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Details on Person Mineralocorticoid receptor (NR3C2 or MR) is a member of the ...
| Class:Id | Summation:9028595 |
|---|---|
| _displayName | Mineralocorticoid receptor (NR3C2 or MR) is a member of the ... |
| _timestamp | 2020-03-10 17:21:57 |
| created | [InstanceEdit:9028579] Shamovsky, Veronica, 2017-11-09 |
| literatureReference | [LiteratureReference:9036358] Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited [LiteratureReference:9036355] A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor [LiteratureReference:9035414] Structural determinants of ligand binding to the mineralocorticoid receptor [LiteratureReference:9035420] Mechanisms of ligand specificity of the mineralocorticoid receptor [LiteratureReference:9036336] Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity [LiteratureReference:9036351] Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue specific protector of the mineralocorticoid receptor [LiteratureReference:9036349] Mineralocorticoid receptors: distribution and activation [LiteratureReference:9036360] Aldosterone regulation of gene transcription leading to control of ion transport [LiteratureReference:9036594] Crystal structure of a mutant mineralocorticoid receptor responsible for hypertension [LiteratureReference:8948322] Structural and biochemical mechanisms for the specificity of hormone binding and coactivator assembly by mineralocorticoid receptor [LiteratureReference:9036390] Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor [LiteratureReference:9036599] Mineralocorticoid receptor binding, structure and function [LiteratureReference:9676864] The severe form of hypertension caused by the activating S810L mutation in the mineralocorticoid receptor is cortisone related [LiteratureReference:9036367] The multifaceted mineralocorticoid receptor [LiteratureReference:9676880] Immunohistochemical localization of the 11 beta-hydroxysteroid dehydrogenase type II enzyme in human kidney and placenta [LiteratureReference:9676856] Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme [LiteratureReference:9676883] The role of 11β-hydroxysteroid dehydrogenase type 2 in human hypertension [LiteratureReference:9028614] Agonistic and antagonistic properties of progesterone metabolites at the human mineralocorticoid receptor [LiteratureReference:9676858] A critical region in the mineralocorticoid receptor for aldosterone binding and activation by cortisol: evidence for a common mechanism governing ligand binding specificity in steroid hormone receptors [LiteratureReference:9677280] Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency [LiteratureReference:9677245] Evolution of hormone selectivity in glucocorticoid and mineralocorticoid receptors [LiteratureReference:9035405] Mechanistic aspects of mineralocorticoid receptor activation [LiteratureReference:8944783] Differential recruitment of tetratricorpeptide repeat domain immunophilins to the mineralocorticoid receptor influences both heat-shock protein 90-dependent retrotransport and hormone-dependent transcriptional activity [LiteratureReference:9028620] Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors [LiteratureReference:8948280] Molecular chaperones, essential partners of steroid hormone receptors for activity and mobility [LiteratureReference:9677718] Interdomain interactions in the mineralocorticoid receptor [LiteratureReference:9677716] Structural and functional characterization of the interdomain interaction in the mineralocorticoid receptor |
| modified | [InstanceEdit:9036332] Shamovsky, Veronica, 2018-02-01 [InstanceEdit:9036601] Shamovsky, Veronica, 2018-02-05 [InstanceEdit:9676872] Shamovsky, Veronica, 2020-02-22 [InstanceEdit:9677289] Shamovsky, Veronica, 2020-03-02 [InstanceEdit:9677721] Shamovsky, Veronica, 2020-03-10 |
| text | Mineralocorticoid receptor (NR3C2 or MR) is a member of the steroid-thyroid hormone receptor superfamily of ligand-dependent transcription factors. NR3C2 is found in both the sodium-transporting epithelia (e.g. kidney, colon) and nonepithelial tissues (e.g. heart, brain) (Horisberger JD and Rossier BC, 1992; Funder JW 2005). In the absence of ligand, NR3C2 is bound to the heat shock protein 90 kDa (HSP90) chaperone complex which maintains it in a ligand-binding competent state (Echeverria PC & Picard D 2010; Huyet J et al, 2012). NR3C2 binds several corticosteroids with high affinity in vitro (deoxycorticosterone = corticosterone >/= aldosterone = cortisol) (Krozowski ZS & Funder JW 1983; Funder JW 2005; Baker ME et al. 2013). Within the body, the mineralocorticoid aldosterone, secreted by the zona glomerulosa, is considered the primary physiological ligand of NR3C2 (Arriza JL et al. 1987; Bledsoe RK et al. 2005). However, other steroid hormones, including cortisol and progesterone, may function as tissue-specific endogenous agonists or antagonists of NR3C2 (Arriza JL et al. 1987; Quinkler M et al. 2002; Ferrari P 2010). In epithelial cells of the kidney and colon, both aldosterone and cortisol can act as NR3C2 agonists. In these cells, despite much higher cortisol circulating levels, aldosterone is the primary ligand where its selectivity is determined by the activity of 11beta-hydroxysteroid dehydrogenase type 2 (11βHSD2 or HSD11B2) that converts 11β-hydroxyl group (11β-OH) of cortisol to an inactive keto-form, yielding cortisone (Funder JW et al. 1988; Edwards CR et al. 1988; Albiston AL et al. 1994; Krozowski Z et al. 1995). Cortisone binds NR3C2 with very low affinity (Rafestin-Oblin ME et al. 2003). Aldosterone differs from cortisol by the presence of an aldehyde group in position 18 on the D ring. Cyclisation of the 11β-OH with the 18-aldehyde group renders aldosterone with the hemiketal conformation resistant to the dehydrogenase activity of HSD11B2 (11βHSD2) (Ferrari P 2010). Mutations in the HSD11B2 gene cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME) (Yau M et al. 2017). In AME patients, defective HSD11B2 (11βHSD2) enzyme activity results in activation of NR3C2 by cortisol, causing sodium retention, hypokalaemia, and salt-dependent hypertension (Ferrari P 2010). In other tissues, including the heart and regions of the central nervous system, that do not express HSD11B2, cortisol is the primary ligand for NR3C2; in some tissues cortisol may act as an antagonist (Funder JW et al. 1988; Fuller PJ et al. 2012). Further, In addition to the metabolic regulation of cortisol by HSD11B2, which protects NR3C2 against cortisol-overload, the intrinsic properties of the NR3C2 structure influence the outcome to ligand binding at the receptor (Hellal-Levy C et al. 1999; Baker ME et al. 2013; Rossier BC et al. 2015). NR3C2 consists of three principal domains: an N-terminal activation function-1 domain (AF-1), a middle DNA binding domain (DBD) and a C-terminal ligand binding domain (LBD) (Arriza JL et al. 1987). The functional activity of both the AF-1 domain and the DBD are controlled by hormone binding to the LBD (Rogerson FM et al. 2004). The NR3C2 LBD contains an activation function-2 domain (AF-2) that is also regulated by hormone binding. Transactivation and [3H]-aldosterone binding assays using the chimeras created between LBD of NR3C2 and LBD of the glucocorticoid receptor (NR3C1 or GR) and expressed in monkey kidney fibroblasts (COS-1) cells revealed that amino acids 820–844 of the NR3C2 LBD are critical for the binding of aldosterone to the NR3C2 (Rogerson FM et al. 2007). This same region was critical for cortisol-induced NR3C2 transactivation in COS-1 cells (Rogerson FM et al. 2007). Structural studies showed that the NR3C2 LBD in a complex with an agonist ligand is composed of 11 helices (H1, H3-H12) and two short beta sheets that are organized in a three-helical sandwich fold, which is common to all nuclear receptors (Fagart J et al. 2005; Li Y et al. 2005; Bledsoe RK et al. 2005). The maximum NR3C2 activation occurs only when there is simultaneous stabilization of the loop preceding the AF-2 helix and a strong interaction of the steroid ligand with helix 10 (H10) (Bledsoe RK et al. 2005). Stabilization of the loop preceding the AF-2 requires hydrogen bonds between Asn770 and Ser767 on H3 and Glu955 present on H11-H12 loop thus forming the ligand-binding pocket of NR3C2. (Hellal-Levy C et al. 2000; Bledsoe RK et al. 2005). Asn770 of NR3C2 makes a hydrogen bond with the C21-hydroxyl group (21-OH) and the 18-hemiketal group of steroids, and the Thr945 γ methyl group on H10 of NR3C2 forms a van der Waals contact with the 21-OH (Hellal-Levy C et al. 2000; Bledsoe RK et al. 2005). Ligands of NR3C2 such as aldosterone that promote this hydrogen bond network and interact with H10 induce a stabilization of helix 3 and a movement of the AF-2, enabling coactivator recruitment and ultimately gene transcription (Bledsoe RK et al. 2005). Kinetic dissociation experiments have demonstrated that the ability of a ligand to activate NR3C2 is linked to the slowness of its dissociation (Hellal-Levy C et al. 1999; Huyet J et al. 2012). Aldosterone remained bound to NR3C2 for a comparatively longer period than cortisol, which stabilized the NR3C2 in a conformation that can more effectively recruit coregulators, resulting in aldosterone having greater potency than cortisol for inducing NR3C2 target gene transcription (Hellal-Levy C et al. 2000, Gallo LI et al. 2007, Huyet J et al. 2012). Another important step toward mineralocorticoid specificity is the interaction between the N- and C-terminal domains of NR3C2 that is stronger in the presence of aldosterone than cortisol or deoxycorticosterone (Rogerson FM & Fuller PJ 2003; Pippal JB et al. 2009). This series of ligand-specific activation steps ensures that ligands such as progesterone (which lacks 21-OH) and cortisone fail to activate NR3C2 even though these ligands will be in excess over aldosterone in many tissues (Bledsoe RK et al. 2005; Pippal JB et al. 2009). The Reactome event shows aldosterone binding to the mineralocorticoid receptor NR3C2. |
| (summation) | [Reaction:9028629] Mineralocorticoid binds NR3C2 within the HSP90 chaperone complex [Homo sapiens] |
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No pathways have been reviewed or authored by Mineralocorticoid receptor (NR3C2 or MR) is a member of the ... (9028595)
