The DNA Binding Domain of Estrogen Receptor α Is Required for High-Affinity Nuclear Interaction Induced by Estradiol†

Biochemistry ◽  
2007 ◽  
Vol 46 (31) ◽  
pp. 8933-8942 ◽  
Author(s):  
Amy L. Weinberg ◽  
Damien Carter ◽  
Minna Ahonen ◽  
Elaine T. Alarid ◽  
Fern E. Murdoch ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Dna Binding ◽  
Nuclear Interaction ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
High Affinity

scholarly journals Phosphorylation of Human Estrogen Receptor α by Protein Kinase A Regulates Dimerization

1999 ◽  
Vol 19 (2) ◽  
pp. 1002-1015 ◽  
Author(s):  
Dongsheng Chen ◽  
Paul E. Pace ◽  
R. Charles Coombes ◽  
Simak Ali
Keyword(s):  
Estrogen Receptor ◽  
Protein Kinase ◽  
Dna Binding ◽  
Ligand Binding ◽  
Protein Kinase A ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Ici 182,780 ◽  
Kinase A

ABSTRACT Phosphorylation provides an important mechanism by which transcription factor activity is regulated. Estrogen receptor α (ERα) is phosphorylated on multiple sites, and stimulation of a number of growth factor receptors and/or protein kinases leads to ligand-independent and/or synergistic increase in transcriptional activation by ERα in the presence of estrogen. Here we show that ERα is phosphorylated by protein kinase A (PKA) on serine-236 within the DNA binding domain. Mutation of serine-236 to glutamic acid prevents DNA binding by inhibiting dimerization by ERα, whereas mutation to alanine has little effect on DNA binding or dimerization. Furthermore, PKA overexpression or activation of endogenous PKA inhibits dimerization in the absence of ligand. This inhibition is overcome by the addition of 17β-estradiol or the partial agonist 4-hydroxy tamoxifen. Interestingly, treatment with the complete antagonist ICI 182,780 does not overcome the inhibitory effect of PKA activation. Our results indicate that in the absence of ligand ERα forms dimers through interaction between DNA binding domains and that dimerization mediated by the ligand binding domain only occurs upon ligand binding but that the complete antagonist ICI 182,780 prevents dimerization through the ligand-binding domain. Heterodimer formation between ERα and ERβ is similarly affected by PKA phosphorylation of serine 236 of ERα. However, 4-hydroxytamoxifen is unable to overcome inhibition of dimerization by PKA. Thus, phosphorylation of ERα in the DNA binding domain provides a mechanism by which dimerization and thereby DNA binding by the estrogen receptor is regulated.

scholarly journals The Role of the C-terminal Extension (CTE) of the Estrogen Receptor α and β DNA Binding Domain in DNA Binding and Interaction with HMGB

2004 ◽  
Vol 279 (15) ◽  
pp. 14763-14771 ◽  
Author(s):  
Vida Senkus Melvin ◽  
Chuck Harrell ◽  
James S. Adelman ◽  
W. Lee Kraus ◽  
Mair Churchill ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Dna Binding ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Dna Binding Domain

scholarly journals Modulation of Runx2 Activity by Estrogen Receptor-α: Implications for Osteoporosis and Breast Cancer

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 5984-5995 ◽  
Author(s):  
Omar Khalid ◽  
Sanjeev K. Baniwal ◽  
Daniel J. Purcell ◽  
Nathalie Leclerc ◽  
Yankel Gabet ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Dna Binding ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Binding Domain ◽  
Breast Epithelial Cell ◽  
Dependent Manner ◽  
Dna Binding Domain

The transcription factors Runx2 and estrogen receptor-α (ERα) are involved in numerous normal and disease processes, including postmenopausal osteoporosis and breast cancer. Using indirect immunofluorescence microscopy and pull-down techniques, we found them to colocalize and form complexes in a ligand-dependent manner. Estradiol-bound ERα strongly interacted with Runx2 directly through its DNA-binding domain and only indirectly through its N-terminal and ligand-binding domains. Runx2’s amino acids 417–514, encompassing activation domain 3 and the nuclear matrix targeting sequence, were sufficient for interaction with ERα’s DNA-binding domain. As a consequence of the interaction, Runx2’s transcriptional activation activity was strongly repressed, as shown by reporter assays in COS7 cells, breast cancer cells, and late-stage MC3T3-E1 osteoblast cultures. Metaanalysis of gene expression in 779 breast cancer biopsies indicated negative correlation between the expression of ERα and Runx2 target genes. Selective ER modulators (SERM) induced ERα-Runx2 interactions but led to various functional outcomes. The regulation of Runx2 by ERα may play key roles in osteoblast and breast epithelial cell growth and differentiation; hence, modulation of Runx2 by native and synthetic ERα ligands offers new avenues in selective ER modulator evaluation and development.

scholarly journals Structure of the XPA DNA binding domain and RPA high-affinity DNA binding domains on a model NER substrate

2019 ◽  
Vol 75 (a1) ◽  
pp. a203-a203
Author(s):  
Walter J. Chazin ◽  
Agnieszka M. Topolska-Woś ◽  
Norie Sugitani ◽  
John J. Cordoba ◽  
Hyun Suk Kim ◽  
...  
Keyword(s):  
Dna Binding ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Dna Binding Domains ◽  
High Affinity ◽  
Binding Domains
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