Identification and characterization of a ligand‐selective mineralocorticoid receptor coactivator. Issue 10 (6th June 2014)

• Record Type: Journal Article
• Authors: Rogerson, Fraser M.; Yao, Yi‐Zhou; Young, Morag J.; Fuller, Peter J.
• Is Part Of: FASEB journal. Volume 28:Issue 10(2014)
• Page Start: 4200
• Page End: 4210
• Publication Date: 2014-06-06
• Subjects: aldosterone -- cortisol -- nuclear receptors; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.13-242479
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract : 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