Structural and functional characterization of the interdomain interaction in the mineralocorticoid receptor

Mol Endocrinol. 2009 Sep;23(9):1360-70. doi: 10.1210/me.2009-0032. Epub 2009 Jun 18.


The mineralocorticoid receptor (MR) plays a central role in electrolyte homeostasis and in cardiovascular disease. We have previously reported a ligand-dependent N/C-interaction in the MR. In the present study we sought to fully characterize the MR N/C-interaction. By using a range of natural and synthetic MR ligands in a mammalian two-hybrid assay we demonstrate that in contrast to aldosterone, which strongly induces the interaction, the physiological ligands deoxycorticosterone and cortisol weakly promote the interaction but predominantly inhibit the aldosterone-mediated N/C-interaction. Similarly, progesterone and dexamethasone antagonize the interaction. In contrast, the synthetic agonist 9alpha-fludrocortisol robustly induces the interaction. The ability of the N/C interaction to discriminate between MR agonists suggests a subtle conformational difference in the ligand-binding domain induced by these agonists. We also demonstrate that the N/C interaction is not cell specific, consistent with the evidence from a glutathione-S-transferase pull-down assay, of a direct protein-protein interaction between the N- and C-terminal domains of the MR. Examination of a panel of deletions in the N terminus suggests that several regions may be critical to the N/C-interaction. These studies have identified functional differences between physiological MR ligands, which suggest that the ligand-specific dependence of the N/C-interaction may contribute to the differential activation of the MR that has been reported in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Line
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Desoxycorticosterone / chemistry
  • Glutathione Transferase / metabolism
  • Humans
  • Hydrocortisone / pharmacology*
  • Ligands
  • Protein Conformation
  • Protein Structure, Tertiary
  • Rats
  • Receptors, Mineralocorticoid / chemistry*
  • Receptors, Mineralocorticoid / metabolism*
  • Swine
  • Two-Hybrid System Techniques


  • Ligands
  • Receptors, Mineralocorticoid
  • Desoxycorticosterone
  • Glutathione Transferase
  • Hydrocortisone