Nuclear receptors Flashcards
describe steroid hormone NR in terms of ligand, dimerisation, receptor
location, and response element recognition
ligand: glucocorticoid, estrogen
dimerisation: homodimer
receptor location: cytoplasm (C) or nucleus
response element recognition: inverted repeat
describe RXR heterodimer in terms of ligand, dimerisation, receptor
location, and response element recognition
ligand: fatty acids, retinoic
acids, cholesterol
dimerisation: heterodimer
(RXR + Class II NR)
receptor location: Nucleus (C) or cytoplasm
response element recognition: Direct repeat
describe dimeric orphan NR in terms of ligand, dimerisation, receptor
location, and response element recognition
ligand: UNKWN
dimerisation: homo- or hetro-
receptor location: Nucleus
response element recognition: Direct repeat
describe monomeric orphan NR in terms of ligand, dimerisation, receptor
location, and response element recognition
ligand: UNKWN
dimerisation: monomer
receptor location: nucleus
response element recognition: binds to one extended response element
half-site
Nuclear receptors
- intracellularly located
- in the cytoplasm or nucleus
- ligand-activated transcription factors
- 4 classes
- interact with dna directly to affect transcription
describe the structure, characteristics, and functions of the A/B domain
- N terminal domain
- varies in length and amino acid sequence
- contains activation function 1 region: area binds co-regulators in a ligand-independent manner
- post-translational modifications
describe the structure, characteristics, and functions of the C domain
- DNA binding Domain (DBD)
- high-conserved
- responsible for DNA binding and recognition
- contains two zinc fingers
1st zinc finger: recognise specific hormone response elements
2nd zinc finger: role in receptor dimerisation
describe the structure, characteristics, and functions of the D domain
- Hinge region
- Links DBD (C) domain to the LBD
- Very flexible
- May contain a nuclear localisation signal (NLS) that is involved in receptor translocation
- NLS can overlap with DBD
describe the structure, characteristics, and functions of the E/F domain
- Ligand binding domain
- fairly conserved structure
- Hydrophobic pocket formed by 12 alpha-helices
- Helix 12 is important for co-activator/co-repressor switching
- Role in receptor dimerisation
- AF2 (Activation function 2): Binds to co-regulators in a ligand-dependent manner
- Can be post-translationally modified
Describe the use of fluorescent proteins as reporters of receptor localisation
Visualises the movement of nuclear receptors into the nucleus from the cytoplasm when stimulated
- confirms slow time scale of action (hours)
Describe the structure of the glucocorticoid receptor (GR),
- N-terminal domain
- DNA binding domain
- Hinge domain
- NLS1: overlaps with the end of DBD
- NLS2: overlaps with the beginning of the LBD - Ligand binding domain
Describe GR-mediated signaling
- Occurs in cytoplasm
1. GR form complexes with other chaperone proteins
2. When a ligand binds the GR dissociates from the protein complex
3. This exposes a nuclear localisation signal
4. The receptor then translocated into the nucleus
Describe direct GR-mediated regulation of gene transcription
Direct
- GR dimer bonds to GRE to increase gene transcription
- GR dimer binds to negative GRE to decrease gene transcription
Describe how GR-mediated regulation of gene transcription treats inflammatory diseases
Tethering
GR binds directly to AP-1 or NF-kB –> transrepression
Composite
GRE-Bound GR interacts with neighbouring DNA-bound AP-1 or NF-kB
Permissive vs Non-permissive RXR heterodimers
Non-Permissive
- heterodimer is activated by
ligands of the partner NR
while RXR is silenced
Permissive
- heterodimer is activated by
ligands of either NR, and
synergistic effects when both NRs are activated
