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BIOC3560 > Biological Signalling: Receptor Enzymes > Flashcards

Biological Signalling: Receptor Enzymes Flashcards

1
Q

Plasma membrane receptors, what binds on the outside?

A
  • ligand binding domain outside

- conformational change on the outside activates the enzyme inside

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2
Q

Plasma membrane receptors, whats on the inside?

A
  • catalytic site on the inside
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3
Q

What is the strucutre of the insulin receptor?

A
  • tetramer

- a2b2

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4
Q

Where does insulin binding occur and what does this do?

A
  • Insulin binds externally
  • activates tyrosine kinase activity on intracellular domain
  • beta chains autophosphorylate (tyrosine residues)
  • opens active site
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5
Q

Activation of insuline receptor occurs through ____

A

autophosphorylation

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6
Q

How is the inactive form of the insulin receptor stabilized?

A
  • H-bond between Tyr-1162 and Asp1132
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7
Q

How are the insulin receptor Hbonds disrupted ?

A
  • tyrosine phosphorylation of Tyrosine kinase domain: Tyr-1158, Tyr1162, Tyr1163
  • disrupts hydrogen bonding
  • the negative charges of PO32- repel
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8
Q

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

A
  • conformational change
  • activation loop moves
  • active site opened
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9
Q

What does the active insulin receptor do?

A
  • the phosphotyrosines of IR recruits IRS-1 to the cell membrane surface
  • activated IR phosphorylates tyrosines of IRS-1
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10
Q

What happens to the phosphorylated IRS-1?

A
  • recognized by signalling proteins - Grb-2

- bound by SH2 domains of Grb-2

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11
Q

What do the SH2 domains bind to?

A

phosphotyrosines on IRS-1

- Tyr-O-PO3-2

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12
Q

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

A
  • protein-protein interactions “signalling complexes”

- phosphorylation/kinase cascade

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13
Q

Grb-2 with IRS-1 bound binds what?

A

SOS

  • via SH3 domain
  • on the poly-Pro of SOS
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14
Q

Grb-2 bound SOS activates what?

A
  • Ras

- G protein (activated)

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15
Q

GTP bound active Ras activates _____

A

protein kinase cascade - amplification

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16
Q

What are GEFs?

A
  • activation of G proteins (GDP to GTP)
    GTP-GDP exhancge factors
    i.e. SOS
    kick out GDP so GTP can bind
17
Q

What are GAPs

A
  • inhibitors of G-proteins (GTP to GDP)

- GTPase activating proteins

18
Q

What does the protein kinase cascade involve?

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

sets of phosphorylation events

19
Q

What does ERK do?

A

phosphorylated ERK enters nucleus and phosphorylates transcription factors

  • bind to response elements on DNA
  • increase/decrease gene transcription
20
Q

What is MAP kinase?

A
  • mitogen activated protein kinase

- this is an example of amplfication

21
Q

Final result of insulin activation:

A
  • 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
Q

Besides changing transcription, what else does insulin pathway do?

A
  • protein protein interactions
  • phosphorylation
  • culminate to activate/inactivate enzymes that are already present
23
Q

What does phospho-IRS-1 do?

A

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

24
Q

What does PI3K do?

A
  • phosphorylates phosphatidyl-inositol bis-phosphate PIP2

- become PIP3 (triphosphate)

25
Q

What does PIP3 do?

A

binds to protein kinase B or Akt

26
Q

PKB does what?

A
  • 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
Q

Inslin acts in muscle cells to: (3 things)

A
  • 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
Q

GSK3 what does it do?

A
  • 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

BIOC3560 (6 decks)

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