Flashcards in Biological Signalling: Receptor Enzymes Deck (28)
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?
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 ____
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
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?
- via SH3 domain
- on the poly-Pro of SOS
Grb-2 bound SOS activates what?
- 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
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?
- 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
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
- 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)
What does PIP3 do?
binds to protein kinase B or Akt
PKB does what?
- reduce phosphorylation of glycogen synthase (GSK3 inactivated)
- therefore increased activity of glycogen synthesis
- movement of glucose transporter to PM GLUT4
- transcription factors - modulation of insulin responsive TFs
Inslin acts in muscle cells to: (3 things)
- GLUT4: increase glucose transport by recruiting GLUT4
- TF: induce synthesis of hexokinase transcription (make glycogen)
- GSK3 inactivated: activate glycogen synthase by phosphorylation of GSK3