Cysteines 638 and 665 in the hormone binding domain of human glucocorticoid receptor define the specificity to glucocorticoids

Biochemistry ◽  
1995 ◽  
Vol 34 (43) ◽  
pp. 14163-14173 ◽  
Author(s):  
Chunying Yu ◽  
Nalini Warriar ◽  
Manjapra V. Govindan
Keyword(s):  
Glucocorticoid Receptor ◽  
Binding Domain ◽  
Hormone Binding ◽  
Hormone Binding Domain

scholarly journals Two Point Mutations in the Hormone-Binding Domain of the Mouse Glucocorticoid Receptor That Dramatically Reduce Its Function

1991 ◽  
Vol 5 (6) ◽  
pp. 752-758 ◽  
Author(s):  
Sujatha Byravan ◽  
Jon Milhon ◽  
Sridhar K. Rabindran ◽  
Brett Olinger ◽  
Michael J. Garabedian ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Point Mutations ◽  
Binding Domain ◽  
Hormone Binding ◽  
Hormone Binding Domain

scholarly journals A Role for the Hsp40 Ydj1 in Repression of Basal Steroid Receptor Activity in Yeast

2000 ◽  
Vol 20 (9) ◽  
pp. 3027-3036 ◽  
Author(s):  
Jill L. Johnson ◽  
Elizabeth A. Craig
Keyword(s):  
Glucocorticoid Receptor ◽  
Steroid Receptors ◽  
Hormonal Control ◽  
Binding Domain ◽  
Receptor Activity ◽  
Hormone Binding ◽  
Mutant Strains ◽  
Elevated Activity ◽  
Carboxy Terminal ◽  
Hormone Binding Domain

ABSTRACT In addition to its roles in translocation of preproteins across membranes, Ydj1 facilitates the maturation of Hsp90 substrates, including mammalian steroid receptors, which activate transcription in yeast in a hormone-dependent manner. To better understand Ydj1's function, we have constructed and analyzed an array of Ydj1 mutants in vivo. Both the glucocorticoid receptor and the estrogen receptor exhibited elevated activity in the absence of hormone in allydj1 mutant strains, indicating a strict requirement for Ydj1 activity in hormonal control. Glucocorticoid receptor containing a mutation in the carboxy-terminal transcriptional activation domain, AF-2, retained elevated basal activity, while mutation of the amino-terminal transactivation domain, AF-1, eliminated the elevated basal activity observed in ydj1 mutant strains. This result indicates that the source of activity is AF-1, which is normally repressed by the carboxy-terminal hormone binding domain in the absence of hormone. Chimeric proteins containing the hormone binding domain of the estrogen or glucocorticoid receptor fused to heterologous activation and DNA binding domains also exhibited elevated activity in the absence of hormone. Thus, Ydj1 mutants appear to increase basal receptor activity by altering the ability of the hormone binding domain of the receptor to repress nearby activation domains. We propose that Ydj1 functions to present steroid receptors to the Hsp90 pathway for folding and hormonal control. In the presence of Ydj1 mutants that fail to bind substrate efficiently, some receptor escapes the Hsp90 pathway, resulting in constitutive activity.

scholarly journals Generalized glucocorticoid resistance caused by a novel two-nucleotide deletion in the hormone-binding domain of the glucocorticoid receptor gene NR3C1

2013 ◽  
Vol 168 (1) ◽  
pp. K9-K18 ◽  
Author(s):  
Kati M Donner ◽  
Timo P Hiltunen ◽  
Olli A Jänne ◽  
Timo Sane ◽  
Kimmo Kontula
Keyword(s):  
Glucocorticoid Receptor ◽  
Frameshift Mutation ◽  
Plasma Renin ◽  
Binding Domain ◽  
Glucocorticoid Resistance ◽  
Causative Mutation ◽  
Hormone Binding ◽  
Nucleotide Deletion ◽  
Glucocorticoid Receptor Gene ◽  
Hormone Binding Domain

ObjectiveGeneralized glucocorticoid resistance is characterized by impaired cortisol signaling, resulting from mutations of the glucocorticoid receptor (GR) geneNR3C1. The objective of our study was to identify the causative mutation in a patient with clinical manifestations compatible with generalized glucocorticoid resistance and to determine the functional consequences of the mutation. The possible occurrence ofNR3C1mutations in a selected group of hypertensive subjects with low plasma renin and aldosterone levels was also explored.PatientsThe proband, a male athlete, was diagnosed with hypertension associated with low plasma renin activity and low serum aldosterone concentration at the age of 27 years. Liddle's syndrome was suspected and the patient was treated with amiloride with initial success. Subsequent examinations revealed elevated serum cortisol and ACTH levels, with resistance to suppression with low doses of dexamethasone. After identification of anNR3C1mutation in the proband, the available family members and 51 nonrelated hypertensive subjects with low plasma renin and aldosterone concentrations were also studied.ResultsA two-nucleotide deletion in exon 9α, predicted to cause a frameshift mutation (p.L773VfsX25) in the hormone-binding domain of the GR, was identified in the patient in a heterozygous form. Affected brother and father died of premature coronary heart disease. Functional studies in COS-1 cells showed that this mutation eliminates both ligand-binding and transactivation ability of the receptor. No pathogenicNR3C1mutations were identified in 51 unrelated hypertensive patients with low plasma renin and aldosterone levels.ConclusionWe identified a novel frameshift mutation inNR3C1as the cause of glucocorticoid resistance. The mutation eliminates the functional activity of the GR, as studied byin vitroexperiments. Mutations inNR3C1do not seem to be common causes for hypertension with low renin and aldosterone levels.

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