Lecture notes control of cellular processes
and cell differentiation
Cell signalling
Different types of signalling exist. These four types
of signalling are shown in the image on the left.
Signal specificity depends on the ligand/receptor
combination or on synaptic contacts (the
connection between cells gives specificity).
Endocrine signalling is very specific.
The principles of signal transduction are based on
four intermediate steps:
1. A signal
2. Reception (after which amplification could
occur)
3. Transduction
4. Response
An extracellular signal molecule can alter protein
function and protein synthesis. Altering protein synthesis is a slow (minutes to hours) process,
altering protein function is fast (seconds to minutes). For cell signalling, the place of the receptor
should also be considered. Namely, receptors could be inside a cell, intracellular receptors, or outside
the cell, cell-surface receptors. Steroid hormones can easily pass through the membrane
(hydrophobic), thus, the characteristics of a signal should be considered to obtain a certain signal
goal.
The same signal can also have different effects depending on the cell type. An example is
acetylcholine, which causes a decreased heart rate and decreased force of contraction in heart
muscle cells, an increased contraction in skeletal muscle cells, and an increased secretion in salivary
gland cells.
Cells can also react abruptly or gradually to signals. Also, the signal concentration influences the
activity of a cell: concentration differences could cause different response of the same molecule.
Molecular instruments of signalling
Because of the logarithmic relationship, hydrogen bonds can
massively change the equilibrium. Addition of 2 hydrogen bonds
changes the equilibrium 25800 fold.
An allosteric enzyme can be in two states, active and inactive.
In the active state, the enzyme binds its substrate at its binding
site and carries out its reaction. In the inactive state, the
enzyme is unable to bind its substrate. This is due to binding of a modulator molecule elsewhere that
alters the shape of the binding site, making it inactive.
Allosteric inhibitors act as 'modulators' in enzyme execution as they can attach themselves to an
enzyme that will alter the binding site for the enzyme.
,An allosteric protein has underwent a fundamental structural change after reacting in the presence of
another molecule. This will alter its ability to react with that particular type of molecule in the future.
Allosteric transition is the transitional stage of a changing of structure in a protein.
Posttranslational modification of proteins can affect the cellular location, the interactions with other
proteins, degradation, and activity. Posttranslational modification is often reversible, making a
transition between two states possible. Modifications include phosphorylation, acetylation and
ubiquitination, but more modifications exist.
Ubiquitin is a special posttranslational modification, as ubiquitin is a protein itself. The entire protein
gets attached to another protein. After one ubiquitin has been added, more ubiquitin can bind. If four
or more ubiquitin proteins are bound, a protein is tagged for degradation.
Phosphorylation is the most common covalent
modification: about 30% of cellular proteins are
phosphorylated. Serine, threonine or tyrosine all
have an OH-group, which is the acceptor for
phosphate (coming from ATP). The transfer of a
phosphate group is catalysed by protein kinases.
Protein phosphatase can remove a phosphate
group. Addition of phosphate will lead to the
occurrence of more negative charges and more
oxygen atoms in the molecule. More oxygen atoms
can lead to more hydrogen bonds. Thus,
phosphorylation can change equilibria in a drastic
way. As phosphorylation is an enzymatic reaction,
the possibility of amplification exists.
Components of signalling
Different types of extracellular receptors:
Enzyme-coupled receptors G-protein-coupled receptors
The inside of these receptors is often the same: it The G-receptor consists of a seven transmembrane
includes a tyrosine-kinase domain. The outside of helix. In animals and humans, these receptors are the
the receptor differs (for specificity). most abundant. For example smell, vision, and taste
Two catalytic domains need to dimerize to become are perceived by these receptors.
active. The activated kinase domains will start to The ligand causes receptor activation -> activated G-
phosphorylate each other. This is because protein -> activated adenylate cyclase -> increased
dimerization arms are strongly bound together cAMP -> activated effectors.
(which are normally free), causing phosphorylation.
Ion-channel-coupled receptors
, Receptors often consist of different domains (see
image), which can be stacked upon each other. Each
domain has a different function.
Domains can be binding domains, which glue together
other domains. Domains can also have an enzymatic
part which are used to activate effectors. Domain
binding is the first step after a receptor becomes
activated.
The SH2 domain is an example: this domain only binds
to target peptides with a phosphorylated tyrosine.
PI 3-kinase: has as a function to add another phosphate group to a molecule to create a binding site
in the membrane. These kinases can help to form a binding site for proteins that could otherwise not
bind to the membrane.
G-proteins: contain an alpha- beta-, and gamma-domain. The alpha-
domain can take up GTP and release GDP after conversion. The P-loop
in the alpha-domain can bind GTP and convert this to GDP. The
domain can only bind GTP when the receptor has become active due
to ligand binding. Ligand binding causes a conformation of the alpha-
domain to release GDP and to take up GTP. Due to GTP uptake, the
inhibitory domains (beta and gamma) can no longer interact with the
alpha-domain.
Types of intracellular signalling proteins:
• An activated domain could cause a whole cascade of activated
kinases. One activated receptor can lead to 10000 reactions. The
enzymes don’t specifically have to be kinases, but they often are. The
scaffold proteins bind all the kinases in the same pathway together. This
is done so that if one kinase becomes activated, all the others in the
same pathway become activated as well.
• Ras proteins can spread signals to different downstream pathways.
Ras families are monomeric GTPases, active when bound with GTP.
• Rho family: GTPases that connect receptors to the cytoskeleton.
All three signalling proteins
have essentially the same
goal, but the intermediate
steps differ.
Second messenger
molecules: molecules that
transmit signals from
receptors on the cell surface to intracellular target molecules (also intracellular signalling molecules).
Common types are cAMP, cGMP, calcium ions, DAG, and IP3.
• cAMP: an enzymatic product made by adenylate cyclase. Adenylate cyclase can interact with
the activated alpha-domain from a G-protein. This causes the enzymatic formation of cAMP.
