Biological Signalling: Receptor Enzymes Flashcards
(28 cards)
Plasma membrane receptors, what binds on the outside?
- ligand binding domain outside
- conformational change on the outside activates the enzyme inside
Plasma membrane receptors, whats on the inside?
- catalytic site on the inside
What is the strucutre of the insulin receptor?
- tetramer
- a2b2
Where does insulin binding occur and what does this do?
- Insulin binds externally
- activates tyrosine kinase activity on intracellular domain
- beta chains autophosphorylate (tyrosine residues)
- opens active site
Activation of insuline receptor occurs through ____
autophosphorylation
How is the inactive form of the insulin receptor stabilized?
- H-bond between Tyr-1162 and Asp1132
How are the insulin receptor Hbonds disrupted ?
- tyrosine phosphorylation of Tyrosine kinase domain: Tyr-1158, Tyr1162, Tyr1163
- disrupts hydrogen bonding
- the negative charges of PO32- repel
What does the repulsion of the PO3 2- residues cause?
- conformational change
- activation loop moves
- active site opened
What does the active insulin receptor do?
- the phosphotyrosines of IR recruits IRS-1 to the cell membrane surface
- activated IR phosphorylates tyrosines of IRS-1
What happens to the phosphorylated IRS-1?
- recognized by signalling proteins - Grb-2
- bound by SH2 domains of Grb-2
What do the SH2 domains bind to?
phosphotyrosines on IRS-1
- Tyr-O-PO3-2
What do SH2 domains binding to IRS-1 lead to?
- protein-protein interactions “signalling complexes”
- phosphorylation/kinase cascade
Grb-2 with IRS-1 bound binds what?
SOS
- via SH3 domain
- on the poly-Pro of SOS
Grb-2 bound SOS activates what?
- Ras
- G protein (activated)
GTP bound active Ras activates _____
protein kinase cascade - amplification
What are GEFs?
- activation of G proteins (GDP to GTP)
GTP-GDP exhancge factors
i.e. SOS
kick out GDP so GTP can bind
What are GAPs
- inhibitors of G-proteins (GTP to GDP)
- GTPase activating proteins
What does the protein kinase cascade involve?
- Raf-1
- MEK
- ERK (MAPK family)
sets of phosphorylation events
What does ERK do?
phosphorylated ERK enters nucleus and phosphorylates transcription factors
- bind to response elements on DNA
- increase/decrease gene transcription
What is MAP kinase?
- mitogen activated protein kinase
- this is an example of amplfication
Final result of insulin activation:
- increase transcription and translation of enzymes like hexokinase (glucose to glycogen in muscle), PK, ACC, FAS (glucose to pyruvate to fat in liver to adipose)
- decreased transcription for gluconeogenic enzymes in liver
- insulin
works in many mechanisms but always to store energy as glycogen or fat (removing glucose from blood)
Besides changing transcription, what else does insulin pathway do?
- protein protein interactions
- phosphorylation
- culminate to activate/inactivate enzymes that are already present
What does phospho-IRS-1 do?
the phosphotyrosine binds to SH2 domain of phospho-inositide 3kinase (PI3K) to activate it
What does PI3K do?
- phosphorylates phosphatidyl-inositol bis-phosphate PIP2
- become PIP3 (triphosphate)
