RECEPTORS

Receptor
In biochemistry , a receptor is a molecule usually found on
the surface of a cell, that receives chemical signals from
outside the cell.

When such external substances bind to a receptor, they direct
the cell to do something, such as divide, die, or allow specific
substances to enter or exit the cell.
Nature of a Receptor
Receptors are proteins embedded in
i. either the cell's plasma membrane (cell surface
receptors), in the cytoplasm or
ii. in the cell's nucleus (nuclear receptors),
to which specific signaling molecules may attach.

A molecule that binds to a receptor is called a ligand,
and can be a peptide (short protein) or another
small molecule such as a neurotransmitter hormone
pharmaceutical drug, or toxin.
An Immune Receptor
An immune receptor (or immunologic receptor) is a
receptor, usually on a cell membrane, which binds to
a substance (for example, a cytokine ) and causes a
response in the immune system.
Immune Receptors
Pattern recognition receptors (PRRs)
Killer activated and killer inhibitor receptors
Complement receptors
Fc receptors
B cell receptors
T cell receptors
Cytokine receptors

Cytokine
Secreted polypeptide or low molecular weight protein
involved in cell-to-cell signaling.

Acts in paracrine or autocrine fashion through specific
cellular receptors.

Can be produced by cells of any tissue and act on many
cells involved in immune and inflammatory response.
Cytokine Names
Lymfokines - produced by activated T lymphocytes direct the
immune system response by signaling between its cells

Interleukins - presumed targets are principally leukocytes.

Chemokines - specific class of cytokines. Mediates chemoattraction
(chemotaxis) between cells, stimulate leukocyte movement and
regulate the migration of leukocytes from the blood to tissues.

Monokines - derived primarily from mononuclear cells such as
macrophages.
Importance of Cytokines
Cytokines are important in growth and differentiation of cells.
They are signaling molecules that lead to long-term genetic
effects by activation of transcription factors
Cytokine receptors
Cytokine receptors are receptors hat bind cytokines

In recent years, the cytokine receptors have come to demand
the attention of more investigators than cytokines
themselves, partly because of their remarkable
characteristics, and partly because a deficiency of cytokine
receptors has now been directly linked to certain debilitating
immunodeficiency states.

In this regard, and also because the redundancy and
pleiotropy of cytokines are, in fact, a consequence of their
homologous receptors, many authorities are now of the
opinion that a classification of cytokine receptors would be
more clinically and experimentally useful.
Action of Cytokines
Cytosine receptors bind tightly to tyrosine kinases,
called as the JAK kinases, which are members of a
family of cytosolic protein.
JAK kinases directly phosphorylate and activate
transcription factors members of STAT (Signal
Transduction and Activation of Transcription) family.

Activation of cytokine receptors initiates the JAK/STAT
pathway.
Action / mechanism of Cytokine receptors
Cytokines bind to specific cell surface receptors chains, which lead to receptor
complex formation and the activation of one or more associated Jaks.

These phosphorylate the intracellular tyrosines of the receptor complex,
creating docking sites for Stats, which themselves become tyrosine-
phosphorylated forming homo- or heterodimeric complexes that translocate
to the nucleus. Here they bind to specific gene promoters to activate
transcription of a range of target genes.

Socs genes are activated by cytokine receptor signaling via the JakStat
pathway. The encoded proteins then act to negatively regulate cytokine
signaling in a negative feedback loop by three distinct mechanisms:
kinase inhibition (of Jaks),
Bindingsite competition (of Stats) and
degradation (of receptor complexes)
Signaling through cytokine receptor
Phosphorylation through kinases:
The addition of a phosphate molecule to a polar R-
group of Tyr can turn a hydrophobic portion of protein
into a polar and extreme hydrophilic portion of molecule.
Kinase is a type of enzyme that transfers phosphate group
(PO
4
) from high-energy donor molecules, such as ATP to
specific target molecules (substrates).
The opposite, an enzyme that removes phosphate groups
from targets, is known as a phosphatase.
Kinase enzymes that specifically phosphorylate tyrosine
amino acids are termed tyrosine kinases.
Signaling through cytokine receptor
The ligand-activated receptor (R) attracts a Janus (JAK) kinase (K). K
phosphorylates both itself and the receptor. A Signal Transducer and Activator of
Transkription (STAT) protein (S) binds to tyrosine-phosphorylated receptor-kinase
complex. After being phosphorylated by JAK, the STATs form active dimers that
translocate into the nucleus to regulate transkription.
Cytokines Influence the Development of Different Cell
Types

Cytokines form a small family of secreting signaling molecules
that contain about 160 amino acids that control different parts
of growth and differentiation of specific types of cells.


CYTOKINE RECEPTORS
Cytokine Receptor Structures

All cytokines have a similar tertiary structure that consists of four
long helices that are folded together in a specific orientation.

Cytokine receptors have the similar structures as well.

They have an extracellular domain that is made of two subdomains.

Each domain contains seven strands folded together.

An example of a cytokine binding to its receptor is the
interaction of erythropoietin molecule with two identical
erythropoietin receptor (EpoR) proteins.
Classification of cytokine receptors
is based on their three-dimensional structure.
(Such a classification, though seemingly cumbersome,
provides several unique perspectives for attractive
pharmacotherapeutic targets.)
Types Cytokine Receptors
Type I cytokine receptors
Type II cytokine receptors
Immunoglobulin (Ig) superfamily
Tumor necrosis factor receptor family
Chemokine receptors
Cytokine Receptor Structures

All cytokines have a similar tertiary structure that consists
of four long alfa helices that are folded together in a specific
orientation.

Cytokine receptors have the similar structures as well. They
have an extracellular domain that is made of two subdomains.

Each domain contains seven strands folded together. An
example of a cytokine binding to its receptor is the interaction
of erythropoietin molecule with two identical erythropoietin
receptor (EpoR) proteins.
Common g chain
The g chain (green), common to all, mediates
intracellular signaling.
Type I cytokine receptor or hematopoietin receptor
family :
IL 2, IL 3, IL 4, IL 5, IL 6, IL7, IL 9, IL 13, IL 15,
GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) and G-CSF
(Granulocyte-Colony Stimulation Factor)

Types of Cytokine Receptors
Types Cytokine Receptors
Type I cytokine receptors whose members have
certain conserved motifs in their extracellular amino-
acid domain. The IL-2 receptor belongs to this chain,
whose -chain (common to several other cytokines)
deficiency is directly responsible for the x-linked form
of Severe Combined Immunodeficiency (X-SCID).
Interleukins are cytokines that are essential for
proliferation and functioning of T cells and antibody-
producing B cells of the immune system.

Type I cytokine receptor
Transmembrane receptors
expressed on the surface of
cells.

These receptors are also
known under the name
hematopoetin receptors, and
share a Trp-Ser-X-Ser-Trp motif
(WSXWS) in the extracellular
portion adjacent to the cell
membrane.
Structure & function of Class1 Cytokine receptors
Types Cytokine Receptors

Type II cytokine receptors, whose members are
receptors mainly for interferons.
Interferons are another family of cytokines that are
produced and secreted by cells after virus infections
and act in nearby cells to induce enzymes that give
these cells more resistance to virus infection. Many
cytokines induce formation of important types of
blood cells.

Protein hormones with antiviral activity.

Secrete by cells in a response to variety of stimuli.

Type I and type II IFN and IFN-like cytokines.

Effects are mediated through cell receptors.

IFN activate cellular signalling pathway (gene induction or
repression).
Type II cytokine receptors Interferons (IFN)
Type I IFNs consist of seven classes:
IFN-a, IFN-b, IFN-e, IFN-w, IFN-d, IFN-k and IFN-t

Type I IFNs are major components of the innate immune system.
Protect against viral infection.
he expression of type I IFNs is induced by viral challenge.

Type II IFN consist of IFN-g only.

IFN-g (immune interferon) is produced by certain activated T-cells
and NK cells.
IFN-g is made in response to antigen (including viral antigens) or
mitogen stimulation of lymphocytes.


Type I IFNs
Produced by macrophages, neutrophils and other somatic cells in
response to infection by viruses or bacteria.
Inducer is double strand RNA provided by viral genom itself.
Receptors are expressed on most cell types.

IFN-g
IFN-g is produced in activated T
H
1 and NK cells, particularly in
response to IL-2 and IL-12.
Binding of IFN-g to its receptor increases the expression of class I
MHC on all somatic cells.
IFN-g may also activate macrophages, neutrophils and NK cells.

Initiation and regulation of
variety responses

antiviral

antiproliferative activity (ability
to arrest cell growth) treatment
for cancer

control of apoptosis

immunomodulatory (INF-g
predominantly modulates
immune response, main antiviral
cytokine).
Function of IFNs:
http://www.virtualsciencefair.org/2007/sank7b2/fig1b.jpg
IFN-g receptor
Expression of on the surface almost of all cell types.

High affinity receptors are located in the T- and
B-lymphocytes, NK-cells, monocytes, macrophages,
neutrophiles, fibroblasts, endotelial cells and smooth
muscle cells.

Receptor is expressed only in response to stimulus by
antigen, only in cells of lymphoid origin (NK cells,
macrophages, and some T cells).
I FN- gR2 - 62 kDa glycoprotein (315 amino acid
residues)
Extracellular domain 226 amino acid residues
Transmembrane domain 23 amino acid residues
Intracellular domain 65 amino acid residues.

Ligand binds to extracellular domain of IFN-gR1 only
(in absence of IFN-gR1, IFN-gR2 cannot bind IFN g)
I FN-gR1 - 90 kDa glycoprotein (472 amino acid
residues)
Extracellular domain 228 amino acid residues
Transmembrane domain 24 amino acid residues
Intracellular domain 220 amino acid residues
IFN-g receptor has two components:
gR1 and gR2
IFN a/b receptor
IFN-aR1 - 530 amino acid residues
(409 residues of protein are extracellular,
100 residues are intracellular.

IFN-aR2 - 217 AA residues in
extracellular space, 251 AA residues in
intracellular space.

Both components bind type-IFNs
cooperatively.
Receptor has ability to bind multiple
ligands (all subspecies of IFN-a and IFN-
b and other types of IFN-type I).
Interferon ligand is boud to IFN-aR1
and than to IFN-aR2 which stabilizes the
complex.

Induces inflammatory reaction.

Induces antibacterial effect (activation of neutrophils, NK
cells and macrophages, increased their ability to recognize, kill,
and digest foreign materials or microbes).

Normal expression of is important in preventing the
development of cancer.
Effect of signalling through IFN-g receptor
Effect of signalling through IFN-a/b receptor
Antiviral defence (protects the cell from viral replication).
Types Cytokine Receptors
Immunoglobulin (Ig) superfamily, which are ubiquitously present
throughout several cells and tissues of the vertebrate body

Immunoglobulin superfamily (IgSF)
The immunoglobulin superfamily (IgSF)
- a large group of cell surface and soluble
proteins that are involved in the recognition,
binding, or adhesion processes of cells.

Molecules are categorized as members of
this superfamily based on shared structural
features with immunoglobulins (antibodies);
they all possess a domain known as an
immunoglobulin domain or fold.

Associated with roles in the immune
system.
Types Cytokine Receptors

Tumor necrosis factor receptor family, whose members share a
cysteine-rich common extracellular binding domain, and includes
several other non-cytokine ligands like receptors, CD40, CD27 and
CD30, besides the ligands on which the family is named (TNF).

Tumor Necrosis Factor receptor
http://en.wikipedia.org/wiki/Chemokine_receptor
Cysteine-rich common extracellular
binding domain
Types Cytokine Receptors

Chemokine receptors, two of which acting as binding proteins for HIV
(CXCR4 and CCR5).
They are G protein coupled receptors. TGF beta receptors
Typical structure of a chemokine receptor, with
seven transmembrane domains. Chemokine
receptors are usually linked to a G-protein
through which they signal. Interaction with their
specific chemokine ligand, chemokine receptors
trigger a flux in intracellular calcium (Ca2+) ions
(calcium signaling) and cause cell response
(chemotaxis).
http://en.wikipedia.org/wiki/Chemokine_receptor
Chemokine receptor
Mechanism of Cytokines
Cytosine receptors bind tightly to tyrosine kinases, the JAK
kinases, which are members of a family of cytosolic protein.

JAK kinases directly phosphorylate and activate transcription
factors members of STAT (Signal Transduction and
Activation of Transcription) family.
Activation of cytokine receptors initiates the JAK/STAT
pathway.
Jak proteins are brought into close after
ligand-receptor complex formation.

Transphosphorylation between Jak1 and
Jak2 proteins (Jak2 phosphorylates Jak1,
Jak1 transphosphorylates Jak2).

phosphorylation of IFN-gR1 (Tyr 440).
Binding of STAT1 protein to each IFN-
gR1.
Bound STAT1 is phosphorylated by Jak.
Dissociation of dimer from the receptor
and formed dimer translocates to the
nucleus.
Induction of transcription of many genes.
Signal transduction is carried out through a series of tyrosine
phosphorylation events and culminates with the activation and
nuclear translocation of STAT protein and new mRNA synthesis is
induced.
Tyk2 associates with IFN-aR1
Jak1, STAT1 and STAT2 associate with
IFN-aR2.

Jak1 transphosphorylates Tyk2 (1). Tyk2
in turn phosphorylates Jak1 and IFN-aR1
(2).

Phosphorylation of IFN-aR1 allows
STAT2 to bind to IFN-aR2.

STAT2 phoshorylates STAT1.

STAT1-STAT2 complex dissociates from
receptor.

Dimer STAT1-STAT2 associates with
interferon regulatory factor to form the
transcription complex.
Signal transduction goes through Jak/STAT pathway.
Involves two different ligand binding proteins (kinases)
Tyk2 and Jak1.
www.nature.com/.../v2/n8/fig_tab/nrc866_F3.html


After ligand binding, (PDGFR or EGFR receptor
tyrosine kinases (RTKs) dimerize, undergo
autophosphorylation (P) and recruit adaptor
proteins (such as GRB2 and SHC) that activate
various downstream effectors.

RAS is an important downstream effector and
functions as a molecular switch by cycling
between the active GTP-bound form and the
inactive GDP-bound form. RAS activity is
regulated positively by guanosine exchange
factors (GEFs), such as SOS, and negatively by
GTPase-activating proteins (GAPs).

At least three downstream effectors can be
activated by RAS. The RAF-mediated signalling
cascade.
Transforming Growth Factor Receptor
Cytokines: main functions
Hematopoiesis (ex. CSFs, colony stimulating factors).
Inflammatory reaction (ex. IL1, TNF).
Chemotaxis (ex. IL8, MIP1- macrophage inflammatory protein 1, BLC
B-lymphocyte chemoatractant).
Immunostimulation (ex. IL12, IFNg).
Suppression (ex. IL10).
Angiogenesis (ex. VEGFs - vacsular endothelial growth factor).
Embryogenesis (ex. TGF-b, LT - lymphotoxin).

Receptor Bind to Function
Pattern recognition
receptors (PRRs)
(e.g. TLRs, NLRs)
Pathogen-associated
molecular patterns
(PAMP)
Mediate cytokine production -->
inflammation --> destroying pathogen
Killer activated and
killer inhibitor
receptors (KARs and
KIRs)
Avails NK cells to identify abnormal host
cells (KAR) or inhibit inappropriate host
cell destruction (KIR)
Complement
receptors
Complement proteins
on e.g. microbes
Allow phagocytic and B cells to
recognize microbes and immune
complexes
Fc receptors
Epitope-antibody
complexes
Stimulate phagocytosis
B cell receptors Epitopes
B cell differentiation into plasma cells
and proliferation
T cell receptors
Linear epitopes bound
to MHC
Activate T cells
Cytokine receptors Cytokines
Regulation and co-ordination of immune
responses
The End
\