Nuclear receptor

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Nuclear receptors are a class of ligand activated intracelluar transcription factors which up or down regulate the expression of genes. Nuclear receptors may be classified either according to mechanism (type I or II),[1] or sequence homology (NR subfamilies 0-6)[2] (see respectively mechanism and homology classifications below).

Ligands

Ligands that bind to nuclear receptors include lipophilic substances such as endogenous hormones, vitamins A and D, drugs, and xenobiotic endocrine disruptors. Because the expression of a large number of genes is regulated by nuclear receptors, ligands that bind to these receptors can have profound effects on the organism.

A number of nuclear receptors, referred to as orphan receptors, have no known (or at least generally agreed upon) endogenous ligands. Some of these receptors such as FXR, LXR, and PPAR may 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 upregulating the expression of cytochrome P450 enzymes that metabolize these xenobiotics.[3]

A few other nuclear receptors, such as the constitutive androstane receptor appear to be active in the absence of ligand. Finally a few nuclear receptors such as the short heterodimer partner (SHP; NR0B2), lack a ligand binding domain and therefore by definition cannot bind ligand.

Structure[4]

Nuclear receptors contain the following domains:

  • A-B) N-terminal regulatory domain
  • C) DNA-binding domain (DBD)
  • D) Hinge region
  • E) Ligand binding domain (LBD)
  • F) C-terminal domain

Mechanism classification[1]

Ligand binding to type I nuclear receptors (includes members of the NR subfamily 3) 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 (HRE's). The nuclear receptor/DNA complex then recruits other proteins which transcribe DNA downstream from the HRE into messenger RNA and eventually protein which causes a change in cell function.


Type II receptors (NR subfamily 1) in contrast are retained in the nucleus regardless of the ligand binding status and in addition bind as hetero-dimers (usually with RXR) to DNA.

Homology classification[2]

The following is a list of the 48 known human nuclear receptors[5] sorted according to sequence homology.

  • Subfamily:Group:Member: Name (Abbreviation; NRNC Symbol - Nuclear Receptor Nomenclature Committee[2]) (endogenous ligand)
  • Subfamily 1: Thyroid Hormone Receptor-like
    • Group A: Thyroid hormone receptor (Thyroid hormone)
      • 1: Thyroid hormone receptor-α (TRα; NR1A1)
      • 2: Thyroid hormone receptor-β (TRβ; NR1A2)
    • Group B: Retinoic acid receptor (Vitamin A and related compounds)
      • 1: Retinoic acid receptor-α (RARα; NR1B1)
      • 2: Retinoic acid receptor-β (RARβ; NR1B2)
      • 3: Retinoic acid receptor-γ (RARγ; NR1B3)
    • Group C: Peroxisome proliferator-activated receptor
      • 1: Peroxisome proliferator-activated receptor-α (PPARα; NR1C1)
      • 2: Peroxisome proliferator-activated receptor-β (PPARβ; NR1C2)
      • 3: Peroxisome proliferator-activated receptor-γ (PPARγ: NR1C3)
    • Group D: Rev-erb
      • 1: Rev-erbα (Rev-erbα; NR1D1)
      • 2: Rev-erbβ (Rev-erbβ; NR1D2)
    • Group F: Retinoid-related orphan receptor
      • 1: Retinoid-related orphan receptor-α (RORα; NR1F1)
      • 2: Retinoid-related orphan receptor-β (RORβ; NR1F2)
      • 3: Retinoid-related orphan receptor-γ (RORγ; NR1F3)
    • Group H: Liver X receptor-like
      • 3: Liver X receptor-α (LXRα; NR1H3)
      • 2: Liver X receptor-β (LXRβ; NR1H2)
      • 4: Farnesoid X receptor (FXR; NR1H4)
    • Group I: Vitamin D receptor-like
  • Subfamily 2: Retinoid X Receptor-like
    • Group A: Hepatocyte nuclear factor-4 (HNF4)
      • 1: Hepatocyte nuclear factor-4-α (HNF4α; NR2A1)
      • 2: Hepatocyte nuclear factor-4-γ (HNF4γ; NR2A2)
    • Group B: Retinoid X receptor (RXRα)
      • 1: Retinoid X receptor-α (RXRα; NR2B1)
      • 2: Retinoid X receptor-β (RXRβ; NR2B2)
      • 3: Retinoid X receptor-γ (RXRγ; NR2B3)
    • Group C: Testicular receptor
      • 1: Testicular receptor 2 (TR2; NR2C1)
      • 2: Testicular receptor 4 (TR4; NR2C2)
    • Group E: TLX/PNR
      • 1: Human homologue of the Drosophila tailless gene (TLX; NR2E1)
      • 3: Photoreceptor-Specific Nuclear Receptor (PNR; NR2E3)
    • Group F: COUP/EAR
      • 1: Chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI; NR2F1)
      • 2: Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII; NR2F2)
      • 6: ERBA-related 2 (EAR2; NR2F6)
  • Subfamily 4: Nerve Growth Factor IB-like
    • Group A: NGFIB/NURR1/NOR1
      • 1: Nerve Growth factor IB (NGFIB; NR4A1)
      • 2: Nuclear receptor related 1 (NURR1; NR4A2)
      • 3: Neuron-derived orphan receptor 1 (NOR1; NR4A3)
  • Subfamily 5: Steroidogenic Factor-like
    • Group A: SF1/LRH1
      • 1: Steroidogenic factor 1 (SF1; NR5A1)
      • 2: Liver receptor homolog 1 (LRH1; NR5A2)
  • Subfamily 6: Germ Cell Nuclear Factor-like
    • Group A: GCN1
      • 1: Germ cell nuclear factor (GCN1; NR6A1)
  • Subfamily 0: Miscellaneous
    • Group B: DAX/SHP
      • 1: Dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1; NR0B1)
      • 2: Short heterodimer partner (SHP; NR0B2)


A novel subfamily: Nuclear receptor with two DNA binding domains (2DBD-NR)

Wu W, Niles EG, El-Sayed N, Berriman M, LoVerde PT. 2006 Schistosoma mansoni (Platyhelminthes, Trematoda) nuclear receptors: sixteen new members and a novel subfamily. Gene. 366(2):303-15.

See also

References

  1. ^ a b Novac N, Heinzel T. Nuclear receptors: overview and classification. Curr. Drug Targets Inflamm. Allergy. 2004; 3(4):335-46. PMID 15584884
  2. ^ a b c Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999; 97(2):161-3. PMID 10219237
  3. ^ Mohan R, Heyman RA, Orphan nuclear receptor modulators. Curr Top Med Chem. 2003; 3(14):1637-47. PMID 14683519
  4. ^ Klinge CM, Estrogen receptor interaction with co-activators and co-repressors. Steroids. 2000; 65(5):227-51. PMID 10751636
  5. ^ Zhang Z, Burch PE, Cooney AJ, Lanz RB, Pereira FA, Wu J, Gibbs RA, Weinstock G, Wheeler DA. Genomic analysis of the nuclear receptor family: new insights into structure, regulation, and evolution from the rat genome. Genome Res. 2004; 14(4):580-90. PMID 15059999

External links

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