Intracellular
receptors
Reading: Lodish 4th ed.,
pp 392-395, 850-852 and see notes from BB310
Molecular Genetics
Lipid soluble hormones diffuse
across the plasma membrane and interact with cytosolic or nuclear receptors.
These receptor-hormone complexes bind to transcription-control regions
of DNA and affect expression of specific genes. They may also affect the
stability of specific mRNAs.
Intracellular receptors
for lipophilic hormones (steroids, retinoids) include:
-
steroid receptors
-
Glucocorticoid Receptor (cortisol)
-
Estrogen Receptor (estradiol)
-
Progesterone Receptor (progesterone)
-
Vitamin D receptor
-
retinoid receptors
-
Retinoic Acid A Receptor (retinoic
acid)
-
thyroid hormone receptor (thyroxine)
These receptors are members
of the Intracellular Receptor Superfamily - the largest family of transcription
factors. This superfamily is subdivided into two groups, according to cellular
location
-
cytosolic receptors
-
held in complexes with other
proteins, such as heat shock proteins
-
nuclear receptors
-
often associated with DNA
Cloning and sequencing several
receptor genes has allowed comparison of amino acid sequences and revealed
that there is a great deal of conservation of amino acid sequence along
with the different functional domains within these proteins.
Fig. 10-64, Lodish 4th ed.
All contain C4 zinc finger
structures that form the DNA binding domain, located near the centre of
the primary amino acid sequence
-
Regions that fold around Zn2+
ions, producing a compact domain from a relatively short length of the
polypeptide chain
-
Contain two groups of 4 critical
cysteines which bind the Zn2+ ions
Other domains include
-
N-terminal region
-
most variable domain between
different receptors
-
contains regions that function
as transcription-activation dominas
-
may interact with additional
factors, stimulating co-operative assembly of initiation complex
-
Variable hinge region
-
lies between the C4 containing
domain and ligand binding domain
-
thought to contain sequences
responsible for localisation of the receptor to the nucleus
-
C-terminal end
-
hormone binding domain/hormone-dependent
activation domaion
-
in the absence of ligand, the
hormone-binding domain can act as a transcriptional REPRESSOR
-
responsible for association
with heat shock proteins and for dimerisation
Receptor-hormone complexes
bind to transcription-control regions of DNA and affect expression of specific
genes
-
Dimerise to bind to DNA
-
Can either form homodimers
or heterodimers, depending on receptor type
Homodimers
-
Found in cytoplasm and nucleus
-
Monomers interact with each
other such that DNA binding domains are inverted
-
Bind to inverted repeat motifs
(short nucleic acid sequences, known as a Response
Element)
eg: GRE, ERE
Heterodimers
-
Found in nucleus only
-
Monomers interact with each
other such that DNA binding domains lie in the same orientation
-
Bind to direct repeat motifs
eg: VDRE ,TRE, RARE
Mechanisms of hormonal control
of nuclear receptor activity
-
Inactive or gene-silencing
conformation
-
unoccupied nuclear receptors
repress transcription by directing histone deacetylation at nearby nucleosomes
-
Ligand binding induces massive
conformational changes to receptor and activates transcription
-
Directs hyperacetylation of
histones, reversing transcription repressing effects
Cytoplasmic receptor activity
regulated by controlling transport from cytoplasm to nucleus
-
Unoccupied receptors are anchored
in the cytoplasm as a large protein aggregated complexed with inhibitor
proteins (Heat shock proteins HSP-90, HSP-70, HSP-56)
-
Ligand binding induces conformational
changes in the receptor which releases it from the cytoplasmic anchor
-
Receptor-ligand complex translocates
to nucleus
-
Binds to response element
-
Activates transcription of
target genes by similar mechanism to nuclear receptors
-
Facilitates co-operative assembly
of initiation complex
Fig. 10-67, Lodish 4th ed.