Biological Signalling: Receptor Enzymes Flashcards Preview

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Flashcards in Biological Signalling: Receptor Enzymes Deck (28)
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1

Plasma membrane receptors, what binds on the outside?

- ligand binding domain outside
- conformational change on the outside activates the enzyme inside

2

Plasma membrane receptors, whats on the inside?

- catalytic site on the inside

3

What is the strucutre of the insulin receptor?

- tetramer
- a2b2

4

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

5

Activation of insuline receptor occurs through ____

autophosphorylation

6

How is the inactive form of the insulin receptor stabilized?

- H-bond between Tyr-1162 and Asp1132

7

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

8

What does the repulsion of the PO3 2- residues cause?

- conformational change
- activation loop moves
- active site opened

9

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

10

What happens to the phosphorylated IRS-1?

- recognized by signalling proteins - Grb-2
- bound by SH2 domains of Grb-2

11

What do the SH2 domains bind to?

phosphotyrosines on IRS-1
- Tyr-O-PO3-2

12

What do SH2 domains binding to IRS-1 lead to?

- protein-protein interactions "signalling complexes"
- phosphorylation/kinase cascade

13

Grb-2 with IRS-1 bound binds what?

SOS
- via SH3 domain
- on the poly-Pro of SOS

14

Grb-2 bound SOS activates what?

- Ras
- G protein (activated)

15

GTP bound active Ras activates _____

protein kinase cascade - amplification

16

What are GEFs?

- activation of G proteins (GDP to GTP)
GTP-GDP exhancge factors
i.e. SOS
kick out GDP so GTP can bind

17

What are GAPs

- inhibitors of G-proteins (GTP to GDP)
- GTPase activating proteins

18

What does the protein kinase cascade involve?

- Raf-1
- MEK
- ERK (MAPK family)

sets of phosphorylation events

19

What does ERK do?

phosphorylated ERK enters nucleus and phosphorylates transcription factors
- bind to response elements on DNA
- increase/decrease gene transcription

20

What is MAP kinase?

- mitogen activated protein kinase
- this is an example of amplfication

21

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)

22

Besides changing transcription, what else does insulin pathway do?

- protein protein interactions
- phosphorylation
- culminate to activate/inactivate enzymes that are already present

23

What does phospho-IRS-1 do?

the phosphotyrosine binds to SH2 domain of phospho-inositide 3kinase (PI3K) to activate it

24

What does PI3K do?

- phosphorylates phosphatidyl-inositol bis-phosphate PIP2
- become PIP3 (triphosphate)

25

What does PIP3 do?

binds to protein kinase B or Akt

26

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

27

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

28

GSK3 what does it do?

- GSK3 keeps glycogen synthase (GS) phosphorylated
- phosphorylated glycogen synthase is inactivated
- therefore insulin INACTIVATES GSK3 so that GS is no longer phosphorylated and active
- glycogen can form