Debbie Hay 4 Flashcards
What is the structure of the insulin receptor?
A dimer, with each monomer consisting of an extracellular alpha and membrane spanning beta unit connected via a disulphide bond
What is the structure of insulin?
A large two chain hormone with two inter chain and 1 intra chain disulphide bonds stabilizing the structure
How does the insulin receptor become active?
Insulin binds in a pocket formed by the two alpha units pulling these units closer together transmitting the fact that the signal has arrived to the beta units
and allowing the flexible activation loop of one beta domain to fit in the active site of the other beta domain
This allows cross phosphorylation of tyrosine residues resulting in a swinging across of the activation loop making the kinase a more compact structure and causing the receptor to be come active
How does the insulin receptor produce a signal?
The activation process of the receptor results in the phosphorylation of other tyrosine residues in the juxtamembrane region, these can act as docking sites for for other proteins allowing transmission of a signal
This includes the IRS (Insulin receptor substrates)
Such as IRS-1 which acts an adapter protein recruiting PI3K which is a lipid kinase which binds to the phosphorylated residues on IRS-1
PI3K generates PIP3 from PIP2 by adding a phosphate group at position 3
PIP3 then regulates the activity of proteins such as PDK1 (PIP3 Dependent protein kinase) which is a ser/thr kinase
Activation of this results in phosphorylation and activation of downstream kinases such as Akt
What is the function of Akt?
It is a kinase that is not membrane bound and is able to transmit signals to different parts of the cell
including the components that control trafficking of the GLUT4 transporter to the cell surface to promoting glucose uptake
What is the structure of the epidermal growth factor receptor and how does it become active?
Dimers of identical units which come together when EGF binds (one EGF to each monomer)
Each monomer contains a dimerisation arm which is in a spring loaded state to another part of that monomer in the extracellular domain
This arm stretches out when EGF is bound inserting into a binding pocket on the other monomer allowing dimerization
This then allows cross phosphorylation of the receptor at the C-terminus
How does EGFR propagate a signal?
The phosphorylated tyrosines on the C terminus of the activated form of the receptor can act as docking sites for the adaptor protein Grb-2
This recruits Sos (a guanine nucleotide exchange factor) which recruits the small G protein Ras and activates it via a GDP to GTP exchange, Ras then activates Raf which is a protein kinase which phosphorylates other protein kinases such as MEK
and extracellular signal regulated kinase
Ultimately transcription factors in the nucleus may be activated leading to gene expression
How is EGFR signalling regulated?
Via phosphatases like protein tyrosine phosphatases which dephosphorylate the EGFR and the other second messenger proteins
Ras has intrinsic GTPase activity causing its own termination this process can be sped up with GTPase activating proteins
