Estrogen Receptor alpha

Domain

Composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ligand-binding domain. The modulating domain, also known as A/B or AF-1 domain has a ligand-independent transactivation function. The C-terminus contains a ligand-dependent transactivation domain, also known as E/F or AF-2 domain which overlaps with the ligand binding domain. AF-1 and AF-2 activate transcription independently and synergistically and act in a promoter- and cell-specific manner. AF-1 seems to provide the major transactivation function in differentiated cells.

Function

Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3 (PubMed:17922032).

Isoform 3

Involved in activation of NOS3 and endothelial nitric oxide production (PubMed:21937726). Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full-length receptor (PubMed:10970861). Binds to ERE and inhibits isoform 1 (PubMed:10970861).

Involvement in disease

Estrogen resistance

ESTRR

A disorder characterized by partial or complete resistance to estrogens, in the presence of elevated estrogen serum levels. Clinical features include absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, reduced bone mineral density, osteoporosis, continued growth into adulthood and very tall adult stature. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

Phosphorylated by cyclin A/CDK2 and CK1. Phosphorylation probably enhances transcriptional activity. Self-association induces phosphorylation. Dephosphorylation at Ser-118 by PPP5C inhibits its transactivation activity. Phosphorylated by LMTK3 in vitro.

Glycosylated; contains N-acetylglucosamine, probably O-linked.

Ubiquitinated; regulated by LATS1 via DCAF1 it leads to ESR1 proteasomal degradation (PubMed:21602804, PubMed:28068668). Deubiquitinated by OTUB1 (PubMed:19383985).

Dimethylated by PRMT1 at Arg-260. The methylation may favor cytoplasmic localization (PubMed:18657504, PubMed:24498420). Demethylated by JMJD6 at Arg-260 (PubMed:24498420).

Palmitoylated (isoform 3). Not biotinylated (isoform 3).

Palmitoylated by ZDHHC7 and ZDHHC21. Palmitoylation is required for plasma membrane targeting and for rapid intracellular signaling via ERK and AKT kinases and cAMP generation, but not for signaling mediated by the nuclear hormone receptor.

Sequence similarities

Belongs to the nuclear hormone receptor family. NR3 subfamily.

Tissue specificity

Widely expressed (PubMed:10970861). Not expressed in the pituitary gland (PubMed:10970861).

Isoform 3

Widely expressed, however not expressed in the pituitary gland.

Cellular localization

• Isoform 1
• Nucleus
• Cytoplasm
• Cell membrane
• Peripheral membrane protein
• Cytoplasmic side
• A minor fraction is associated with the inner membrane.
• Isoform 3
• Nucleus
• Cytoplasm
• Cell membrane
• Peripheral membrane protein
• Cytoplasmic side
• Cell membrane
• Single-pass type I membrane protein
• Associated with the inner membrane via palmitoylation (Probable). At least a subset exists as a transmembrane protein with a N-terminal extracellular domain.
• Nucleus
• Golgi apparatus
• Cell membrane
• Colocalizes with ZDHHC7 and ZDHHC21 in the Golgi apparatus where most probably palmitoylation occurs. Associated with the plasma membrane when palmitoylated.

Alternative names

• Estrogen receptor
• ER
• ER-alpha
• Estradiol receptor
• Nuclear receptor subfamily 3 group A member 1
• NR3A1
• ESR1
• ESR

Database links

• entrezGene:2099
• entrezGene:2100
• omim:133430
• omim:601663
• swissprot:P03372
• swissprot:Q92731

Target type

Proteins

Primary research area

Oncology

Molecular weight

66216Da