Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor

Diego M Presman, M Florencia Ogara, Martín Stortz, Lautaro D Alvarez, John R Pooley, R Louis Schiltz, Lars Grøntved, Thomas A Johnson, Paul R Mittelstadt, Jonathan D Ashwell, Sundar Ganesan, Gerardo Burton, Valeria Levi, Gordon L Hager, Adali Pecci

Research output: Contribution to journalArticle (Academic Journal)peer-review

78 Citations (Scopus)

Abstract

Glucocorticoids are essential for life, but are also implicated in disease pathogenesis and may produce unwanted effects when given in high doses. Glucocorticoid receptor (GR) transcriptional activity and clinical outcome have been linked to its oligomerization state. Although a point mutation within the GR DNA-binding domain (GRdim mutant) has been reported as crucial for receptor dimerization and DNA binding, this assumption has recently been challenged. Here we have analyzed the GR oligomerization state in vivo using the number and brightness assay. Our results suggest a complete, reversible, and DNA-independent ligand-induced model for GR dimerization. We demonstrate that the GRdim forms dimers in vivo whereas adding another mutation in the ligand-binding domain (I634A) severely compromises homodimer formation. Contrary to dogma, no correlation between the GR monomeric/dimeric state and transcriptional activity was observed. Finally, the state of dimerization affected DNA binding only to a subset of GR binding sites. These results have major implications on future searches for therapeutic glucocorticoids with reduced side effects.

Original languageEnglish
Pages (from-to)e1001813
JournalPLoS Biology
Volume12
Issue number3
DOIs
Publication statusPublished - 18 Mar 2014

Bibliographical note

Publication coordinated by National Cancer Institute, USA despite listing elsewhere.

Keywords

  • Animals
  • Cells, Cultured
  • DNA
  • Mice
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Receptors, Glucocorticoid

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