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Identification and characterization of a ligand‐selective mineralocorticoid receptor coactivator
Author(s) -
Rogerson Fraser M.,
Yao YiZhou,
Young Morag J.,
Fuller Peter J.
Publication year - 2014
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/fj.13-242479
Subject(s) - mineralocorticoid receptor , mineralocorticoid , identification (biology) , coactivator , ligand (biochemistry) , nuclear receptor coactivator 2 , chemistry , characterization (materials science) , receptor , medicine , biology , materials science , biochemistry , nanotechnology , transcription factor , ecology , gene
The mineralocorticoid receptor (MR) is unique in responding to 2 physiological ligands: aldosterone and cortisol. In epithelial tissues, aldosterone selectivity is determined by the activity of 11 β‐hydroxysteroid dehydrogenase type 2. In other tissues, cortisol is the primary ligand. To understand the structural determinants of ligand‐specific MR activation, we sought to identify coregulatory molecules that interact with the ligand‐binding domain (LBD) of the MR. A yeast‐2‐hybrid (Y2H) kidney cDNA library was screened with the human MR‐LBD in the presence of aldosterone and cortisol. One clone, identified as aldosteronespecific in the Y2H assay, exhibited a 7‐fold greater response, aldosterone vs. cortisol, in a mammalian‐2‐hybrid (M2H) assay. This clone encodes the region of the tesmin gene that has 2 leucine‐x‐x‐leucine‐leucine (LxxLL) motifs. Full‐length tesmin coactivates (>2‐fold) MR‐mediated transactivation in the presence of aldosterone, but not of cortisol; this specificity is observed with a range of promoters. GST pulldown and coimmunoprecipitation of the MR by tesmin supports a direct interaction, mediated by the 2 LxxLL motifs. Tesmin thus represents a novel MR coregulator that exhibits a differential interaction, providing further evidence of the adoption of ligand‐dependent conformations by the MR‐LBD.—Rogerson, F. M., Yao, Y.‐Z., Young, M. J., Fuller, P. J., Identification and characterization of a ligand‐selective mineralocorticoid receptor coactivator. FASEB J. 28, 4200‐4210 (2014). www.fasebj.org