MODELLING THE HORMONE-BINDING DOMAIN OF STEROID RECEPTORS INCLUDING VITAMIN D3 RECEPTOR

Vitamin D ◽  
1991 ◽  
pp. 64-74 ◽  
Keyword(s):  
Vitamin D3 ◽  
Steroid Receptors ◽  
Binding Domain ◽  
D3 Receptor ◽  
Hormone Binding ◽  
Vitamin D3 Receptor ◽  
Hormone Binding Domain

Ligand modulates the conversion of DNA-bound vitamin D3 receptor (VDR) homodimers into VDR-retinoid X receptor heterodimers

1994 ◽  
Vol 14 (5) ◽  
pp. 3329-3338
Author(s):  
B Cheskis ◽  
L P Freedman
Keyword(s):  
Ligand Binding ◽  
Vitamin D3 ◽  
Hormone Receptors ◽  
Steroid Receptors ◽  
Dependent Manner ◽  
D3 Receptor ◽  
Vitamin D3 Receptor ◽  
Binding Domains

Protein dimerization facilitates cooperative, high-affinity interactions with DNA. Nuclear hormone receptors, for example, bind either as homodimers or as heterodimers with retinoid X receptors (RXR) to half-site repeats that are stabilized by protein-protein interactions mediated by residues within both the DNA- and ligand-binding domains. In vivo, ligand binding among the subfamily of steroid receptors unmasks the nuclear localization and DNA-binding domains from a complex with auxiliary factors such as the heat shock proteins. However, the role of ligand is less clear among nuclear receptors, since they are constitutively localized to the nucleus and are presumably associated with DNA in the absence of ligand. In this study, we have begun to explore the role of the ligand in vitamin D3 receptor (VDR) function by examining its effect on receptor homodimer and heterodimer formation. Our results demonstrate that VDR is a monomer in solution; VDR binding to a specific DNA element leads to the formation of a homodimeric complex through a monomeric intermediate. We find that 1,25-dihydroxyvitamin D3, the ligand for VDR, decreases the amount of the DNA-bound VDR homodimer complex. It does so by significantly decreasing the rate of conversion of DNA-bound monomer to homodimer and at the same time enhancing the dissociation of the dimeric complex. This effectively stabilizes the bound monomeric species, which in turn serves to favor the formation of a VDR-RXR heterodimer. The ligand for RXR, 9-cis retinoic acid, has the opposite effect of destabilizing the heterodimeric-DNA complex. These results may explain how a nuclear receptor can bind DNA constitutively but still act to regulate transcription in a fully hormone-dependent manner.

scholarly journals Ligand modulates the conversion of DNA-bound vitamin D3 receptor (VDR) homodimers into VDR-retinoid X receptor heterodimers.

1994 ◽  
Vol 14 (5) ◽  
pp. 3329-3338 ◽  
Author(s):  
B Cheskis ◽  
L P Freedman
Keyword(s):  
Ligand Binding ◽  
Vitamin D3 ◽  
Hormone Receptors ◽  
Steroid Receptors ◽  
Dependent Manner ◽  
D3 Receptor ◽  
Vitamin D3 Receptor ◽  
Binding Domains

Protein dimerization facilitates cooperative, high-affinity interactions with DNA. Nuclear hormone receptors, for example, bind either as homodimers or as heterodimers with retinoid X receptors (RXR) to half-site repeats that are stabilized by protein-protein interactions mediated by residues within both the DNA- and ligand-binding domains. In vivo, ligand binding among the subfamily of steroid receptors unmasks the nuclear localization and DNA-binding domains from a complex with auxiliary factors such as the heat shock proteins. However, the role of ligand is less clear among nuclear receptors, since they are constitutively localized to the nucleus and are presumably associated with DNA in the absence of ligand. In this study, we have begun to explore the role of the ligand in vitamin D3 receptor (VDR) function by examining its effect on receptor homodimer and heterodimer formation. Our results demonstrate that VDR is a monomer in solution; VDR binding to a specific DNA element leads to the formation of a homodimeric complex through a monomeric intermediate. We find that 1,25-dihydroxyvitamin D3, the ligand for VDR, decreases the amount of the DNA-bound VDR homodimer complex. It does so by significantly decreasing the rate of conversion of DNA-bound monomer to homodimer and at the same time enhancing the dissociation of the dimeric complex. This effectively stabilizes the bound monomeric species, which in turn serves to favor the formation of a VDR-RXR heterodimer. The ligand for RXR, 9-cis retinoic acid, has the opposite effect of destabilizing the heterodimeric-DNA complex. These results may explain how a nuclear receptor can bind DNA constitutively but still act to regulate transcription in a fully hormone-dependent manner.

scholarly journals Examination of the Potential Functional Role of Conserved Cysteine Residues in the Hormone Binding Domain of the Human 1,25-Dihydroxyvitamin D3 Receptor

1996 ◽  
Vol 271 (9) ◽  
pp. 5143-5149 ◽  
Author(s):  
Shigeo Nakajima ◽  
Jui-Cheng Hsieh ◽  
Peter W. Jurutka ◽  
Michael A. Galligan ◽  
Carol A. Haussler ◽  
...  
Keyword(s):  
Functional Role ◽  
Binding Domain ◽  
Cysteine Residues ◽  
D3 Receptor ◽  
Hormone Binding ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
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.

Impact of the Vitamin D3 receptor on growth-regulatory pathways in mammary gland and breast cancer

2002 ◽  
Vol 83 (1-5) ◽  
pp. 85-92 ◽  
Author(s):  
JoEllen Welsh ◽  
Jennifer A. Wietzke ◽  
Glendon M. Zinser ◽  
Sarah Smyczek ◽  
Saara Romu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Vitamin D3 ◽  
D3 Receptor ◽  
Regulatory Pathways ◽  
Vitamin D3 Receptor
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