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The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor

X Edward Zhou1, Kelly M Suino-Powell, Yong Xu

  • 1Laboratory of Structural Sciences and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. edward.zhou@vai.org

The Journal of Biological Chemistry
|November 12, 2010
PubMed

Insights

Testicular receptor 4 (TR4) is an orphan nuclear receptor. Retinoids like retinol and retinoic acid activate TR4, revealing its ligand-regulated function and potential roles in various biological processes.

Area of Science:

  • Nuclear receptor biology
  • Molecular endocrinology
  • Structural biology

Background:

  • Testicular receptors 2 and 4 (TR2/4) are orphan nuclear receptors involved in spermatogenesis, lipid regulation, and CNS development.
  • Limited knowledge exists regarding the structural characteristics and ligand regulation of TR2/4 subfamily members.

Purpose of the Study:

  • To elucidate the structural features of the TR4 ligand-binding domain (LBD).
  • To investigate the ligand-dependent regulation of TR4 transcriptional activity.

Main Methods:

  • X-ray crystallography to determine the structure of ligand-free TR4 LBD.
  • Reporter gene assays to assess TR4 transcriptional activity.
  • Site-directed mutagenesis to evaluate the roles of cofactor binding, dimerization, and ligand binding.

Main Results:

  • The crystal structure of ligand-free TR4 LBD revealed an autorepressed conformation with the ligand-binding pocket and AF-2 helix occupied.
  • TR4 exhibits constitutive transcriptional activity, potentiated by coactivators.
  • Retinol and retinoic acid were identified as ligands that promote TR4 coactivator recruitment and transcriptional activation.
  • Mutations affecting cofactor binding, dimerization, or ligand binding reduced TR4 activity.

Conclusions:

  • TR4 functions as a ligand-regulated nuclear receptor.
  • Retinoids may play a broader role in regulating orphan receptors like TR4.
  • Structural insights into TR4's autorepressed state inform its ligand-dependent activation mechanism.

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