Nuclear receptor

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Crystallographic structure of a heterodimer of the nuclear receptors PPAR-g (green) and RXR-a (cyan) bound to double stranded DNA (magenta) and two molecules of the NCOA2 coactivator (red). The PPAR-g antagonist GW9662 and RXR-a agonist retinoic acid are depicted as space-filling models (carbon = white, oxygen = red, nitrogen = blue, chlorine = green). PPARg RXRa 3E00.png
Crystallographic structure of a heterodimer of the nuclear receptors PPAR-γ (green) and RXR-α (cyan) bound to double stranded DNA (magenta) and two molecules of the NCOA2 coactivator (red). The PPAR-γ antagonist GW9662 and RXR-α agonist retinoic acid are depicted as space-filling models (carbon = white, oxygen = red, nitrogen = blue, chlorine = green).

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.

Contents

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]

Species distribution

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

Structures of selected endogenous nuclear receptor ligands and the name of the receptor that each binds to. NR ligands.png
Structures of selected endogenous nuclear receptor ligands and the name of the receptor that each binds to.

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]

Structure

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 N-terminal (A/B), DNA-binding (C), and ligand binding (E) domains are independently well folded and structurally stable while the 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]

Structural Organization of Nuclear Receptors Top - Schematic 1D amino acid sequence of a nuclear receptor. Bottom - 3D structures of the DBD (bound to DNA) and LBD (bound to hormone) regions of the nuclear receptor. The structures shown are of the estrogen receptor. Experimental structures of N-terminal domain (A/B), hinge region (D), and C-terminal domain (F) have not been determined therefore are represented by red, purple, and orange dashed lines, respectively. Nuclear Receptor Structure.png
Structural Organization of Nuclear Receptors
Top – Schematic 1D amino acid sequence of a nuclear receptor.
Bottom – 3D structures of the DBD (bound to DNA) and LBD (bound to hormone) regions of the nuclear receptor. The structures shown are of the estrogen receptor. Experimental structures of N-terminal domain (A/B), hinge region (D), and C-terminal domain (F) have not been determined therefore are represented by red, purple, and orange dashed lines, respectively.
DNA binding domain (DBD)
PR DBD 2C7A.png
Crystallographic structure of the human progesterone receptor DNA-binding domain dimer (cyan and green) complexed with double stranded DNA (magenta). Zinc atoms of are depicted as grey spheres. [25]
Identifiers
Symbolzf-C4
Pfam PF00105
InterPro IPR001628
SMART SM00399
PROSITE PDOC00031
SCOP2 1hra / SCOPe / SUPFAM
CDD cd06916
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Ligand-binding domain (LBD)
RORC 3L0L.png
Crystallographic structure of the ligand binding domain of the human RORγ (rainbow colored, N-terminus = blue, C-terminus = red) complexed with 25-hydroxycholesterol (space-filling model (carbon = white, oxygen = red) and the NCOA2 coactivator (magneta). [26]
Identifiers
SymbolHormone_recep
Pfam PF00104
InterPro IPR000536
SMART SM00430
SCOP2 1lbd / SCOPe / SUPFAM
CDD cd06157
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Mechanism of action

Mechanism of class I nuclear receptor action. A class I nuclear receptor (NR), in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex in turn recruits other proteins that are responsible for transcription of downstream DNA into mRNA, which is eventually translated into protein, which results in a change in cell function. Nuclear receptor action.png
Mechanism of class I nuclear receptor action. A class I nuclear receptor (NR), in the absence of ligand, is located in the cytosol. Hormone binding to the NR triggers dissociation of heat shock proteins (HSP), dimerization, and translocation to the nucleus, where the NR binds to a specific sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex in turn recruits other proteins that are responsible for transcription of downstream DNA into mRNA, which is eventually translated into protein, which results in a change in cell function.
Mechanism of class II nuclear receptor action. A class II nuclear receptor (NR), regardless of ligand-binding status, is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein, which, in turn, recruits additional proteins such as RNA polymerase that are responsible for transcription of downstream DNA into RNA and eventually protein. Type ii nuclear receptor action.png
Mechanism of class II nuclear receptor action. A class II nuclear receptor (NR), regardless of ligand-binding status, is located in the nucleus bound to DNA. For the purpose of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of coactivator protein, which, in turn, recruits additional proteins such as RNA polymerase that are responsible for transcription of downstream DNA into RNA and eventually protein.

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.

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]

Type I

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.

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.

Type II

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

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

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.

Dimerization

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]

Coregulatory proteins

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]

Coactivators

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.

Corepressors

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.

Agonism vs antagonism

Structural basis for the mechanism of nuclear receptor agonist and antagonist action. The structures shown here are of the ligand binding domain (LBD) of the estrogen receptor (green cartoon diagram) complexed with either the agonist diethylstilbestrol (top, PDB: 3ERD ) or antagonist 4-hydroxytamoxifen (bottom, 3ERT ). The ligands are depicted as space filling spheres (white = carbon, red = oxygen). When an agonist is bound to a nuclear receptor, the C-terminal alpha helix of the LDB (H12; light blue) is positioned such that a coactivator protein (red) can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so-called NR box containing the LXXLL amino acid sequence motif. Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which sterically displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked. NR mechanism.png
Structural basis for the mechanism of nuclear receptor agonist and antagonist action. The structures shown here are of the ligand binding domain (LBD) of the estrogen receptor (green cartoon diagram) complexed with either the agonist diethylstilbestrol (top, PDB: 3ERD ​) or antagonist 4-hydroxytamoxifen (bottom, 3ERT ​). The ligands are depicted as space filling spheres (white = carbon, red = oxygen). When an agonist is bound to a nuclear receptor, the C-terminal alpha helix of the LDB (H12; light blue) is positioned such that a coactivator protein (red) can bind to the surface of the LBD. Shown here is just a small part of the coactivator protein, the so-called NR box containing the LXXLL amino acid sequence motif. Antagonists occupy the same ligand binding cavity of the nuclear receptor. However antagonist ligands in addition have a sidechain extension which sterically displaces H12 to occupy roughly the same position in space as coactivators bind. Hence coactivator binding to the LBD is blocked.

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]

Agonists

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).

Antagonists

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).

Inverse agonists

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]

Selective receptor modulators

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]

Alternative mechanisms

Phylogenetic tree of human nuclear receptors Nr alignment tree.jpg
Phylogenetic tree of human nuclear receptors

Transrepression

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.

Non-genomic

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]

Family members

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).

SubfamilyGroupMember
NRNC Symbol [6] AbbreviationNameGeneLigand(s)
1Thyroid Hormone Receptor-likeA 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
EE78C-like
(arthropod, trematode, mullosc, nematode) [50] [52] 		NR1E1Eip78CEcdysone-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
GCNR14-like (nematode) [50] NR1G1sex-1Steroid hormone receptor cnr14 [53] sex-1
H Liver X receptor-likeNR1H1 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
IVitamin D receptor-likeNR1I1 VDR Vitamin D receptor VDR vitamin D
NR1I2 PXR Pregnane X receptor NR1I2 xenobiotics
NR1I3 CAR Constitutive androstane receptor NR1I3 androstane
JHr96-like [50] NR1J1Hr96/Daf-12 Nuclear hormone receptor HR96 Hr96 cholesterol/dafachronic acid [55]
NR1J2
NR1J3
KHr1-like [50] NR1K1Hr1Nuclear hormone receptor HR1
2Retinoid X Receptor-likeA 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
ETLX/PNRNR2E1 TLX Homologue of the Drosophila tailless gene NR2E1
NR2E3 PNR Photoreceptor cell-specific nuclear receptor NR2E3
F COUP/EARNR2F1 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
3Estrogen Receptor-likeA 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
C3-Ketosteroid receptorsNR3C1 GR Glucocorticoid receptor NR3C1 cortisol
NR3C2 MR Mineralocorticoid receptor NR3C2 aldosterone
NR3C3 PR Progesterone receptor PGR progesterone
NR3C4 AR Androgen receptor AR testosterone
DEstrogen Receptor-like
(in lophotrochozoa) [58] 		NR3D
EEstrogen Receptor-like
(in cnidaria) [59] 		NR3E
FEstrogen Receptor-like
(in placozoa) [59] 		NR3F
4Nerve Growth Factor IB-likeANGFIB/NURR1/NOR1NR4A1 NGFIB Nerve Growth factor IB NR4A1
NR4A2 NURR1 Nuclear receptor related 1 NR4A2
NR4A3 NOR1 Neuron-derived orphan receptor 1 NR4A3
5Steroidogenic
Factor-like		ASF1/LRH1NR5A1 SF1 Steroidogenic factor 1 NR5A1 phosphatidylinositols
NR5A2 LRH-1 Liver receptor homolog-1 NR5A2 phosphatidylinositols
BHr39-likeNR5B1 [50] HR39/FTZ-F1 Nuclear hormone receptor fushi tarazu factor I beta Hr39
6Germ Cell Nuclear Factor-likeAGCNFNR6A1 GCNF Germ cell nuclear factor NR6A1
7NRs with two DNA binding domains [60] [50] [61] A2DBD-NRαNR7A12DBD-NRA2
B2DBD-NRβNR7B12DBD-NRA3
C2DBD-NRγNR7C12DBD-NRA1arthropod "α/β"  
8NR8 [62] (eumetazoa)ANR8ANR8A1CgNR8A1Nuclear receptor 8 AKG49571
0Miscellaneous (lacks either LBD or DBD)Aknr/knrl/egon [50] (arthropods)NR0A1KNIZygotic gap protein knirps knl
BDAX/SHPNR0B1 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 very 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 an 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]

Evolution

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:

  1. The nuclear receptor sequences that had been identified in the earliest metazoans (cnidarians and Schistosoma) were all members of the COUP-TF, RXR, and FTZ-F1 groups of receptors. Both COUP-TF and FTZ-F1 are orphan receptors, and RXR is only found to bind a ligand in vertebrates. [68]
  2. While orphan receptors had known arthropod homologs, no orthologs of liganded vertebrate receptors had been identified outside vertebrates, suggesting that orphan receptors are older than liganded-receptors. [69]
  3. Orphan receptors are found amongst all six subfamilies of nuclear receptors, while ligand-dependent receptors are found amongst three. [7] Thus, since the ligand-dependent receptors were believed to be predominantly member of recent subfamilies, it seemed logical that they gained the ability to bind ligands independently.
  4. The phylogenetic position of a given nuclear receptor within the tree correlates to its DNA-binding domain and dimerization abilities, but there is no identified relationship between a ligand-dependent nuclear receptor and the chemical nature of its ligand. In addition to this, the evolutionary relationships between ligand-dependent receptors did not make much sense as closely related receptors of subfamilies bound ligands originating from entirely different biosynthetic pathways (e.g. TRs and RARs). On the other hand, subfamilies that are not evolutionarily related bind similar ligands (RAR and RXR both bind all-trans and 9-cis retinoic acid respectively). [69]
  5. In 1997, it was discovered that nuclear receptors did not exist in static off and on conformations, but that a ligand could alter the equilibrium between the two states. Furthermore, it was found that nuclear receptors could be regulated in a ligand-independent manner, through either phosphorylation or other post-translational modifications. Thus, this provided a mechanism for how an ancestral orphan receptor was regulated in a ligand-independent manner, and explained why the ligand binding domain was conserved. [69]

Over the next 10 years, experiments were conducted to test this hypothesis and counterarguments soon emerged:

  1. Nuclear receptors were identified in the newly sequenced genome of the demosponge Amphimedon queenslandica, a member Porifera, the most ancient metazoan phylum. The A. queenslandica genome contains two nuclear receptors known as AqNR1 and AqNR2 and both were characterized to bind and be regulated by ligands. [70]
  2. Homologs for ligand-dependent vertebrate receptors were found outside vertebrates in mollusks and Platyhelminthes. Furthermore, the nuclear receptors found in cnidarians were found to have structural ligands in mammals, which could mirror the ancestral situation.
  3. Two putative orphan receptors, HNF4 and USP were found, via structural and mass spectrometry analysis, to bind fatty acids and phospholipids respectively. [56]
  4. Nuclear receptors and ligands are found to be a lot less specific than was previously thought. Retinoids can bind mammalian receptors other than RAR and RXR such as, PPAR, RORb, or COUP-TFII. Furthermore, RXR is sensitive to a wide range of molecules including retinoids, fatty acids, and phospholipids. [71]
  5. Study of steroid receptor evolution revealed that the ancestral steroid receptor could bind a ligand, estradiol. Conversely, the estrogen receptor found in mollusks is constitutively active and did not bind estrogen-related hormones. Thus, this provided an example of how an ancestral ligand-dependent receptor could lose its ability to bind ligands. [72]

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]

History

Below is a brief selection of key events in the history of nuclear receptor research. [73]

See also

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<span class="mw-page-title-main">Transcription factor</span> Protein that regulates the rate of DNA transcription

In molecular biology, a transcription factor (TF) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The function of TFs is to regulate—turn on and off—genes in order to make sure that they are expressed in the desired cells at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a coordinated fashion to direct cell division, cell growth, and cell death throughout life; cell migration and organization during embryonic development; and intermittently in response to signals from outside the cell, such as a hormone. There are 1500-1600 TFs in the human genome. Transcription factors are members of the proteome as well as regulome.

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.

<span class="mw-page-title-main">Peroxisome proliferator-activated receptor</span> Group of nuclear receptor proteins

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.

<span class="mw-page-title-main">Estrogen receptor</span> Proteins activated by the hormone estrogen

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors, which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs), which are mostly G protein-coupled receptors. This article refers to the former (ER).

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.

<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

<span class="mw-page-title-main">Constitutive androstane receptor</span> Protein-coding gene in humans

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.

<span class="mw-page-title-main">Nuclear receptor coactivator 1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Nuclear receptor coactivator 3</span> Protein-coding gene in the species Homo sapiens

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).

<span class="mw-page-title-main">Nuclear receptor 4A1</span> Mammalian protein found in Homo sapiens

The nuclear receptor 4A1 also known as Nur77, TR3, and NGFI-B is a protein that in humans is encoded by the NR4A1 gene.

<span class="mw-page-title-main">Small heterodimer partner</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Rev-ErbA alpha</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Retinoid X receptor alpha</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor alpha (RXR-alpha), also known as NR2B1 is a nuclear receptor that in humans is encoded by the RXRA gene.

<span class="mw-page-title-main">Retinoid X receptor beta</span> Protein-coding gene in the species Homo sapiens

Retinoid X receptor beta (RXR-beta), also known as NR2B2 is a nuclear receptor that in humans is encoded by the RXRB gene.

<span class="mw-page-title-main">COUP-TFI</span> Protein found in humans

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.

<span class="mw-page-title-main">Estrogen-related receptor alpha</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Liver X receptor beta</span> Protein-coding gene in the species Homo sapiens

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.

The first antiandrogen was discovered in the 1960s. Antiandrogens antagonise the androgen receptor (AR) and thereby block the biological effects of testosterone and dihydrotestosterone (DHT). Antiandrogens are important for men with hormonally responsive diseases like prostate cancer, benign prostatic hyperplasia (BHP), acne, seborrhea, hirsutism and androgen alopecia. Antiandrogens are mainly used for the treatment of prostate diseases. Research from 2010 suggests that ARs could be linked to the disease progression of triple-negative breast cancer and salivary duct carcinoma and that antiandrogens can potentially be used to treat it.

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