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Structural and Functional Characterization of the Interdomain Interaction in the Mineralocorticoid Receptor

Prince Henry’s Institute of Medical Research, Clayton 3168, Victoria, Australia

Address all correspondence and requests for reprints to: Professor Peter J. Fuller, Prince Henry’s Institute of Medical Research, P.O. Box 5152, Clayton 3168, Victoria, Australia. E-mail: peter.fuller{at}princehenrys.org.

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 9-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.

NURSA Molecule Pages Link:

Nuclear Receptors:   MR

Coregulators:   PIAS1

Ligands:   Deoxycorticosterone  |  Dexamethasone  |  Aldosterone  |  Progesterone