Estrogen receptor

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The Estrogen receptor (ER) is a specific member of the NR3 receptor family. The Estrogen (hormone) will bind to these receptor. This hormone is expressed in females during embryo development and puberty[1]. The ER structure is designed so that the genomic mechanism can take place. The Estrogen receptors can be either ER-alpha or ER-Beta receptors[2].

The ER shares a common intracellular steroid hormone structure of four units that are functionally homologous[3]; the variable domain starts at the N-terminal. There is also the DNA binding domain, this controls which genes will be activated[4]. The hinge region[5] controls movement of the receptor to the nucleus. Lastly the hormone binding unit, which is a ligand-binding domain which has a c-terminal connecting homodimer or heterodimer pair molecule.

The genomic mechanism of ER:

ER’s specifically are located inside the nucleus of target cells. The Estrogen can diffuse through the plasma membrane as the hormone is a small hydrophobic signalling molecule. ER is type 1, so the receptor has an HSP (heat shock protein) associated with the inactive receptor. The steroids move into the cytoplasm and interact with the estrogen receptor, the HSP is dissociated. This causes a conformational change in the receptors that causes dissociation from chaperones and the ER forms a dimer[6]. The activated receptor-ligand complex is then translocated into the nucleus. This dimerization activates the ‘receptors transcriptional domain’. This dimer binds to many specific sites in the DNA estrogen response elements, which are strategically next to the genes that need to be activated. Then the DNA-bound receptor activates the DNA-reading machinery and starts the production of messenger RNA[7]. The dimeric estrogen receptor can also bind directly to the DNA sequences. These specific inverted palindromic DNA sequences interact with the ER. The ER can also interact with promotors directly through a protein-protein interaction along with other DNA-binding transcription factors[8]. All routes will lead to transcriptional activation of associated genes. The ER will also need the help of coactivators and components of the basal transcriptional machinery. The ER is acting as an activating transcription factor. The enzyme RNA polymerase can now bind to the promotor region on the DNA, which makes a new RNA molecule from the DNA template. A protein will be translated and will cause changes to the cell.

References

  1. PDB 101. 1. Rcsborg.Molecule of the month- estrogen.2003. [Cited 21/11/17]. Available from: http://pdb101.rcsb.org/motm/45
  2. Norman AW, Mizwicki MT, Norman DP (Jan 2004). "Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model". N ature Reviews. Drug Discovery. 3 (1): 27–41
  3. Worldwide protein bank. Macromolecule-steroids[Online]. [Cited 21/11/17] Available from: https://www.wwpdb.org/
  4. Norman AW, Mizwicki MT, Norman DP (Jan 2004). "Steroid-hormone rapid actions, membrane receptors and a conformational ensemble model". Nature Reviews. Drug Discovery.2013.3 (27-41)
  5. Schwabe JW, Chapman L, Finch JT, Rhodes D (Nov 1993). "The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements". Cell. 75 (3): 567–78.
  6. Raegan O, Martin CF, Elinor K.K, Ulla H.Molecular endocrinology. Issue 8, London, Endocrine Society, 1st August 2014.
  7. PDB 101. 1. Rcsborg.Molecule of the month- estrogen.2003. [Cited 21/11/17]. Available from: http://pdb101.rcsb.org/motm/45
  8. Khan Academy. (2017). Khan Academy. Site 21 Nov. 2017].Available at: https://www.khanacademy.org/science/biology/gene-regulation/gene-regulation-in-eukaryotes/a/eukaryotic-transcription-factors
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