterodimers. [27] In addition, two additional classes, type III which are a variant of type I, and type IV that bind DNA as monomers have also been identified. [4]
Accordingly, nuclear receptors may be subdivided into the following four mechanistic classes: [4] [5]
Ligand binding to type I nuclear receptors in the cytosol results in the dissociation of heat shock proteins, homo-dimerization, translocation (i.e., active transport) from the cytoplasm into the cell nucleus, and binding to specific sequences of DNA known as hormone response elements (HREs). Type I nuclear receptors bind to HREs consisting of two half-sites separated by a variable length of DNA, and the second half-site has a sequence inverted from the first (inverted repeat). Type I nuclear receptors include members of subfamily 3, such as the androgen receptor, estrogen receptors, glucocorticoid receptor, and progesterone receptor. [28]
It has been noted that some of the NR subfamily 2 nuclear receptors may bind to direct repeat instead of inverted repeat HREs. In addition, some nuclear receptors that bind either as monomers or dimers, with only a single DNA binding domain of the receptor attaching to a single half site HRE. These nuclear receptors are considered orphan receptors, as their endogenous ligands are still unknown.[ citation needed ]
The nuclear receptor/DNA complex then recruits other proteins that transcribe DNA downstream from the HRE into messenger RNA and eventually protein, which causes a change in cell function.[ citation needed ]
Type II receptors, in contrast to type I, are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA. [27] In the absence of ligand, type II nuclear receptors are often complexed with corepressor proteins. Ligand binding to the nuclear receptor causes dissociation of corepressor and recruitment of coactivator proteins. Additional proteins including RNA polymerase are then recruited to the NR/DNA complex that transcribe DNA into messenger RNA.
Type II nuclear receptors include principally subfamily 1, for example the retinoic acid receptor, retinoid X receptor and thyroid hormone receptor. [29]
Type III nuclear receptors (principally NR subfamily 2) are similar to type I receptors in that both classes bind to DNA as homodimers. However, type III nuclear receptors, in contrast to type I, bind to direct repeat instead of inverted repeat HREs.
Type IV nuclear receptors bind either as monomers or dimers, but only a single DNA binding domain of the receptor binds to a single half site HRE. Examples of type IV receptors are found in most of the NR subfamilies.
Human nuclear receptors are capable of dimerizing with many other nuclear receptors (homotypic dimerization), as has been shown from large-scale Y2H experiments and text mining efforts of the literature that were focused on specific interactions. [30] [31] [27] Nevertheless, there exists specificity, with members of the same subfamily having very similar NR dimerization partners and the underlying dimerization network has certain topological features, such as the presence of highly connected hubs (RXR and SHP). [27]
Nuclear receptors bound to hormone response elements recruit a significant number of other proteins (referred to as transcription coregulators) that facilitate or inhibit the transcription of the associated target gene into mRNA. [32] [33] [34] The function of these coregulators are varied and include chromatin remodeling (making the target gene either more or less accessible to transcription) or a bridging function to stabilize the binding of other coregulatory proteins. Nuclear receptors may bind specifically to a number of coregulator proteins, and thereby influence cellular mechanisms of signal transduction both directly, as well as indirectly. [35]
Binding of agonist ligands (see section below) to nuclear receptors induces a conformation of the receptor that preferentially binds coactivator proteins. These proteins often have an intrinsic histone acetyltransferase (HAT) activity, which weakens the association of histones to DNA, and therefore promotes gene transcription.
Binding of antagonist ligands to nuclear receptors in contrast induces a conformation of the receptor that preferentially binds corepressor proteins. These proteins, in turn, recruit histone deacetylases (HDACs), which strengthens the association of histones to DNA, and therefore represses gene transcription.
Depending on the receptor involved, the chemical structure of the ligand and the tissue that is being affected, nuclear receptor ligands may display dramatically diverse effects ranging in a spectrum from agonism to antagonism to inverse agonism. [38]
The activity of endogenous ligands (such as the hormones estradiol and testosterone) when bound to their cognate nuclear receptors is normally to upregulate gene expression. This stimulation of gene expression by the ligand is referred to as an agonist response. The agonistic effects of endogenous hormones can also be mimicked by certain synthetic ligands, for example, the glucocorticoid receptor anti-inflammatory drug dexamethasone. Agonist ligands work by inducing a conformation of the receptor which favors coactivator binding (see upper half of the figure to the right).
Other synthetic nuclear receptor ligands have no apparent effect on gene transcription in the absence of endogenous ligand. However they block the effect of agonist through competitive binding to the same binding site in the nuclear receptor. These ligands are referred to as antagonists. An example of antagonistic nuclear receptor drug is mifepristone which binds to the glucocorticoid and progesterone receptors and therefore blocks the activity of the endogenous hormones cortisol and progesterone respectively. Antagonist ligands work by inducing a conformation of the receptor which prevents coactivator binding, and promotes corepressor binding (see lower half of the figure to the right).
Finally, some nuclear receptors promote a low level of gene transcription in the absence of agonists (also referred to as basal or constitutive activity). Synthetic ligands which reduce this basal level of activity in nuclear receptors are known as inverse agonists. [39]
A number of drugs that work through nuclear receptors display an agonist response in some tissues and an antagonistic response in other tissues. This behavior may have substantial benefits since it may allow retaining the desired beneficial therapeutic effects of a drug while minimizing undesirable side effects. Drugs with this mixed agonist/antagonist profile of action are referred to as selective receptor modulators (SRMs). Examples include Selective Androgen Receptor Modulators (SARMs), Selective Estrogen Receptor Modulators (SERMs) and Selective Progesterone Receptor Modulators (SPRMs). The mechanism of action of SRMs may vary depending on the chemical structure of the ligand and the receptor involved, however it is thought that many SRMs work by promoting a conformation of the receptor that is closely balanced between agonism and antagonism. In tissues where the concentration of coactivator proteins is higher than corepressors, the equilibrium is shifted in the agonist direction. Conversely in tissues where corepressors dominate, the ligand behaves as an antagonist. [40]
The most common mechanism of nuclear receptor action involves direct binding of the nuclear receptor to a DNA hormone response element. This mechanism is referred to as transactivation . However some nuclear receptors not only have the ability to directly bind to DNA, but also to other transcription factors. This binding often results in deactivation of the second transcription factor in a process known as transrepression . [41] One example of a nuclear receptor that are able to transrepress is the glucocorticoid receptor (GR). Furthermore, certain GR ligands known as Selective Glucocorticoid Receptor Agonists (SEGRAs) are able to activate GR in such a way that GR more strongly transrepresses than transactivates. This selectivity increases the separation between the desired antiinflammatory effects and undesired metabolic side effects of these selective glucocorticoids.
The classical direct effects of nuclear receptors on gene regulation normally take hours before a functional effect is seen in cells because of the large number of intermediate steps between nuclear receptor activation and changes in protein expression levels. However it has been observed that many effects of the application of nuclear hormones, such as changes in ion channel activity, occur within minutes which is inconsistent with the classical mechanism of nuclear receptor action. While the molecular target for these non-genomic effects of nuclear receptors has not been conclusively demonstrated, it has been hypothesized that there are variants of nuclear receptors which are membrane associated instead of being localized in the cytosol or nucleus. Furthermore, these membrane associated receptors function through alternative signal transduction mechanisms not involving gene regulation. [42] [43]
While it has been hypothesized that there are several membrane associated receptors for nuclear hormones, many of the rapid effects have been shown to require canonical nuclear receptors. [44] [45] However, testing the relative importance of the genomic and nongenomic mechanisms in vivo has been prevented by the absence of specific molecular mechanisms for the nongenomic effects that could be blocked by mutation of the receptor without disrupting its direct effects on gene expression.
A molecular mechanism for non-genomic signaling through the nuclear thyroid hormone receptor TRβ involves the phosphatidylinositol 3-kinase (PI3K). [46] This signaling can be blocked by a single tyrosine to phenylalanine substitution in TRβ without disrupting direct gene regulation. [47] When mice were created with this single, conservative amino acid substitution in TRβ, [47] synaptic maturation and plasticity in the hippocampus was impaired almost as effectively as completely blocking thyroid hormone synthesis. [48] This mechanism appears to be conserved in all mammals but not in TRα or any other nuclear receptors. Thus, phosphotyrosine-dependent association of TRβ with PI3K provides a potential mechanism for integrating regulation of development and metabolism by thyroid hormone and receptor tyrosine kinases. In addition, thyroid hormone signaling through PI3K can alter gene expression. [49]
The following is a list of the 48 known human nuclear receptors (and their orthologs in other species) [14] [50] [51] categorized according to sequence homology. [6] [7] The list also includes selected family members that lack human orthologs (NRNC symbol highlighted in yellow).
Subfamily | Group | Member | ||||||
---|---|---|---|---|---|---|---|---|
NRNC Symbol [6] | Abbreviation | Name | Gene | Ligand(s) | ||||
1 | Thyroid Hormone Receptor-like | A | Thyroid hormone receptor | NR1A1 | TRα | Thyroid hormone receptor-α | THRA | thyroid hormone |
NR1A2 | TRβ | Thyroid hormone receptor-β | THRB | |||||
B | Retinoic acid receptor | NR1B1 | RARα | Retinoic acid receptor-α | RARA | vitamin A and related compounds | ||
NR1B2 | RARβ | Retinoic acid receptor-β | RARB | |||||
NR1B3 | RARγ | Retinoic acid receptor-γ | RARG | |||||
C | Peroxisome proliferator-activated receptor | NR1C1 | PPARα | Peroxisome proliferator-activated receptor-α | PPARA | fatty acids, prostaglandins | ||
NR1C2 | PPAR-β/δ | Peroxisome proliferator-activated receptor-β/δ | PPARD | |||||
NR1C3 | PPARγ | Peroxisome proliferator-activated receptor-γ | PPARG | |||||
D | Rev-ErbA | NR1D1 | Rev-ErbAα | Rev-ErbAα | NR1D1 | heme | ||
NR1D2 | Rev-ErbAβ | Rev-ErbAα | NR1D2 | |||||
E | E78C-like (arthropod, trematode, mullosc, nematode) [50] [52] | NR1E1 | Eip78C | Ecdysone-induced protein 78C | Eip78C | |||
F | RAR-related orphan receptor | NR1F1 | RORα | RAR-related orphan receptor-α | RORA | cholesterol, ATRA | ||
NR1F2 | RORβ | RAR-related orphan receptor-β | RORB | |||||
NR1F3 | RORγ | RAR-related orphan receptor-γ | RORC | |||||
G | CNR14-like (nematode) [50] | NR1G1 | sex-1 | Steroid hormone receptor cnr14 [53] | sex-1 | |||
H | Liver X receptor-like | NR1H1 | EcR | Ecdysone receptor, EcR (arthropod) | EcR | ecdysteroids | ||
NR1H2 | LXRβ | Liver X receptor-β | NR1H2 | oxysterols | ||||
NR1H3 | LXRα | Liver X receptor-α | NR1H3 | |||||
NR1H4 | FXR | Farnesoid X receptor | NR1H4 | |||||
NR1H5 [54] | FXR-β | Farnesoid X receptor-β (pseudogene in human) | NR1H5P | |||||
I | Vitamin D receptor-like | NR1I1 | VDR | Vitamin D receptor | VDR | vitamin D | ||
NR1I2 | PXR | Pregnane X receptor | NR1I2 | xenobiotics | ||||
NR1I3 | CAR | Constitutive androstane receptor | NR1I3 | androstane | ||||
J | Hr96-like [50] | NR1J1 | Hr96/Daf-12 | Nuclear hormone receptor HR96 | Hr96 | cholesterol/dafachronic acid [55] | ||
NR1J2 | ||||||||
NR1J3 | ||||||||
K | Hr1-like [50] | NR1K1 | Hr1 | Nuclear hormone receptor HR1 | ||||
2 | Retinoid X Receptor-like | A | Hepatocyte nuclear factor-4 | NR2A1 | HNF4α | Hepatocyte nuclear factor-4-α | HNF4A | fatty acids |
NR2A2 | HNF4γ | Hepatocyte nuclear factor-4-γ | HNF4G | |||||
B | Retinoid X receptor | NR2B1 | RXRα | Retinoid X receptor-α | RXRA | retinoids | ||
NR2B2 | RXRβ | Retinoid X receptor-β | RXRB | |||||
NR2B3 | RXRγ | Retinoid X receptor-γ | RXRG | |||||
NR2B4 | USP | Ultraspiracle protein (arthropod) | usp | phospholipids [56] | ||||
C | Testicular receptor | NR2C1 | TR2 | Testicular receptor 2 | NR2C1 | |||
NR2C2 | TR4 | Testicular receptor 4 | NR2C2 | |||||
E | TLX/PNR | NR2E1 | TLX | Homologue of the Drosophila tailless gene | NR2E1 | |||
NR2E3 | PNR | Photoreceptor cell-specific nuclear receptor | NR2E3 | |||||
F | COUP/EAR | NR2F1 | COUP-TFI | Chicken ovalbumin upstream promoter-transcription factor I | NR2F1 | |||
NR2F2 | COUP-TFII | Chicken ovalbumin upstream promoter-transcription factor II | NR2F2 | retinoic acid (weak) [57] | ||||
NR2F6 | EAR-2 | V-erbA-related | NR2F6 | |||||
3 | Estrogen Receptor-like | A | Estrogen receptor | NR3A1 | ERα | Estrogen receptor-α | ESR1 | estrogens |
NR3A2 | ERβ | Estrogen receptor-β | ESR2 | |||||
B | Estrogen related receptor | NR3B1 | ERRα | Estrogen-related receptor-α | ESRRA | |||
NR3B2 | ERRβ | Estrogen-related receptor-β | ESRRB | |||||
NR3B3 | ERRγ | Estrogen-related receptor-γ | ESRRG | |||||
C | 3-Ketosteroid receptors | NR3C1 | GR | Glucocorticoid receptor | NR3C1 | cortisol | ||
NR3C2 | MR | Mineralocorticoid receptor | NR3C2 | aldosterone | ||||
NR3C3 | PR | Progesterone receptor | PGR | progesterone | ||||
NR3C4 | AR | Androgen receptor | AR | testosterone | ||||
D | Estrogen Receptor-like (in lophotrochozoa) [58] | NR3D | ||||||
E | Estrogen Receptor-like (in cnidaria) [59] | NR3E | ||||||
F | Estrogen Receptor-like (in placozoa) [59] | NR3F | ||||||
4 | Nerve Growth Factor IB-like | A | NGFIB/NURR1/NOR1 | NR4A1 | NGFIB | Nerve Growth factor IB | NR4A1 | |
NR4A2 | NURR1 | Nuclear receptor related 1 | NR4A2 | |||||
NR4A3 | NOR1 | Neuron-derived orphan receptor 1 | NR4A3 | |||||
5 | Steroidogenic Factor-like | A | SF1/LRH1 | NR5A1 | SF1 | Steroidogenic factor 1 | NR5A1 | phosphatidylinositols |
NR5A2 | LRH-1 | Liver receptor homolog-1 | NR5A2 | phosphatidylinositols | ||||
B | Hr39-like | NR5B1 [50] | HR39/FTZ-F1 | Nuclear hormone receptor fushi tarazu factor I beta | Hr39 | |||
6 | Germ Cell Nuclear Factor-like | A | GCNF | NR6A1 | GCNF | Germ cell nuclear factor | NR6A1 | |
7 | NRs with two DNA binding domains [60] [50] [61] | A | 2DBD-NRα | NR7A1 | 2DBD-NRA2 | |||
B | 2DBD-NRβ | NR7B1 | 2DBD-NRA3 | |||||
C | 2DBD-NRγ | NR7C1 | 2DBD-NRA1 | arthropod "α/β" | ||||
8 | NR8 [62] (eumetazoa) | A | NR8A | NR8A1 | CgNR8A1 | Nuclear receptor 8 | AKG49571 | |
0 | Miscellaneous (lacks either LBD or DBD) | A | knr/knrl/egon [50] (arthropods) | NR0A1 | KNI | Zygotic gap protein knirps | knl | |
B | DAX/SHP | NR0B1 | DAX1 | Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 | NR0B1 | |||
NR0B2 | SHP | Small heterodimer partner | NR0B2 |
Of the two 0-families, 0A has a family 1-like DBD, and 0B has a unique LBD. The second DBD of family 7 is probably related to the family 1 DBD. Three probably family-1 NRs from Biomphalaria glabrata possess a DBD along with a family 0B-like LBD. [50] The placement of C. elegans nhr-1 ( Q21878 ) is disputed: although most sources place it as NR1K1, [50] manual annotation at WormBase considers it a member of NR2A. [63] There used to be a group 2D for which the only member was Drosophila HR78/NR1D1 ( Q24142 ) and orthologues, but it was merged into group 2C later due to high similarity, forming a "group 2C/D". [50] Knockout studies on mice and fruit flies support such a merged group. [64]
A topic of debate has been on the identity of the ancestral nuclear receptor as either a ligand-binding or an orphan receptor. This debate began more than twenty-five years ago when the first ligands were identified as mammalian steroid and thyroid hormones. [65] Shortly thereafter, the identification of the ecdysone receptor in Drosophila introduced the idea that nuclear receptors were hormonal receptors that bind ligands with a nanomolar affinity. At the time, the three known nuclear receptor ligands were steroids, retinoids, and thyroid hormone, and of those three, both steroids and retinoids were products of terpenoid metabolism. Thus, it was postulated that ancestral receptor would have been liganded by a terpenoid molecule. [66]
In 1992, a comparison of the DNA-binding domain of all known nuclear receptors led to the construction of a phylogenic tree of nuclear receptor that indicated that all nuclear receptors shared a common ancestor. [67] As a result, there was an increased effort upon uncovering the state of the first nuclear receptor, and by 1997 an alternative hypothesis was suggested: the ancestral nuclear receptor was an orphan receptor and it acquired ligand-binding ability over time [7] This hypothesis was proposed based on the following arguments:
Over the next 10 years, experiments were conducted to test this hypothesis and counterarguments soon emerged:
A combination of this recent evidence, as well as an in-depth study of the physical structure of the nuclear receptor ligand binding domain has led to the emergence of a new hypothesis regarding the ancestral state of the nuclear receptor. This hypothesis suggests that the ancestral receptor may act as a lipid sensor with an ability to bind, albeit rather weakly, several different hydrophobic molecules such as, retinoids, steroids, hemes, and fatty acids. With its ability to interact with a variety of compounds, this receptor, through duplications, would either lose its ability for ligand-dependent activity, or specialize into a highly specific receptor for a particular molecule. [71]
Below is a brief selection of key events in the history of nuclear receptor research. [73]
A hormone receptor is a receptor molecule that binds to a specific hormone. Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other receptors for various ligands, such as fatty acids and prostaglandins. Hormone receptors are of mainly two classes. Receptors for peptide hormones tend to be cell surface receptors built into the plasma membrane of cells and are thus referred to as trans membrane receptors. An example of this is Actrapid. Receptors for steroid hormones are usually found within the protoplasm and are referred to as intracellular or nuclear receptors, such as testosterone. Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.
In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism, and tumorigenesis of higher organisms.
Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors and initiate signal transduction for steroid hormones which lead to changes in gene expression over a time period of hours to days. The best studied steroid hormone receptors are members of the nuclear receptor subfamily 3 (NR3) that include receptors for estrogen and 3-ketosteroids. In addition to nuclear receptors, several G protein-coupled receptors and ion channels act as cell surface receptors for certain steroid hormones.
Estrogen receptors (ERs) are proteins found in cells that function as receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen receptors, namely ERα and ERβ, which belong to the nuclear receptor family. The second class consists of membrane estrogen receptors (mERs), such as GPER (GPR30), ER-X, and Gq-mER, which are primarily G protein-coupled receptors. This article focuses on the nuclear estrogen receptors.
A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.
The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.
In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription are referred to as coactivators while those that repress are known as corepressors. The mechanism of action of transcription coregulators is to modify chromatin structure and thereby make the associated DNA more or less accessible to transcription. In humans several dozen to several hundred coregulators are known, depending on the level of confidence with which the characterisation of a protein as a coregulator can be made. One class of transcription coregulators modifies chromatin structure through covalent modification of histones. A second ATP dependent class modifies the conformation of chromatin.
The constitutive androstane receptor (CAR) also known as nuclear receptor subfamily 1, group I, member 3 is a protein that in humans is encoded by the NR1I3 gene. CAR is a member of the nuclear receptor superfamily and along with pregnane X receptor (PXR) functions as a sensor of endobiotic and xenobiotic substances. In response, expression of proteins responsible for the metabolism and excretion of these substances is upregulated. Hence, CAR and PXR play a major role in the detoxification of foreign substances such as drugs.
The nuclear receptor coactivator 1 (NCOA1), also called steroid receptor coactivator-1 (SRC-1), is a transcriptional coregulatory protein that contains several nuclear receptor–interacting domains and possesses intrinsic histone acetyltransferase activity. It is encoded by the gene NCOA1.
The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the NCOA3 gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone receptor activator molecule 1 (TRAM-1).
The nuclear receptor 4A1 also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the NR4A1 gene.
The small heterodimer partner (SHP) also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.
Rev-Erb alpha (Rev-Erbɑ), also known as nuclear receptor subfamily 1 group D member 1 (NR1D1), is one of two Rev-Erb proteins in the nuclear receptor (NR) family of intracellular transcription factors. In humans, REV-ERBɑ is encoded by the NR1D1 gene, which is highly conserved across animal species.
Rev-Erb beta (Rev-Erbβ), also known as nuclear receptor subfamily 1 group D member 2 (NR1D2), is a member of the Rev-Erb protein family. Rev-Erbβ, like Rev-Erbα, belongs to the nuclear receptor superfamily of transcription factors and can modulate gene expression through binding to gene promoters. Together with Rev-Erbα, Rev-Erbβ functions as a major regulator of the circadian clock. These two proteins are partially redundant. Current research suggests that Rev-Erbβ is less important in maintaining the circadian clock than Rev-Erbα; knock-out studies of Rev-Erbα result in significant circadian disruption but the same has not been found with Rev-Erbβ. Rev-Erbβ compensation for Rev-Erbα varies across tissues, and further research is needed to elucidate the separate role of Rev-Erbβ.
Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.
Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.
COUP-TF1 also known as NR2F1 is a protein that in humans is encoded by the NR2F1 gene. This protein is a member of nuclear hormone receptor family of steroid hormone receptors.
Estrogen-related receptor alpha (ERRα), also known as NR3B1, is a nuclear receptor that in humans is encoded by the ESRRA gene. ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha, but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα. Currently, ERRα is considered an orphan nuclear receptor.
Liver X receptor beta (LXR-β) is a member of the nuclear receptor family of transcription factors. LXR-β is encoded by the NR1H2 gene.
Nuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily. A comprehensive database of coregulators for nuclear receptors and other transcription factors was previously maintained at the Nuclear Receptor Signaling Atlas website which has since been replaced by the Signaling Pathways Project website.
an NIH-funded research consortium and database; includes open-access PubMed-indexed journal, Nuclear Receptor Signaling