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

Abstract

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.

Authors:
 [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)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH)
OSTI Identifier:
1022280
Grant/Contract Number:  
DK071662; DK066202; HL089301; 085P1000817
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 286; Journal Issue: 4; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
ENGLISH
Subject:
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

Citation Formats

Zhou, X. Edward, Suino-Powell, Kelly M., Xu, Yong, Chan, Cee-Wah, Tanabe, Osamu, Kruse, Schoen W., Reynolds, Ross, Engel, James Douglas, and Xu, H. Eric. The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor. United States: N. p., 2010. Web. doi:10.1074/jbc.M110.168740.
Zhou, X. Edward, Suino-Powell, Kelly M., Xu, Yong, Chan, Cee-Wah, Tanabe, Osamu, Kruse, Schoen W., Reynolds, Ross, Engel, James Douglas, & Xu, H. Eric. The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor. United States. https://doi.org/10.1074/jbc.M110.168740
Zhou, X. Edward, Suino-Powell, Kelly M., Xu, Yong, Chan, Cee-Wah, Tanabe, Osamu, Kruse, Schoen W., Reynolds, Ross, Engel, James Douglas, and Xu, H. Eric. 2010. "The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor". United States. https://doi.org/10.1074/jbc.M110.168740. https://www.osti.gov/servlets/purl/1022280.
@article{osti_1022280,
title = {The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor},
author = {Zhou, X. Edward and Suino-Powell, Kelly M. and Xu, Yong and Chan, Cee-Wah and Tanabe, Osamu and Kruse, Schoen W. and Reynolds, Ross and Engel, James Douglas and Xu, H. Eric},
abstractNote = {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.},
doi = {10.1074/jbc.M110.168740},
url = {https://www.osti.gov/biblio/1022280}, journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 4,
volume = 286,
place = {United States},
year = {Tue Nov 09 00:00:00 EST 2010},
month = {Tue Nov 09 00:00:00 EST 2010}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 59 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

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


Activation of Nuclear Receptors
journal, July 2003


Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
journal, September 1998


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


Transactivation of the proximal promoter of human oxytocin gene by TR4 orphan receptor
journal, December 2006


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


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


Identification of COUP-TFII Orphan Nuclear Receptor as a Retinoic Acid–Activated Receptor
journal, September 2008


Works referencing / citing this record:

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


Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ
journal, December 2019


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