Nuclear Receptors Flashcards
NRs in humans
48 NRs organised into 7 subfamilies:
- regulate body clock, immunity, inflammation, reproduction, ion/osmotic balance
What are Nuclear Recptors
Transcription Factors (TFs) that bind DNA - recruit CoActivators (CoA) or CoRepressors (CoR) to promote/block transcription machinery
NR activation
Ligand can cross membrane to bind the intracellular NR receptor which then translocate into the nucleus to alter gene expression
- provides rapid response (faster than normal signalling cascade)
Subfamilies 1-3
1) biggest subfamily, responsible for clock regulation, xenobiotic metabolism and homeostasis
2) Responsible for metabolism and energy homeostasis, development and cell fate (least studied)
3) Steroid receptors (bind steroid hormones) and nuclear hormone receptors (widely studied)
- responsible for cell fate, development, immunity, metabolism, reproduction
NR modular structure
N-terminal Domain (NTD)
- highly variable, sensitive to modification
DNA Binding Domain (DBD)
- Induces changes in conformation upon DNA binding
Hinge region
- flexible linker between DBD & LBD (transmit signal)
Ligand Binding Domain (LBD)
- C-terminal binding site for ligand
Ligand binding activating NRs
Each NR has a unique ligand binding domain (LBD) to ensure specificity of activation
Subfamily 1 ligands: hormones, vitamins, lipids, metabolites
Subfamily 3 ligands: cholesterol derivative-based ligands
Orphan NRs
NRs with unknown ligand
Cytoplasmic vs Nuclear NRs
Determined by 2 signals:
1) Nuclear Export Signal (NES)
- Presenting NES, hide NLS in globular DBD domain
- Held in cytoplasm (upon ligand binding, conformation change presents NLS, hiding NES)
2) Nuclear Localisation Signal (NLS)
- Always presents NLS, always in nucleus (ligand must diffuse into nucelus)
Direct/Indirect binding of NR to DNA
Direct:
- binding to DNA response elements
- DBD binds to specific DNA response elements (specific sequence and length)
- Shorter sequence = less specific; longer sequence = less frequent and more specific
Indirect:
- Tethering to other transcription factors using any domain
- specificity from protein-protein interaction
NRs changing gene expression
Recruit coregulators:
- CoActivators recruit transcriptional machinery
- CoRepressor block transcriptional machinery
Glucocorticoid Receptor - NR3C1
Can bind DNA as a homodimer or monomer (bind other TFs as a monomer)
- Activates anti-inflammatory genes; inhibits pro-inflammatory
Part of body clock and stress response
- expressed in all cells (in cytoplasm until ligand)
- 100% ligand-dependent activation, regulated by HPA axis (cortisol released in stress and every morning)
Estrogen Receptor A - NR3A1
Can bind DNA as a homodimer or heterodimer (bind other TFs as a monomer)
- Activates survival & cell cycle progression; inhibits apoptotic genes
Important in development, cell growth and differentiation, it needs strict control to avoid cancer
- expression restricted to bone, liver, ovary, uterus and breast
- 100% ligand dependent activation
- In cytoplasm when inactive
Retinoid X Receptor - NR2B1
Only functions as a heterodimer (formed by binding to subfamily 1 receptor)
- always nuclear, binds a repressor when inactive
- Upon activation, repressor switches to activator for lipid transport and metabolism genes
Very high regulation: ligand availability = control point
- RXR metabolises its own ligand (retanoic acid) when active (negative feedback)
Reverba - NR1D1
Only binds DNA as a monomer (no CoA, just one CoR)
- NCoR only inhibits target genes (body clock, metabolism, inflammation)
- important in maintaining rhythmic expression of target genes all over body
- Doesn’t require ligand and always in nucleus (always active) but it inhibits its own expression
- Only expressed ~4hrs a day
