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Advanced Cell Signalling > 14-3-3 Binding Phosphoproteome > Flashcards

14-3-3 Binding Phosphoproteome Flashcards

1
Q

How do 14-3-3 proteins bind to proteins?

A

Through specific tandem pairs of phosphosites

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2
Q

What is the dual-docking conformation?

A

14-3-3 will act as a singalling intergrator when its two binding sites on a target are phosphorylated by different kinases

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3
Q

How can 14-3-3 binding affect its binding protein?

A

Can mask a domain
If bound to a disordered region, it can force a disorder-to-order transition which creates a new functional site in the target
Alter the interactions between the domains in a protein

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4
Q

What is the 14-3-3 structure?

A

As homo- and hetero- dimers with phosphopeptides in them

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5
Q

Where are 14-3-3 located?

A

In every eukaryotic cell

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6
Q

What is an ‘AND’ gate?

A

A coincidence detector

Needs 2 inputs before it can generate an output

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7
Q

Name a protein which 14-3-3 masks

A

Q96RKO CAPICUA

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8
Q

How does 14-3-3 mask Capicua?

A

HMG is straddled in Capicua

the DNA interaction site is masked since HMG is phosphorylated twice and therefore 14-3-3 bind to and masks it

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9
Q

What is ASK1?

A

Apoptosis signal-regulating kinase 1

Member of MAP3K5

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10
Q

How does 14-3-3 inhibit MAP3K5?

A

It is phosphorylated on linker region which binds to the central groove of 14-3-3. This pulls the kinase domain against the back end of 14-3-3 and inhibits the kinase activity since ATP accessibility is removed

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11
Q

What is ZNRF2?

A

A RING-E3 Ubiquitin ligase

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12
Q

What is the structure of ZNRF2?

A

It is tethered to the intracellular membrane through its lipid tail

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13
Q

What is the function of ZNRF2?

A

Facilitates the ubiquitylation of ion channels and regulates the trafficking of ions when it is tethered to the membrane

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14
Q

What phosphorylates ZNRF2?

A

PKA
PKB
PKC

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15
Q

What does ZNRF2 phosphorylation induce?

A

14-3-3 binding

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16
Q

What happens when 14-3-3 binds to ZNRF2?

A

It is soluble and inhibited - dissociated from the membrane and goes into the cytoplasm

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17
Q

What is GNF-2?

A

Memetic myristoyl

Binds to BCR-Abl myristoyl pocket

18
Q

How does GNF-2 impact ZNRF2?

A

It stops ZNFR2 from leaving the membrane, even when phosphorylation has occured

19
Q

What do the kinases which create phosphosites do and what is specific for their phosphorylation?

A

Phosphorylate a serine or threonine

They never have a proline in the +1 position

20
Q

What does insulin do in terms of 14-3-3?

A

Generates phosphosites for 14-3-3 to bind in the spleen, kidney, pancreas, adipose and gastro

21
Q

How does insulin drive glucose into skeletal muscles?

A

Through the translocation of GLUT4 in intracellular vesicles to the plasma membrane

22
Q

How does 14-3-3 aid GLUT4 translocation in response to insulin?

A

AS160 is phosphorylated and 14-3-3 docks onto it -> inhibits Rab-GAP activating protein -> gets loaded with GTP -> Activate Rab bring GLUT4 to the plasma membrane

23
Q

What is AS160?

A

a 14-3-3 binding protein which has an active site of Rab-GAP

24
Q

What are Rabs involved in?

A

Specific vesicle trafficking events

25
Q

what disease is associated with AS160 mutation?

A

Type 2 diabetes

26
Q

What is the phenotype of AS160 mutated type 2 diabetes? And what does this suggest?

A

Heavy pigmentation behind the neck and knees

Involved in trafficking melanin containing vesicles in the skin cells

27
Q

What happens when there is no amino acids in the heart available for it to function?

A

The heart can use glucose from AS160

28
Q

What is the function of SPEG?

A

Can bind to SERCA2A and phosphorylates it in response to insulin

29
Q

Where is SPEG found?

A

The heart

30
Q

What is SERCA2A?

A

A calcium pump

31
Q

What happens if SPEG is mutated at phosphorylated sites?

A

Impaired Ca2+ reuptake into SR and cardiac dysfunction

32
Q

What processes does insulin-induced 14-3-3 binding downregulate?

A

Lipolysis
Gluconeogenesis
Autophagy

33
Q

What processes does insulin-induced 14-3-3 binding upregulate?

A 
Glucose uptake 
Amino acid uptake 
K+ and PO43- uptake 
Glycogen synthase 
Glycolysis in the heart 
Lipid synthesis 
Esterification of fatty acids
34
Q

What physiological functions does insulin-induced 14-3-3 binding control?

A

Arterial muscle tone relaxation
Endothelial permeability and inflammation
Cytoskeletal remodelling
HCl production by parietal cells of the stomach
Bone remodelling
Feedback control of pancreatic function
Brain functions

35
Q

If you have diabetes, what are common chronic secondary diseases?

A

renal disease

cardio myopathy

36
Q

How does the brain respond to insulin?

A

A huge dephosphorylation of 14-3-3 binding proteins

Inhibits cerebral PKA

37
Q

What protein in the brain is associated with Alzheimer’s?

A

TAU

38
Q

How can diabetes cause Alzheimer’s?

A

An increase in the insulin levels causes neurofibril tangles in the brain

39
Q

In fasted animals, what does 14-3-3 bind to?

A

PhosphoSer?

PhosphoSer948

40
Q

Ser858 is phosphorylated in fasted animals, what does this do?

A

Activates Rac1 GAP domain

41
Q

In fasted animals, what does phosphoFAM122A - 14-3-3 complex do?

A

It is translocated to the nucleus, which inhibits dephosphorylation of TAU by PP2A

42
Q

How is sleep linked to insulin resistance?

A

1 night of bad sleep can lead to insulin resistance to a higher degree compared to a high fat diet for several months

Advanced Cell Signalling (12 decks)

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