skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor

Journal Article · · Journal of Biological Chemistry
 [1];  [1];  [1];  [1];  [2];  [3];  [4];  [2];  [1]
  1. Van Andel Research Inst., Grand Rapids, MI (United States)
  2. Univ. of Michigan Medical School, Ann Arbor, MI (United States)
  3. Van Andel Research Inst., Grand Rapids, MI (United States); Rocky Vista Univ., Parker, CO (United States)
  4. Van Andel Research Inst., Grand Rapids, MI (United States); Grand Valley State Univ., Allendale, MI (United States)
+ Show Author Affiliations

Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. Here, these findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH)
Grant/Contract Number:
DK071662; DK066202; HL089301; 085P1000817
OSTI ID:
1022280
Journal Information:
Journal of Biological Chemistry, Vol. 286, Issue 4; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 59 works
Citation information provided by
Web of Science

References (33)

Context-dependent EKLF responsiveness defines the developmental specificity of the human varepsilon -globin gene in erythroid cells of YAC transgenic mice journal November 2000
Vitamin A regulation of BMP4 expression in the male germ line journal October 2005
Role of FXR in Regulating Bile Acid Homeostasis and Relevance for Human Diseases journal September 2005
Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α journal June 1995
The Structural Basis of Gas-Responsive Transcription by the Human Nuclear Hormone Receptor REV-ERBβ journal February 2009
Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily journal August 2002
Regulation of the promoters for the human bone morphogenetic protein 2 and 4 genes journal October 2000
Promotion of Feeder-Independent Self-Renewal of Embryonic Stem Cells by Retinol (Vitamin A) journal July 2008
Chicken ovalbumin upstream promoter transcription factor (COUP-TF) dimers bind to different GGTCA response elements, allowing COUP-TF to repress hormonal induction of the vitamin D3, thyroid hormone, and retinoic acid receptors. journal September 1992
Activation of Nuclear Receptors journal July 2003
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination journal September 1998
Orphan Nuclear Receptors: Shifting Endocrinology into Reverse journal April 1999
Loss of TR4 Orphan Nuclear Receptor Reduces Phosphoenolpyruvate Carboxykinase Mediated Gluconeogenesis journal September 2007
Human and rat TR4 orphan receptors specify a subclass of the steroid receptor superfamily. journal June 1994
Crystal structure of the human RXRalpha ligand-binding domain bound to its natural ligand: 9-cis retinoic acid journal June 2000
Transactivation of the proximal promoter of human oxytocin gene by TR4 orphan receptor journal December 2006
An embryonic/fetal beta-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer journal July 2002
Targeted Inactivation of Testicular Nuclear Orphan Receptor 4 Delays and Disrupts Late Meiotic Prophase and Subsequent Meiotic Divisions of Spermatogenesis journal June 2004
Retinoic acid receptor-related orphan receptor alpha as a therapeutic target in the treatment of dyslipidemia and atherosclerosis journal January 2006
Identification of SRC3/AIB1 as a Preferred Coactivator for Hormone-activated Androgen Receptor journal January 2010
RXR: From Partnership to Leadership in Metabolic Regulations book January 2007
Structural Insight into the Constitutive Repression Function of the Nuclear Receptor Rev-erbβ journal October 2007
The CCP4 suite programs for protein crystallography journal September 1994
Elements of the Glucocorticoid and Retinoic Acid Response Units Are Involved in cAMP-mediated Expression of the PEPCK Gene journal January 2003
A Novel Nuclear Receptor Heterodimerization Pathway Mediated by Orphan Receptors TR2 and TR4 journal September 1998
The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1 journal November 2008
The Emerging Role of Nuclear Receptor RORα and Its Crosstalk with LXR in Xeno- and Endobiotic Gene Regulation journal October 2008
9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRα journal January 1992
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
COUP-TF Upregulates NGFI-A Gene Expression through an Sp1 Binding Site journal April 1999
Crystallographic Identification and Functional Characterization of Phospholipids as Ligands for the Orphan Nuclear Receptor Steroidogenic Factor-1 journal February 2005
Structural basis for autorepression of retinoid X receptor by tetramer formation and the AF-2 helix journal September 2000
Identification of COUP-TFII Orphan Nuclear Receptor as a Retinoic Acid–Activated Receptor journal September 2008

Cited By (10)

Recent insights on the role and regulation of retinoic acid signaling during epicardial development journal May 2019
Strategies for developing pregnane X receptor antagonists: Implications from metabolism to cancer journal November 2019
The roles of endogenous retinoid signaling in organ and appendage regeneration journal March 2013
ROR nuclear receptors: structures, related diseases, and drug discovery journal December 2014
Targeting TR4 nuclear receptor with antagonist bexarotene increases docetaxel sensitivity to better suppress the metastatic castration-resistant prostate cancer progression journal November 2019
Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ journal December 2019
Compound loss of function of nuclear receptors Tr2 and Tr4 leads to induction of murine embryonic β-type globin genes journal February 2015
Vitamin A and retinoid signaling: genomic and nongenomic effects: Thematic Review Series: Fat-Soluble Vitamins: Vitamin A journal February 2013
The orphan nuclear receptors at their 25-year reunion journal October 2013
MMEJ-assisted gene knock-in using TALENs and CRISPR-Cas9 with the PITCh systems journal December 2015

Similar Records

Identification of COUP-TFII Orphan Nuclear Receptor as a Retinoic Acid-Activated Receptor
Journal Article · Tue Jan 12 00:00:00 EST 2010 · PLoS Biol. · OSTI ID:1022280
+8 more
Structural basis for corepressor assembly by the orphan nuclear receptor TLX
Journal Article · Sun Feb 15 00:00:00 EST 2015 · Genes & Development · OSTI ID:1022280
+5 more
NR4A orphan nuclear receptors influence retinoic acid and docosahexaenoic acid signaling via up-regulation of fatty acid binding protein 5
Journal Article · Fri Dec 25 00:00:00 EST 2009 · Biochemical and Biophysical Research Communications · OSTI ID:1022280

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Crystal Structure
Gene Regulation
Ligand-binding Protein
Nuclear Receptors
Transcription Factors
Ligand Identification
Orphan Nuclear Receptor
Testicular Receptor 4
Transcription Activation
Vitamin A