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Receptor Tyrosine kinase
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Receptor tyrosine kinaseSignal transduction across a membrane.
Receptor tyrosine kinases (RTKs) are an example of cell surface receptors that
receive an extracellular signal and transduce that signal across the cell membrane to
initiate signalling events within the receiving cell.
Structure of insulin.
Insulin is a peptide hormone.
It consists of two peptide chains, the A chain and the b chain.
These two chains are linked together by two disulphide bonds.
There is also an additional disulphide bond within the A chain itself.
Different insulin molecules taken from different species share highly conserved
features.
The features are the positions of these disulphide bonds, the N-terminal and C
terminal of the A chain and the C terminal region of the B chain.
These structural features mean that the 3-dimensional structure of insulin is very
similar in different animals.
Insulin used to be taken from pig pancreas for diabetic patients this is because the
insulin molecules are so structurally similar that pig insulin will bind to the human
insulin receptor and activate the same signal transduction pathway.
Receptor tyrosine kinase (RTKs)
Receptor for insulin is part of this family of receptors, the receptor tyrosine kinases
(RTKs).
If we look at different members of this family, we can see regions where they look
very similar and there are regions of the receptor where they look very different.
A number of receptors from this family are receptors for growth factors and several
growth factors, including insulin-like growth factors, do signal through RTKs.
Most members of this family exist as a single receptor molecule, with the exception
of the insulin receptor and the IGF-1 receptor, which both sit as dimers, within the
plasma membrane.
Typical RTK structure.
If we compare different RTKs within this family, we can see that they share a similar
overall domain structure.
They all contain an extracellular domain, and this is the region of the receptor family
that is most different between each family member, and this is because each
receptor will carry different characteristic motifs and these motifs are required for
ligand binding.
You need different motifs to bind different ligands.
They all have a transmembrane domain, which allows them to span the cell
membrane.
They all have an intracellular domain; this is the region that is most conserved
between members of the family.
In this region sits the catalytic activity of the receptor through its kinase domain.
Insulin receptor
, There is a single receptor for insulin which is expressed from a single insulin receptor
gene.
Transcription of this gene produces two mRNAs by alternative splicing, IR-A and IR-B.
The translated proteins produced from those two transcripts are then proteolytically
cleaved into alpha and beta chains.
IR-A can be cleaved into alpha and beta chains and IR-B can be cleaved into alpha
and beta chains.
Different combinations of these alpha and beta chains then come together to form a
mature receptor.
Depending on this conformation, they will form either homodimers or hetero
dimers.
Insulin receptor dimers.
In homodimeric receptors both the alpha chains and both the beta chains come from
the same IR-A or IR-B polypeptide.
In heterodimeric receptors the alpha and beta chains will have been supplied by
both IR-A and IR-B polypeptides.
Insulin receptor dimers.
These receptor dimers are then held together by disulphide bonds.
Two alpha chains, the alpha chains form the extracellular region of the receptor.
Two beta chains form the transmembrane domain and intracellular kinase domain.
Two disulphide bonds between the two alpha chains and then a disulphide bond
links each beta chain with each alpha chain.
Insulin receptor: ligand binding.
Insulin receptor has one important difference compared to other RTKs.
It already exists as a dimer in the unbound state.
But for other RTKs ligand binding induces receptor dimerisations, similar to the
growth hormone receptor.
Only one insulin molecule binds to each receptor dimer with high affinity and insulin
binding shows negative cooperativity.
Binding of the first ligand actually decreases the rate of subsequent binding by
additional ligand molecules.
Each receptor dimer extracellular domain contains 4 ligand binding sites. Two on
each monomer. Site 1 is made up of an L1 region. The second insulin binding site is
site 2 which consists of loops at the junctions of this FM32 and FM33 domains.
The site one of one monomer will face site 2 within the other monomer.
This is where insulin will bind to the receptor, site 1 at one monomer and site 2 of
the other monomer. Essentially cross linking the two monomers.
Cross-linking is thought to be the driving force for the conformational change of the
receptor structure upon ligand binding. Essentially receptor changes shape which
will reduce subsequent binding of ligand to the insulin receptor.
Insulin receptor activation:
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