Lecture 11 - nuclear receptors Flashcards
What are nuclear receptors?
ligand-dependent TFs involved in reproduction, development & tissue homeostasis
ligands are small & hydrophobic - enter cells by diffusion
~50 family members in humans, e.g. steroid receptors & retinoic acid receptor
C-terminal ligand-binding domain (LBD) mediates dimerization & txn actn
bind DNA as homo- or heterodimers
Receptors, but not found at the cell surface, found inside the cells
Ligands are small and hydrophobic, can penetrate cells – include sex hormones progesterone, oestrogen, testosterone – target progesterone, oestrogen and androgen receptors
Another example is cortisol – activates glucocorticoid receptor
All examples of steroid ligands – as well as steroid receptor there are other members of nuclear receptor family such as retinoic acid receptor
Share common structure – DNA binding domain linked by hinge region to ligand binding domain at C-terminal region of the protein
N-terminal domain more variable both in sequence and in size
All function through dimerization – as homodimers or obligate heterodimers
Describe Nuclear Receptor DNA-Binding Domains
compact globular DNA-binding domains (DBD) built around two zinc ions, both coordinated to four Cys residues – a type of zinc finger
an a-helix fits in major groove of DNA & reads 6 bp of sequence
two adjacent 6bp DNA half-sites make a hormone response element, each read by one DBD after dimerization
Explain how LBDs Recruit Co-activators or Co-repressors
When bound by appropriate ligand, the LBD recruits coactivators which allow transcriptional activation of target genes
Antagonists have also been developed for a number of nuclear receptors – when these are bound, the LBD assumes a different conformation to when the agonist is bound
Helix 12 orientated differently in presence of antagonist
As a consequence of this alternative conformation the LBD recruits corepressors such as cofactor N-CoR, which in turn recruits histone deacetylases in order to silence txn
So nuclear receptors can be active repressors of transcription or active stimulators on the same genes depending on the nature of the ligand that they are exposed to
