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Protein
Glycoprotein
Dr. Viliran
SIGNAL TRANSDUCTION/INTRODUCTION
It is a way of cell to cell communication
SIGNAL
TRASDUCTION
from the word transduce
it is the process of converting extracellular signal to
an intracellular response
process of converting one form to another -- one
form of energy to another form of energy
Example: Dr. Viliran communicating to us through
speaking and you as the students, how will you
accept the signal and how are you going to interpret
the signal? Through listening and answering
CELL SIGNALLING
How do cells receive and respond to signals from their
surroundings?
Prokaryotes(unicellular organism) and unicellular
eukaryotes are largely independent and
autonomous
Multicellular organisms need intercellular
integration and coordination of cell functions by
way of signaling molecules that are secreted or
expressed on the cell surface of one cell and bind to
receptors expressed by other cells.
If there are signaling molecules, there should be
something to accept the signal; and we call these
RECEPTORS expressed by other cells.
Inside the cell, we have here the signaling molecule interacting with the
receptor usually on the cell membrane. This is the first part of the signal
transduction pathways and then binding of the signaling molecule or the
first messenger with the receptor will cause conformational change that
will lead to activation of proteins functioning as Transcription Factors.
Eventually it will stimulate the gene for expression; either synthesis of
different transcription factors or synthesis of proteins that we gave the
cells response to the first messenger. Transcription factors also help in
expression of other genes.
You learned before the importance of the gene which is being expressed
to produce proteins. You produce chemical substances through gene
expression, and the secreting molecule will now communicate with
another cell through interaction with receptors. These cells will produce
a response now converting it into a intracellular response. When it
produces protein it will interact with another cell.
CELL TO CELL COMMUNICATION
Send Signals as Hormones (speak)
Type of Compound/Classification
Peptide, Protein
BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina
Membrane Receptors
They are located OUTSIDE of the cell
Extracellular recognition domain binds hormone
Intramembrane
Channel function
Intracellular
Coupling domain
kinase cascade
Steroid Receptors
Located INSIDE the cell
Recognition domain binds hormone
Coupling domain binds to
So you have here lipid soluble messenger; since its lipid soluble, the
receptor is directly in the DNA. It can pass through the cell membrane and
the nuclear membrane. And still, you have the response. Again, ligand
interacts with receptor. It could be a protein or glycoprotein.
Receptor a specific protein that specifically binds a
signaling molecule to initiate a response in a target cell
Cell responses :
changes in gene expression
BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina
cell morphology
cell movements
As you can what is being shown here is the specificity of the ligand with
the receptor. It cannot bind to cell B and C because the receptor is not
appropriate. It only binds to Cell A, with the appropriate specific
receptor. It demonstrates the ligand specificity to the receptor.
2.
3.
BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina
2.
3.
4.
(A) In the presence of the ligands such as Ach, there is change in the
conformation of the receptor from a closed position, it will then open up.
(B) G-protein linked receptor. GPCR. So this is your G-protein but upon
binding of the ligand, this activates the protein. Example: Glucagon. So
binding of this ligand glucagon to the receptor activates the G-protein.
Once the G-protein is activated, it activates now the enzyme and then the
active enzyme will have an effect on sugar.
(C) Enzyme-linked Receptor. Insulin and the Growth Factors. So without
the ligand, the catalytic domain or the enzyme is inactive. But upon
binding of the ligand for example, insulin, this activates the enzyme.
So you have here the gated ion channel. It opens up with the
ligand/signal binds to it. This is receptor enzyme activity. The
enzyme is activated with the binding of the signal or the ligand.
Serpentine Receptor or G-protein coupled receptor. So binding
of the ligand activates the G-protein which then activates the
enzyme.
Receptor with no intrinsic enzyme activity.
Adhesion Receptor.
Steroid Receptor. It is direct. There are signals that can pass
the membrane and then it acts on the DNA.
Calcium
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BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina
2.
3.
PROTEIN KINASES
carry out the process of phosphorylation
opposed by the activity of protein phosphatases
ADAPTER PROTEINS
no catalytic activity
contain domains as docking sites for other protein
cAMP Pathway
Binding of ligand with G-protein coupled receptor
It then activates the G-protein into a coupled receptor
It then activates enzyme adenylate cyclase
Then there is production of cAMP
Calcium Pathway
Ligand-receptor interaction, GPCR because you have the Gprotein.
Activation of the enzyme causing the release of Calcium
Mainly it is phospholipase enzyme that is activated
Release of Calcium
Calcium interacts with protein
Calmodulin
BIGGER
b. Monomeric Ras and Ras-like proteins
So you have here, GPP, GPCR. Take note that the G-protein is not yet
bound with your receptor. It is still inactive but upon binding of the
ligand, when the G-protein will be activated, it will now interact with the
receptor. Upon binding of the receptor with the G-protein, it becomes
active, activating the enzyme.
G PROTEINS (guanine nucleotide-binding proteins)
G protein-coupled receptors are transmembrane
receptors. Signal molecules bind to a domain located
outside the cell
G proteins regulate metabolic enzymes, ion channels,
transporters, and other parts of the cell machinery,
controlling transcription, motility, contractility, and
secretion, which in turn regulate systemic functions such
as embryonic development, learning and memory, and
homeostasis
BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina
G-PROTEIN-COUPLED RECEPTOR/SERPENTINE
On the outside, you have here the domain or the signal interacting with
the ligand.
CELLS RESPONSE
So you have here the subunit and the subunit and subunit. Which
subunit has the binding site for GDP and the GTP?
Its the subunit
This is where GTP binds when it is OFF and GDP when it is ON.
The receptor, the G-protein and ligand. Activation then activates the
enzyme and the enzyme will cause these effects.
BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina
this causes the subunit to dissociate from the GS complex. The subunit
will dissociate then it will bind and activate the enzyme adenylate cyclase.
When the enzyme is active, cAMP is produced. And then it will go back to
the original position, GTP is placed because the receptor has GTPase
enzymatic activity. GTPase acts on GTP, converting it back to GDP.
The glycerol with the fatty acid and the phosphate here and the inositol.
Phospholipase C acts on this part and you produce a diacylglycerol (DAG),
and you remove the phosphate and inositol group. So you have DAG and
the inositol phosphate.
Phosphorylate it further and it becomes inositol triphosphate. So these
are your second messengers. IP3 (Inositol Phosphate) and DAG
(diacylglycerol).
And you have the same receptor; G-protein coupled receptor
TRIMERIC G. but instead of adenyl cyclase, you activate enzyme
phospholipase C.
So what is the effect of the second messenger?
DAG inactivate C kinase enzyme
Inositol phosphate causes the release of Calcium from ER
Ca is also considered a second messenger
BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina
So you have here the GEF and the GAP. GEF promotes the activation of
Ras. GAP is needed for inactivation of Ras.
ACTIVATION of RAS following BINDING of LIGAND to RTK
1. Binding of ligand causes dimerization and
autophosphorylation of tyrosine residues
2. Binding GRB2 and Sos couples receptor to inactive Ras
3. SOS promotes dissociation of GDP from Ras
4. GTP binds and SOS dissociates from active Ras
GRB2 = growth factor receptor binding protein 2
SOS = son of sevenless
MAP KINASES
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NF-kB
P50 p65 NF kappa beta, inhibitor kappa beta, stress, bacterial, viral
incfections, cytokines, phosphorylation of the inhibitor kappa beta.
So una, maactivate muna ang inhibitor kappa beta kinase. If the kinase is
activated, IPB will be phosphorylated. If it is phosphorylated, it will be
degraded; and the p50 & p65 will now translocate here causing gene
expression.
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Given that this is a signal, what is a possible signal for NF kappa beta?
BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina
GLUCOCORTICOIDS
For the treatment of inflammatory and immune diseases
Inhibition of NF-Kappa beta by glucocorticoids
/Mechanisms:
1. Glucocorticoids increase IB mRNA, which leads to
an increase IB protein and more efficient
sequestration of NF- B in the cytoplasm
3.
CAMP SYSTEM
Phsophodiesterase increases the level of cAMP.
If we will enter the cell, there are several reactions occurring.
If you have the cAMP activating the kinase, kinase enzyme
works on the different pathways not only gene expression.
Binding of ligand G protein activation enzyme activation
Activation of glycogen phosphorylase and inhibition of
glycogen synthase. So this is GLYCOGENESIS.
BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina
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Same.
What is the receptor? G-protein
What kind of G-protein? Trimeric G-protein
Binding of the ligand.
Once the G protein is activcated, it activates what enzyme?
Phospholipase C beta.
It acts on phosphotidyl inositol, producing diacylglycerol plus
inositol triphosphate.
What is the effect of Inositol Triphosphate? Release of
calcium from the endoplasmic reticulum
And what is the effect of calcium? Another second
messenger. This is your second messenger, it binds with
Calmodulin. And then once activated, calmodulin has other
effects.
How about diacylglycerol? It activates the protein C kinase
enzyme, phosphorylating also other proteins.
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