Nuclear receptor
From Wikipedia, the free encyclopedia
Nuclear receptors are a class of ligand activated intracelluar transcription factors which up or down regulate the expression of genes.[1] Nuclear receptors may be classified either according to mechanism (type I or II),[2] or sequence homology (NR subfamilies 0-6)[3] (see respectively mechanism and homology classifications below).
[edit] 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 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.[4]
A few other nuclear receptors, such as the constitutive androstane receptor appear to be active in the absence of ligand. Finally seveal nuclear receptors such as the short heterodimer partner (SHP; NR0B2), lack a ligand binding domain and therefore by definition cannot bind ligand.
[edit] Structure
Nuclear receptors contain the following structural domains:[5]
- A-B) N-terminal regulatory domain
- C) DNA-binding domain (DBD)
- D) Hinge region
- E) Ligand binding domain (LBD)
- F) C-terminal domain
[edit] Mechanism classification
Nuclear receptors may be classified into the following two mechanistic classes:[2]
[edit] Type I
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.
[edit] Type II
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.
[edit] Homology classification
The following is a list of the 48 known human nuclear receptors[6] sorted according to sequence homology.[3]
Subfamily:Group:Member: Name (Abbreviation; NRNC Symbol - Nuclear Receptor Nomenclature Committee[3]) (endogenous ligand)
[edit] Subfamily 1: Thyroid Hormone Receptor-like
- Group A: Thyroid hormone receptor (Thyroid hormone)
- Group B: Retinoic acid receptor (Vitamin A and related compounds)
- Group C: Peroxisome proliferator-activated receptor
- Group D: Rev-erb
- Group F: Retinoid-related orphan receptor
- 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
- 1: Vitamin D receptor (VDR; NR1I1, VDR) (vitamin D)
- 2: Pregnane X receptor (PXR; NR1I2)
- 3: Constitutive androstane receptor (CAR; NR1I3)
[edit] Subfamily 2: Retinoid X Receptor-like
- Group A: Hepatocyte nuclear factor-4 (HNF4)
- Group B: Retinoid X receptor (RXRα)
- Group C: Testicular receptor
- Group E: TLX/PNR
- Group F: COUP/EAR
[edit] Subfamily 3: Estrogen Receptor-like (Steroid hormone receptors)
- Group A: Estrogen receptor (Sex hormone receptors; sex hormones: Estrogen)
- Group B: Estrogen related receptor
- Group C: 3-Ketosteroid receptors
- 1: Glucocorticoid receptor (GR; NR3C1) (Cortisol)
- 2: Mineralocorticoid receptor (MR; NR3C2) (Aldosterone)
- 3: Progesterone receptor (PR; NR3C3, PGR) (Sex hormone receptor; Sex hormones: Progesterone)
- 4: Androgen receptor (AR; NR3C4, AR) (Sex hormone receptors; Sex hormones: Testosterone)
[edit] Subfamily 4: Nerve Growth Factor IB-like
- Group A: NGFIB/NURR1/NOR1
[edit] Subfamily 5: Steroidogenic Factor-like
[edit] Subfamily 6: Germ Cell Nuclear Factor-like
- Group A: GCN1
- 1: Germ cell nuclear factor (GCN1; NR6A1)
[edit] Subfamily 0: Miscellaneous
- Group B: DAX/SHP
- Group C: Nuclear receptors with two DNA binding domains (2DBD-NR) (A novel subfamily)[7][8]
[edit] See also
[edit] References
- ^ Evans, R.M. The steroid and thyroid hormone receptor superfamily. Science. 1988 240(4854):889-895. PMID 3283939.
- ^ a b Novac N, Heinzel T. Nuclear receptors: overview and classification. Curr. Drug Targets Inflamm. Allergy. 2004; 3(4):335-46. PMID 15584884
- ^ a b c Nuclear Receptors Nomenclature Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999; 97(2):161-3. PMID 10219237
- ^ Mohan R, Heyman RA, Orphan nuclear receptor modulators. Curr Top Med Chem. 2003; 3(14):1637-47. PMID 14683519
- ^ Klinge CM, Estrogen receptor interaction with co-activators and co-repressors. Steroids. 2000; 65(5):227-51. PMID 10751636
- ^ 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
- ^ Wu W, Niles EG, El-Sayed N, Berriman M, LoVerde PT. Schistosoma mansoni (Platyhelminthes, Trematoda) nuclear receptors: sixteen new members and a novel subfamily. Gene. 2006. 366(2):303-15. PMID 16406405
- ^ Wu W, Niles EG, Hirai H, LoVerde PT. Evolution of a novel subfamily of nuclear receptors with members that each contain two DNA binding domains. BMC Evol Biol. 2007, 7:27.PMID 17319953
[edit] External links
- Nuclear Receptor journal homepage
- Nuclear receptor resource at Georgetown University
- Nuclear Receptor Signalling Atlas (NURSA, NIH-funded research consortium and database; includes open-access PubMed-indexed journal, Nuclear Receptor Signaling)
- MeSH Nuclear+Receptors
CAP - CBF - E2F - KlF - Nanog - NF-kB - Oct-4 - P300/CBP - PIT-1 - Rho/Sigma - R-SMAD - Sox2 - Sp1 - STAT (STAT1, STAT3, STAT5)
Basic-helix-loop-helix: AhR - HIF - MYC - Twist - Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6)
Basic leucine zipper: C/EBP - CREB - AP-1
Basic helix-loop-helix leucine zipper: MITF - SREBP
Nuclear receptors: subfamily 1 (Thyroid hormone, RAR, PPAR, LXR, FXR, Calcitriol, PXR, CAR) - subfamily 2 (HNF4, RXR) - subfamily 3/Steroid hormone (Estrogen, Estrogen related, Glucocorticoid, Mineralocorticoid, Progesterone, Androgen) - subfamily 0 (NR0B1)