Difference between

Steroid hormone receptors

and
cell membrane receptors.
LS 503 Unit 4

Index
Introduction
History
- Cell Membrane Receptors
- Nuclear Receptors (Steroid Hormone
Receptors).
Differences in:
- Ligands, that are binding.
- Localization.
- Structural differences.
Certain Examples of Both the Classes of Receptors.
Pathophysiology related to the malfunctioning of
Steroid and Cell membrane Receptors.

History

Differences

Ligands that are Binding Nuclear

Receptors

Ligands that are Binding Cell

Membrane Receptors

Bradykinin

Calcitonin

Hepatocyte Growth factor (HGF)

Acetylcoline

Localization
of
Steroid Hormone receptors

 Intracellular Distribution of SHR: Is the result of Nuclearcytoplasmic & ATP Dependent cytoplasmic shuttling.
Majority of AR PR and ER are in the nucleus due to the
presence of Nuclear Localization Signal (NLS).

Localization of Cell Membrane

Receptors

 These are the Membrane Receptors.

Expressed at between 1000-100,000
copies.

Structure of Nuclear Hormone

Receptors
(Steroid Hormone Receptors)

Steroid Hormone Receptor sub Classes

Receptors for Estrogens (ER)
Estrogen Related Receptors (ERR)
Receptors for Glucocorticoids (GR)
Receptors for Mineralocorticoids (MR)
Receptors for Progestins (PR)
Receptors for Androgens (AR)

Trivial and Nomencleature names of Steroid

Hormone Receptors SHRs,
according to the Nuclear Receptor
Nomenclature Committee (1999).

Overview of the SHR Structure

A variable N-terminus(domains A and B) that confers immunogenicity and
modulates transcription in a gene and cell specic manner through its Nterminal Activation Function 1 (AF1)
A central DNA binding domain (DBD), or C domain, comprised of two
functionally distinct zinc ngers through which the receptor physically
interacts directly with the DNA helix.
D is the exible hinge region and helps in DBD dimerization.
The ligand binding domain (LBD, domains E and in some receptors F i.e.
PR, GR, AR) that contains Activation Function 2 (AF2).

Transactivation Domain:
Transcriptional
competence of SHRs,
at AF-1 & AF-2;
mediating SHR and
Transcription apparatus
interactions via binding
of Afs and basal
Transcription factors.

SHR-Chromatin Interaction
The DBD interacts with specic
conserved sequences on target genes
which are called Hormone response
elements(HRE).
HRE consists of direct repeat (DR)
elements, palindromic (inverted)
repeats, or extended monomeric sites

In-depth analysis of DBD-Chromatin

Eight perfectly conserved cysteine residues coordinate two zinc

ions to maintain the overall core DBD fold, which encompasses a
total of 66 amino acid residues. Two a-helices that pack in a
perpendicular fashion are contained in this core unit, one of which
is responsible for DNA half-site recognition.

In-depth analysis of DBD-Chromatin

NMR and X-ray crystallographic studies shows that one helix inserts
directly into the major groove of the conserved hexamers present in the
HREs.
GR, PR, the androgen receptor (AR), and the mineralocorticoid receptor
use the same consensus 5-AGGACA-3 conserved half sites, whereas
ER and most non-steroid receptors use 5 -AGGTCA-3 half sites.

Half Site recognition and HRE Specicity

a-Helix recognition + Geometry of HREs, i.e in various
bipertite fashions
Half-site spacing is crucial for establishing response element
selectivity, as each additional spacer between the repeats
displaces the half sites by 3.4 A , and ~35 degrees

The Ligand Binding Domain

Characterized by a
hydrophobic cavity or pocket
in which lipophilic ligands are
captured and shielded from
the solvent environment.
The ligand pockets within
these LBDs are sufciently
unique in size and character,
with diverse amino acid
compositions that ensure
specicity for endogenous
ligands.
GR Ligand Binding Domain

Presence of Conformational Switch (Helix 12/H12)

Ligand Binding and
Stabilization of H12

Coactivator
Binding and
relay of SHR
Signal

Mouse Trap model and Dynamic Stabilization

Models for LBD
According to Mouse Trap Model, ligand binding induces H12
movement that traps the ligand inside the ligand pocket not
allowing its escape.
Not True Every time.
New model was evoked called Dynamic Stabilization Model.
- H12- molten State
- Ligand (when bound) Stabilizes the receptor folding
globally; decreasing the degree of conformational
dynamics overall including xing H12 in stable position
along with stabilizing other surface elements for
coactivator binding
Ligand
Activation

Relatively unstable LBD fold

More Rigid & Well

ordered Structure

Structure of Cell Membrane

Receptors

 Extracellular domains: Some of the residues exposed to the

outside of the cell interact with and bind the hormone; ligandbinding domain.
Transmembrane domains: Hydrophobic stretches of amino
acids present in the lipid bilayer and serve to anchor the
receptor in the membrane.
Cytoplasmic or intracellular domains: Tails or loops of the
receptor; within the cytoplasm, react to hormone binding by
interacting in some way with other molecules, leading to
generation of second messengers. Also termed as effector
region of the molecule.

Example of Steroid Hormone

Receptor
(Glucocorticoid Receptor)

 Glucocorticoids maintain
the metabolic and
Homeostatic functions.
GR is the product of a
single gene, NR3C1,
location: chromosome
5q3132 in humans, that
undergoes alternative
processing to yield
multiple functionally
distinct subtypes of GR..

 The GR share the same structural Features with SHR

family as discussed previously.
Being localized in cytoplasm along with chaperone
proteins (hsp90).
Ligand Binding and activation leads to Nuclear
localization, where they interact with GREs
(Glucocorticoid Response elements) on DNA and exert
their function.
Genes Upregulated

Genes Down regulated

leucine zipper (GILZ)

-arrestin 2

serum/glucocorticoid
regulated kinase 1 (SGK1)

osteocalcin

Tristetraproline (TTP)

GR gene, NR3C1

Mitogen-activated protein
kinase phosphatase-1
(MKP-1)

Example of Cell Membrane Receptor

G Protein Coupled Receptors

Pathophysiology related to SHR

Androgen Insensitivity Syndrome

(AIS)
Results from androgen receptor dysfunction and is a
common cause of the disorder of sex development.
Characterized by: Hormone Resistance leading to
female phenotype in an Individual with an XY karyotype &
testes producing age appropriate normal concentration
of androgens.
Pathogenesis due to Mutated X Linked Androgen
Receptor Gene where most of the mutations affect the
ligand binding domain of these receptors (Expressed).

Figure: Simplied pathway of fetal sex development

AR=androgen receptor. CAIS=complete androgen insensitivity syndrome.
AMH=antimullerian hormone

Pathophysiology Related to Cell

Membrane Receptors

Nuclear Translocation of Epidermal

Growth Factor Receptor (EGFR)
IS one of the four members of HER family of
receptor tyrosine kinases
EGFR family proteins are oncogenic proteins
involved in cancer Initiation, tumor growth/
progression, metastasis etc.
Over expression reported in many cancers.
They are involved in transcriptional regulation, cellproliferation, DNA Repair and chemo/radio
resistance.
The endosytosis and endosomal sorting mediates
their nuclear localization.

Three possibilities of
EGFR trafcking; internalized
in endosome:
1) Recycled Back to CM,
Recycling endosome/
Rapid Recycling.
2) Degraded by Lysosome.
3) Transported to Nucleus
(Novel Pathway).

EV= Endocytic Vesicle

EE= Early Endosome
LE= Late Endosome
RE= Recycling Endosome
NPC= Nuclear Pore Complex
ER= Endoplasmic Reticulum

References

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Courvalin, J. C., Mester, J., ... & De Catalogne, D. (1976). Steroid
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Faria, J. A., de Andrade, C., Goes, A. M., Rodrigues, M. A., &
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Hughes, I. A., Werner, R., Bunch, T., & Hiort, O. (2012, October).
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Klinge, C, Rao, C, Glob. libr. women's med(ISSN: 1756-2228) 2008; DOI

10.3843/GLOWM.10281

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Tata, J. R. (2002). Signalling through nuclear receptors. Nature Reviews

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