Identification and characterization of a ligand-selective mineralocorticoid receptor coactivator

Fraser M Rogerson, Yi Zhou Yao, Morag Young, Peter J. Fuller

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21 Citations (Scopus)

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 11β-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 liganddependent conformations by the MR-LBD.

Original languageEnglish
Pages (from-to)4200-4210
Number of pages11
JournalThe FASEB Journal
Volume28
Issue number10
DOIs
Publication statusPublished - 1 Oct 2014
Externally publishedYes

Keywords

  • Aldosterone
  • Cortisol
  • Nuclear receptors

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