Nuclear Receptors Flashcards
Plasma membrane associated receptor
signal outside cell covered to signal inside cell without signaling molecule entering the cell
nuclear receptors vs GPCR and tyrosine kinase receptors
nuclear receptors 99% of their role is the regulate transcription; GPCR and tyrosine kinase receptors eventually will talk to genome but not main existence
nuclear receptors
directly affect transcription since they are essentially ligand regulated transcription factors (ligand has to get into cell, it is hydrophobic so it can passively cross membrane); directly interact with DNA
what do GPCRs affect
go through complicated pathway to affect transcription, also have global affect on cell
Regulation of gene transcription by enzyme-linked receptors
Direct or indirect activation of tyrosine kinase -> cascasde protein interactions -> changes gene transcription
How do nuclear receptors work
ligand passively crosses membrane, binds specifically to receptors in cytoplasm or nucleus to induce conformation change in receptor
steroid recepor family
Reside in cytoplasm; bind to DNA as homodimers so need 2 binding to DNA;
- adrenal cortical receptors (glucocorticoids, mineralocorticoids)
- sex hormone receptors (progestins, estrogens, androgens)
Family= NR3
RXR heterodimer receptor family
already associated with DNA; sometimes with corepressors; bind as heterodimers
- thyroid hormone receptor (T3)
- Vitamin D receptor
- Retinoic acid receptors
- Retinoid X receptors (RXR)
- Others including PPAR, LXR, FXR
ligand-receptor complex
bound to DNA can -> activation (via coactivator association) or -> inhibition (association with corepressors) of gene transcription
nuclear receptor famillies
numbered NR0-NR6
NR3- steroid receptor family
NR1 and NR2- rxr heterodimeric receptor family
NR0, NR4-NR6
Most are orphan receptors (no endogenous ligands identified)
Ligand structures sex hormones
very similar structure which is why it is important to have highly specific binding site
Receptor domains
- Regulatory domain
- DNA binding domain
- Hinge domain
- Ligand Binding domain
Regulatory domain
binds coregulators (coactivators or corepressors) and is responsible for most effects on gene transcription, may also contain phosphorylation sites for kinase mediated modulation
DNA-Binding domain
contains two zinc fingers; binds to specific response elements determining which genes will be influenced and also contributes to dimerization
hinge domain
involved in nuclear localization and dimer formation
ligand binding domain
determines binding specificity and can also bind coregulators
Estrogen and progesterone receptors
DNA and hinge receptors v similar variations in regulatory and ligand binding domain (most differences in regulatory bit some in ligand binding domain)
mechanism of steroid receptor action
homodimers; receptors found in cytoplasm not nucleus; usually associated with hsp; take final shape when ligand binds to receptor; when ligand binds releases hsps exposes nls so receptor bound to ligand -> nucleus -> binds to DNA and recognizes palindromic sequence in DNA -> binding transactivation factors communicating with transcription apparatus
Steroid receptors and dimers
bc hormone response elements are generally palindromic 2 monomers of receptor can bind to 1 surface of response element making extensive dimer interface; dimers face head to head so identical DNA binding domains contact different strands DNA in opposite directions
RXR dimers
heterodimersl not same; not looking for palindromic sequence; bound to DNA in absence of ligand attached to corepressors, hormones or ligand come in and activate receptor-> release corepressor and binding of coactivator; receptors generally reside in nucleus
- corepressor doesn’t require ligand**
- binding of ligand and activation of receptor induces release of corepressor and binidng of coactivator, can occur in absence of ligand for RXR
transactivation
effect of nuclear receptor on transcription; binding of ligand-bound dimeric receptor to response element will activate transcription at distant core promotor site
early response
secondary gene expressions
late response
initial gene expression
coactivators
mediate transactivation; these bind to ligand-receptor complex and preinitation complex to initiate activation of transcription (short distance mediation between activated receptor and initiation complex); huge amount of protein scaffolding and communication with activation complex
coactivators and chromatin structure
coactivators can have intrinsic histone acetyltransferanse (HAT) activity (loosens chromatin via histone acetylation on lysin residues on amino terminus of histone)
Transcriptional inhibitors
antagonists and corepressors
antagonists
ligand that binds to receptor preventing interaction of coactivators with the receptor or recruits binding of corepressors rather than coactivators -> active repression of transcription (via active antagonists)
how do corepressors work
may bind to free receptor or antagonist-receptor complex and preinitation complex to inhibit transcription; binding of this complex -> HDAC activity or enzyme recruitment -> tightening of chromatin
HAT transcription
activates it
HDAC transcription
suppresses it
other actions of nuclear receptors
- can have effects outside of effects on genome
- can effect enzyme activity with in cell
- can involve interactions with and effects on cytoplasmic proteins
Examples of nuclear receptors and effects on cytoplasmic proteins
- progesterone receptor interacts with cytoplasmic kinases -> activation in ligand dependent manner
- glucocorticoid receptor can directly interact with cellular signaling factors inhibiting them
- estrogen receptor can interact directly with PI3K to increase its activity
- Growing evidence for “membrane associated” steroid hormone receptors (variants of nuclear receptors or unrelated proteins)
hormones and drugs that are ligands for nuclear receptors
can directly regulate transcription of specific genes
regulation of gene expression by response elements
cell specific; dependent on receptor expression, avaliblity of coregulators, presence of TFs and phosphorylation state of many proteins involved
