期刊
FASEB JOURNAL
卷 28, 期 10, 页码 4200-4210出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.13-242479
关键词
aldosterone; cortisol; nuclear receptors
资金
- Australia National Health and Medical Research Council [1002559, 1002575]
- Endocrine Society through a bridge grant
- National Heart Foundation of Australia through a project grant
- Victorian Government's Operational Infrastructure Support Program
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 beta-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 aldosterone-specific in the Y2H assay, exhibited a 7-fold greater response, aldosterone vs. cortisol, in a mammalian-2hybrid (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.
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