BIOL 2020 Lecture 20: section 7 (mar.22)
26 Mar 2019
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BIOL2020: Section 7 (continued)
March 22, 2019
Receptor Kinases:
• in plasma membranes *shared with GPCR
• bind ligands and undergoes a conformational change *shared with GPCR
• Otherwise, receptor kinases are TOTALLY different than GPCRs
- When they bind a ligand, their OWN kinase activity is stimulated, and then they start a
phosphorylation cascade
- The pathway is often involved in growth (the cell divides almost always) – the ligand (1st
messenger) will often be a growth factor.
The receptor kinases work with a different mechanism.
when the receptor kinases bind the ligand, the receptor itself becomes an activated kinase
(unique to this class of receptors). Eventually, the receptor itself is the kinase that can go onto
phosphorylate other things and kick off the phosphorylation cascade.
• Tyrosine Kinases: *talked about exclusively in reference to receptor kinases
- Activated by phosphorylation on a tyrosine amino acid residue
• Serine/threonine kinases: *not talked about
- Activated by phosphorylation on a serine/threonine residue.
There are technically 2 types of receptor kinases.
Receptor Tyrosine Kinases:
• Binding site for ligand on the outside (ligand binding domain)
• A single transmembrane domain
• Tyrosine amino acid residues are on the cytoplasmic portion
at the top, we have a part that sticks out the extracellular membrane – a spot
where the ligand can bind. The ligand is usually a growth factor. The end result fo
the pathway: the cell divides and starts going through mitosis.
It has a single transmembrane domain – 1 alpha helix that passes through the
membrane, in contrast to the GPCRs - have 7 of the transmembrane domains.
There is also a long tail that extends into the cytoplasm. On the tail. We have a
whole bunch of tyrosine residues. Finally, in the cytoplasm, there is also a kinase
domain. Kinase by definition is anything that can put a phosphate on another
protein.
• Once the ligands bind, the receptors will cluster
- Autophosphorylation: [activates the receptor kinase]
o Each receptor puts phosphates on its neighboring receptor
If a couple of these receptors bind a ligand (2 of them), the two receptors will cluster together
and physically move – there will be a conformational change. They form a dimer. One of the
receptors is going to phosphorylate the tyrosines on the other receptor. The other receptor
phosphorylates the other tyrosines’ on other one. Each receptor puts phosphates on its
neighboring receptor [autophosphorylation].
Only at this point, do we say that the entire receptor kinase is active.
It now has full kinase activity – the receptor itself can now phosphorylate other proteins in the
cell. the other proteins have to come to IT. (a phosphorylation hub). Other proteins travel to
where that receptor is, and the receptor will then phosphorylate it.
Proteins with SH2 domains (i.e. GRB2) bind to phosphorylated tyrosines:
• This is how receptor kinases work!
Recall: PH domain – attracted to and stick to phosphorylated inositol groups.
Another domain (SH2) – the proteins that have this structure within it, are called SH2 proteins.
These proteins will be attracted to and will attach to a phosphorylated tyrosine.
Active tyrosine. Any protein with a SH2 domain can stick to the receptor (interact with the
receptor). The receptor will then phosphorylate it and activate it.
There is only one example we need to know: GRB2.
**change the diagram to include the SH2**
Summary of Receptor Tyrosine Kinases:
1. A couple of the receptor kinases in the membrane are hanging out as monomers – waits
for a growth factor to bind.
2. Growth factor comes in (red ball), binds to a couple of these receptors. The receptors
change shape and they form a dimer (clustered).
3. Once they clustered, there is autophosphorylation – each receptor phosphorylates the
other.
4. Once fully phosphorylated, the receptor is active and works as a kinase – puts
phosphates on other proteins that come to it.
5. Proteins with the SH2 domains travel through the cells to the receptors. Once they
arrive, they interact with it and become phosphorylated – kicks off a phosphorylation
cascade to result in an amplification of the signal and second messenger activation.
Ras Pathway – a receptor kinase pathway:
• Ras is a small monomeric G protein (a single unit protein)
- Ras-GTP = “ON”
o When ras is on, it will lead to cell proliferation
- Ras-GDP = “OFF”
• Ras is anchored at the inner surface of the plasma membrane by lipid group
Ras is a protein – specifically, a G protein.
But it is one of the small monomeric G proteins – like Ran or ARF or Sar1.
It is a single subunit – not the same as the trimeric ones with the alpha, beta, and gamma.
It is a G-protein, however. It can bind a GTP and become active.
The GTP can then be hydrolyzed to GDP to become inactive.
We care a lot about ras. Many cancers labs study ras.
It is this pathway that ends with a cell starting to divide. In about 30% of all cancers, there is a
mutation in this particular pathway. Something is wrong with one of these proteins, and all of
the cell cycle control has gone askew.
Document Summary
Receptor kinases: bind ligands and undergoes a conformational change *shared with gpcr, otherwise, receptor kinases are totally different than gpcrs in plasma membranes *shared with gpcr. When they bind a ligand, their own kinase activity is stimulated, and then they start a phosphorylation cascade. The pathway is often involved in growth (the cell divides almost always) the ligand (1st messenger) will often be a growth factor. The receptor kinases work with a different mechanism. when the receptor kinases bind the ligand, the receptor itself becomes an activated kinase (unique to this class of receptors). Eventually, the receptor itself is the kinase that can go onto phosphorylate other things and kick off the phosphorylation cascade: tyrosine kinases: *talked about exclusively in reference to receptor kinases. Activated by phosphorylation on a tyrosine amino acid residue: serine/threonine kinases: *not talked about. Activated by phosphorylation on a serine/threonine residue. There are technically 2 types of receptor kinases.
