Enzyme-Coupled Receptors, Molecular Mechanisms Of Flashcards
List the 6 classes of ECRs
Receptor tyrosine kinases
Tyrosine kinase-associated receptors
Receptor serine/threonine kinases
Histidine-kinase-associated receptors (bacteria)
Receptor guanylyl cyclases
Receptor-like tyrosine phosphates (very small group)
What do kinases lead to?
Phosphorylation events
What do phosphatases do?
Dephosphorylation
Enzyme which removes a phosphate group
What do receptor tyrosine kinases (class 1) do?
They phosphorylate tyrosine residues on a specific set of substrates
What are receptor tyrosine kinases (class 1) usually activated by?
Secreted growth factors and hormones
e. g. insulin (carbohydrate utilisation and protein synthesis)
e. g. epidermal growth factor (causes proliferation = cell division)
How many sub-classes of receptor tyrosine kinase (class 1) are there and how are they assigned?
There are 7 sub-classes of receptor tyrosine kinase They are assigned a sub-class based on their primary structure
How are signals transduced across the plasma membrane (RTKs)?
Structure of ECRs = a single α helix spanning the membrane so binding of a ligand does not cause a conformational change
Dimerisation or oligomerisation of the receptor sub-units occurs instead (= several receptors = several α helices = complex)
This causes a conformational change
Leads to signal transduction
Therefore oligomerisation of receptors causes reorientation of the internal α helices = initiates signalling = autophosphorylation events
Define: Oligomerisation
The formation of an oligomer from a monomer
Define: Oligomer
Molecule consisting of 2-100 repeating units
Define: Dimerisation
A compound formed of 2 identical simpler molecules (a kind of oligomer)
Can be due to growth factor
What does the reorientation of the α helices cause in receptor tyrosine kinases?
Causes the intracellular domain to have kinase activity = a kinase
How does autophosphorylation cause biological effects?
Growth factor binds and cause dimerisation of the 2 receptors = complex of 2 receptors and a growth factor
Reorientation of α helices occurs
Intracellular tyrosine kinase domains are activated - can now convert ATP to ADP and phosphorylate particular tyrosine residues (=autophosphorylation)
So receptor is now acting as a enzyme
Autophosphorylation causes an increase in its intrinsic activity (becomes even more active)
The phospho-tyrosine residues then act as sites for docking of signalling proteins (attracted by phosphorylation)
Formation of signalling complexes occurs
This will activate downstream events
How are signals generated by epidermal growth factor (EGF)?
PHOSPHORYLATION CASCADE:
Tyrosine kinase is the active form of the receptor
This will bind some intracellular proteins (e.g. GRB2, SOS) and forms a signalling complex
Activates another protein, RAS = a kinase (tethered to the membrane in its inactive GDP form)
GRB2 and SOS positively regulate RAS so exchange of GDP to GTP occurs
RAS will phosphorylate Raf1 –> Raf1 phosphorylates MEK –> MEK phosphorylates ERK
Therefore activation by 1 EGF activates multiple RAS’s and exponential activation from then on
—–
Conformational change of ERK = allows opening of a nuclear localisation 6 sequence
This causes translocation of the ERK into the nucleus
= Promotes gene transcription and cellular proliferation by phosphorylating c-Fos (transcription factor)
Describe the structure of an insulin receptor
Is a tyrosine kinase receptor
Exists as a tetramers (4 monomers) linked by disulphide bridges
Cross-membrane receptor
How does signalling through the insulin receptor occur?
Ligand (insulin) binds
IRS-1 & PI3K (a kinase) also bind - attracted by phosphotyrosine residues of the receptor
PIP2 (in the membrane) acted on by PI3K (kinase) = phosphorylation = PIP3
PIP3 acts on PKD1 (protein kinase)
PKD1 acts on Akt (kinase) –> Akt acts on GSK3 (kinase)
GSK3 phosphorylates glycogen synthase
This results in promotion of glycogen synthesis
What is the role of Akt?
2 roles:
1. Promotes glycogen synthesis by acting on GSK3
2. Phosphorylates glucose transporters inside of cell, causes them to translocate to the cell surface = more transporters on the cell surface bringing in the glucose to make glycogen
Therefore: brings in more glucose and makes more glycogen