NIH Research Festival
Transcription factors (TFs) dynamically bind to chromatin and are essential for the regulation of genes. While a large percentage of these proteins appear to self-associate to form dimers or higher-order oligomers, the stoichiometry of DNA-bound transcription factors has been poorly characterized in vivo. The glucocorticoid receptor (GR) is a ligand-regulated TF and one of the most targeted proteins in the pharmaceutical industry due to its powerful anti-inflammatory actions. The search for safer, side effects-free glucocorticoids relies exclusively on a model whereby the GR oligomerization state dictates its transcriptional output. It is still widely accepted that GR directly binds DNA as a homodimer, even though this paradigm has been exclusively established from in vitro studies. Using a unique set of imaging techniques coupled with a cell line containing an array of DNA binding elements, we show that GR is predominantly a tetramer when bound to its target DNA. We find that DNA binding triggers an inter-domain allosteric regulation within the GR, leading to tetramerization. We therefore propose that dynamic changes in GR stoichiometry represent a new level of regulation in steroid receptor activation. Quaternary structure analysis of other members of the steroid receptor family (estrogen, androgen and progesterone receptors) reveals variation in oligomerization states among this family of TFs. As GR’s oligomerization state has been implicated in therapy outcome, our findings open new doors to the rational design of novel GR ligands and re-define the quaternary structure of steroid receptors.
Scientific Focus Area: Molecular Biology and Biochemistry
This page was last updated on Friday, March 26, 2021