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Phosphorylation of Mineralocorticoid Receptor at Residue S839 Impairs Aldosterone‐dependent Gene Transactivation Coupling in a Dominant Negative Manner
Author(s) -
JimenezCanino Ruben,
Fernandes Miguel,
MartinMartinez Mercedes,
GonzalezMuñiz Rosario,
Giraldez Teresa,
Alvarez de la Rosa Diego
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.974.12
Subject(s) - transactivation , mineralocorticoid receptor , aldosterone , mutant , receptor , phosphorylation , nuclear receptor , agonist , biology , mineralocorticoid , microbiology and biotechnology , wild type , glucocorticoid receptor , binding site , chemistry , biophysics , endocrinology , medicine , transcription factor , gene , biochemistry
The mineralocorticoid receptor (MR), a member of the nuclear receptor family, transduces the biological effects of the corticosteroid hormone aldosterone. Aldosterone interaction with MR ligand binding domain (LBD) induces nuclear translocation, dimerization and gene transactivation. It has recently been demonstrated that phosphorylation of S843, a residue near LBD, inactivates human MR. In this work we examined the mechanisms involved in MR modulation by S843p using mouse MR phosphomimetic mutant S839D (equivalent to S843 in human). MR‐S839D is inactive and significantly decreases wild type MR activity when both forms are coexpressed, consistent with a dominant negative role of MR‐S839D in the dimer. Surprisingly, aldosterone is able to induce nuclear translocation of MR‐S839D, although at a slower rate than wild type receptors. Therefore aldosterone is still able to bind to MR‐S839D but it is inefficient for gene transactivation. In silico modeling of MR LBD with S839D mutation or S839p show the same effect, namely a small decrease in steady‐state agonist docking energy. Our results suggest that the effect of S839p cannot be fully explained by decreased aldosterone binding affinity and may imply a defect in transactivation coupling.