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Advanced Cell Signalling > AMPK > Flashcards

AMPK Flashcards

1
Q

What is the structure of the alpha subunit of AMPK?

A 
Kinase domain (with a N and C lobe)
Autoinhibitory domain 
alpha C terminal domain 
Autoinhibitory domain and C terminal domain are joined by a flexible linekr
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2
Q

What is the function of the autoinhibitory domain?

A

To inhibit the kinase domain in the absence of AMP

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3
Q

What are the alpha subunits of AMPK?

A

Alpha 1 and 2

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4
Q

what are the beta subunits of AMPK?

A

Beta 1 and 2

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5
Q

What are the gamma subunits of AMPK?

A

Gamma 1, 2 and 3

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6
Q

What is the structure of the beta domain of AMPK?

A

beta carbohydrate-binding molecule

beta C-terminal domain

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7
Q

What is the function of the beta carbohydrate-binding molecule?

A

causes a portion of AMPK to bind to glycogen

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8
Q

What is the function of the beta C-terminal domain?

A

forms the core complex by bridging the alpha and gamma subunits

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9
Q

What is the structure of the gamma domain of AMPK?

A

It has 4 tandem repeats of sequence known as CBS motif

- CBS1, 2, 3 and 4

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10
Q

What is the function of the CBS motif?

A

It forms the allosteric regulatory sites for AMP, ADP and ATP
However, there is only 3 sites for nucleotide binding even though there is 4 of them

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11
Q

In a human alpha1beta1gamma1 complex, where does 991 bind?

A

In the cleft been the beta-carbohydrate-binding module and the kinase domain N-lobe

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12
Q

What is staurosporine?

A

A kinase inhibitor

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13
Q

In a human alpha1beta1gamma1 complex, where does staurosporine bind?

A

In the cleft between the N and C lobes of the kinase domain

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14
Q

In a human alpha1beta1gamma1 complex, where does AMP bind? and how many bind?

A

3 bind
1 between CBS1 and CBS2
2 between CBS3 and CBS4

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15
Q

In a human alpha1beta1gamma1 complex, how does the linker interact with a molecule of AMP?

A

By wrapping around the face of the gamma subunit

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16
Q

What effect does the linker interacting with AMP have on AMPK?

A

Pulls the autoinhibitory domain away from the kinase domain and removes the inhibitory effect

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17
Q

How does AMPK restore energy homeostasis?

A

By switching on catabolic pathways which generate ATP

18
Q

What long term effects does AMPK induce to restore energy homeostasis?

A

Switch on catabolic genes and switch on anabolic genes

Increases the expression of GLUT4 n the muscle - enhancing the breakdown of glucose by muscles to generate ATP

19
Q

What binding sites are in the promoters of GLUT4?

A

Myocyte enhancer factors (MEFs)

20
Q

What represses MEF transcription?

A

Class II histone deacetylases

21
Q

How do histone deactylases inhibit transcription?

A

They expose the lysine side chains
The positive lysine side chains bind to DNA
The tight binding inhibits transcription

22
Q

What does histone acetyl transferases do?

A

Neutralise the positive charge of lysine via lysine acetylation
This allows transcription

23
Q

How does AMPK induce GLUT4 expression?

A

AMPK phosphorylates class IIa HDACs at multiple sites -> binding of 14-3-3 proteins -> masks their nucleur localisation signals (since they normally shuttle in between the cytoplasm and nucleus) -> blocking re-entry of the HDACs into the nucleus -> net acetylation of histones at the GLUT4 promoter -> GLUT4 transcription via MEF2

24
Q

2 main proteins involved in lipid synthesis

A

Acetyl-CoA carboxylase-1

Fatty acid synthase

25
Q

What transcription factor is required for the synthesis of acetyl-CoA carboxylase-1 and fatty acid synthase?

A

SREBP-1

26
Q

Where is SREBP-1 located?

A

In the ER by a transmembrane anchor

27
Q

How does insulin cause acetyl-CoA carboxylase-1 and fatty acid synthase production?

A

Insulin -> proteolytic cleavage of SREBP-1 -> releasing the TF domain -> translocates to the nucleus -> promotes expression of acetyl-CoA carboxylase-1 and fatty acid synthase

28
Q

How does AMPK effect fatty acid synthase and acetyl-CoA carboxylase-1 production?

A

When activated by energy stress, it phosphorylates SREBP-1, preventing its cleavage and therefore inhibits expression of acetyl-CoA carboxylase-1 and fatty acid synthase

29
Q

If glucose is removed from medium containing mammalian cells, what happens?

A

AMPK is activated by non-canonical activation

30
Q

Under glucose starvation, what does AMPK form?

A

A ternary complex with LKB1 and the adaptor protein, AXIN

31
Q

What is the function of Axin?

A

It is an adaptor protein for LKB1 and AMPK and therefore allows the phosphorylation and activation of AMPK

32
Q

What is LAMTOR1?

A

An interactor

Part of the Regulator complex that regulates mTORC1

33
Q

Where is LAMTOR1 found?

A

on the lysosomal membrane

34
Q

How is LAMTOR1 bound to the lysosomal membrane?

A

N-terminal modifications by C14 and C16 fatty acids

Interaction with the vacuolar ATPase

35
Q

What s the vacuolar ATPase?

A

A transmembrane H+ pump that acidifies the lysosomal lumen

36
Q

What is the ‘super-complex’?

A

What LAMTOR1, AMPK, LKB1 and AXIN form at the lysosomal membrane when glucose is absent

37
Q

What glycolytic metabolite is able to dissociate from the super-complex?

A

Fructose-1,6-bisphosphate

38
Q

What is the function of aldolase?

A

Converts fructose-1,6-bisphosphate into glucose-3-phosphate and DHAP

39
Q

What does aldolase bind to on the lysosomal surface?

A

v-ATPase

40
Q

What evidence is there that aldolase is the sensor which triggers AMPK?

A

KO of aldolase inhibited glucose from repressing AMPK activation but KO of enzymes downstream did not
Mutant aldolase which can still bind FBP, prevented activation of AMPK in low glucose

41
Q

How does aldolase trigger AMPK activation?

A

Aldolase which is not bound to FBP triggers formation of the supercomplex and therefore AMPK activation

Advanced Cell Signalling (12 decks)

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