Identification and characterization of a ligand‐selective mineralocorticoid receptor coactivator
| Autor: | Yi-Zhou Yao, Fraser M. Rogerson, Morag J. Young, Peter J. Fuller |
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| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
Hydrocortisone Nuclear Receptor Coactivators Clone (cell biology) Biology Biochemistry Substrate Specificity Transactivation chemistry.chemical_compound Mineralocorticoid receptor Two-Hybrid System Techniques Internal medicine Chlorocebus aethiops Coactivator Genetics medicine Animals Humans Promoter Regions Genetic Aldosterone Molecular Biology Binding Sites cDNA library Promoter Cell biology Receptors Mineralocorticoid Endocrinology Nuclear receptor chemistry COS Cells Metallothionein hormones hormone substitutes and hormone antagonists Protein Binding Biotechnology |
| Zdroj: | The FASEB Journal. 28:4200-4210 |
| ISSN: | 1530-6860 0892-6638 |
| DOI: | 10.1096/fj.13-242479 |
| Popis: | 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 aldosterone-specific 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. |
| Databáze: | OpenAIRE |
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