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Quantitative proteomics of the thyroid hormone receptor-coregulator interactions
Jamie M R Moore1, Sarah J Galicia, Andrea C McReynolds
1Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94143-2280, USA.
The Journal of Biological Chemistry
|April 22, 2004
Summary
Thyroid hormone receptor (THR) interactions with coregulators are ligand-dependent. This study identifies specific THR-coregulator binding patterns, revealing how different ligands dictate biological responses and enabling prediction of these outcomes.
Area of Science:
- Molecular Endocrinology
- Gene Regulation
- Protein-Protein Interactions
Background:
- Thyroid hormone receptors (THR) orchestrate gene expression crucial for development and homeostasis.
- THR function involves dynamic interactions with corepressor and coactivator proteins, mediated by conserved NR box motifs.
- Understanding the selectivity of these interactions is key to deciphering specific biological responses.
Purpose of the Study:
- To investigate the principles governing thyroid receptor-coregulator selectivity.
- To identify specific coregulator NR boxes that bind THR.
- To determine how ligand binding influences THR-coregulator interactions and downstream biological effects.
Main Methods:
- Development of a high-throughput in vitro binding assay to measure equilibrium affinity.
- Testing THR binding to a library of coregulators in the presence of various ligands (T3, GC-1, NH-3).
- Analysis of differential binding patterns to predict biological responses.
Main Results:
- Identification of multiple coregulator NR boxes binding THR at physiological concentrations, including those from coactivators (SRC1, SRC2, TRAP220, TRBP, p300, ARA70) and corepressors (RIP140, DAX-1).
- Demonstration that THR-coregulator binding patterns are ligand-dependent.
- Correlation of differential binding with predictable biological responses.
Conclusions:
- Ligand-modulated binding of coregulators to the thyroid hormone receptor dictates biological outcomes.
- The developed assay provides a generalizable method for studying nuclear receptor-coregulator selectivity.
- This work establishes a foundation for defining rules governing nuclear receptor-coregulator interactions.