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MCB > Intracellular Proteolysis > Flashcards

Intracellular Proteolysis Flashcards

1
Q

How can protein activity be regulated?

A
  • Active site and allosteric regulators
  • Pro-proteins and zymogens
  • Phosphorylation
  • pH and protein degradation
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2
Q

How quickly are abnormal variants turned over?

A

Quickly (more quickly than normal proteins)

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3
Q

When do cells increase rate of protein turnover?

A
  • Times of starvation
  • Breakdown of muscle protein
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4
Q

What is the N-terminal rule?

A

Half-life of a protein is dependent on which amino acid on the N-terminal

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5
Q

How was the N-terminal rule tested for?

A

By mutating the N-terminal residue of Beta-galactosidase and half life is observed

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6
Q

What are the features of caspases?

A
  • Cysteine dependent aspartate-directed proteases
  • Mediators of apoptosis
  • Regulated post-trans via pro-enzyme activation
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7
Q

What are the features of cathepsins?

A
  • Major lysosomal protease family
  • Cysteine proteases optimally active at low pH
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8
Q

What are the features of calpains?

A
  • Ca2+ dependent non-lysosomal proteases
  • Res
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9
Q

What are the features of pro-protein convertases?

A
  • Ca2+ dependent serine proteases
  • Cleave various proteins (e.g hormones and neurotransmitters)
  • Activated by growth factors
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10
Q

What are the features of proteasomes?

A
  • Only example of threonine protease family
  • Major site of intracellular protein degradation
  • Ubiquitin dependent
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11
Q

What are the pathways used to degrade proteins?

A
  1. Lysosomal pathway
  2. Ubiquitin-mediated
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12
Q

Where are the end products of lysosomal degradation exported to?

A

The cytosol

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13
Q

What are the 4 ways of delivery of substrate proteins to the lysosome?

A
  1. Endocytosis
  2. Autophagy
  3. Phagocytosis
  4. Chaperone-mediated autophagy
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14
Q

How does autophagy delivery substrate proteins to lysosome?

A

Macromolecules and/or organelles are engulfed by ER-dervied membrane and delivered to the lysosome

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15
Q

What do acid hydrolases require to ensure they are transported to the lysosome?

A

Mannose-6-phosphate tag added at the golgi

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16
Q

How are mannose-6-phosphate tags added to an N-linked oligosaccharide?

A
  • Addition of GlcNAc to an N-linked oligosaccharide in cis-golgi
  • Phosphodiesterase removes GlcNAc, leaving just the M6P tag
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17
Q

Why are incorrectly folded amino acids not tagged with Mannose-6-phosphate?

A

If not properly folded then the amino acids are not in the correct place for the signal patch so it won’t bind

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18
Q

What recognises the M6P tag?

A

Receptor proteins in trans-golgi network

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19
Q

How is the M6P tag recognised to allow acid hydrolase to be transported to lysosome?

A
  • M6P tagged acid hydrolase binds to M6P receptor in TGN
  • Clathrin coasted vesicle is transported to early/late endosome and then to the lysosome
  • Low pH causes M6P tagged acid hydrolase ro dissociate from the receptor
20
Q

How is the M6P recycled?

A
21
Q

What can lysosomal storage diseases result in?

A

The formation of inclusion bodies

22
Q

What causes the formation of inclusion bodies in lysosomal storage diseases?

A
  • Problems with GlcNAc phosphotransferase
  • Substrates gets delivered but enzymes do not so substrates are not degraded
23
Q

What is the structure of ubiquitin?

A
  • small 76 residue protein
  • Lysine residues exposed on surface that are critical to function
24
Q

How does ubiquitin attach to proteins?

A

Via isopeptide bond between ubituitin’s C-terminal carboxylate and lysine residue on substrate

25
Q

What reads ubiquitin signals?

A

Ubiquitin binding domains on proteins

26
Q

Why is the ubiquitin-lysine bond not a peptide bond?

A

It is not in the backbone of the protein

27
Q

What must happen to ubiquitin before it can bind to substrate?

A

It must be activated

28
Q

What kind of ubiquitination targets proteins to the proteasome for destruction?

A

Polyubiquitination

29
Q

Which enzymes activate ubiquitin?

A

E1, E2, E3

30
Q

What does E1 do to activate ubiquitin?

A
  • C-terminal carboxylate of ubiquitin forms a thioester bond with a key cyteine residue of E1
  • E1 then binds E2 which uses ATP
31
Q

What does E2 do to activate ubiquitin?

A
  • Ubiquitin conjugating enzyme
  • The E1 to E2 shuttle moves the activated ubiquitin onto a key cysteine residue on E2
32
Q

What does E3 do to activate ubiquitin?

A
  • E3 is bound to E2
  • E2/E3 complex binds to substrate protein and catalyses isopeptide bond formation
33
Q

What is monoubiquitination used for?

A

Histone regulation

34
Q

What is multiubiquitination used for?

A

Endocytosis

35
Q

What are defects in E3 linked to?

A

Early onset Parkinson’s and breast and ovarian cancer (BRCA1 codes for an E3)

36
Q

How are E3 enzymes activated?

A
  • Requires ATP for activation by phosphorylation
  • or allosteric activation by a ligand
37
Q

How is a protein activated for ubiquitination?

A
  1. Activated via phosphorylation by a protein kinase
  2. or by unmasking a recognition site on substrate
  3. or removal of N-terminal residues to create a new destabilising N-terminal residue
38
Q

What is the structure of the proteosome?

A
  • Central catalytic core component which is hollow in middle
  • Two caps
  • Active sites inside central cavity of catalytic core
39
Q

How is the catalytic core of the proteosome activated?

A
  • Unfolded proteins can pass through the centre and make contact with the active sites located on the inside of the 20s core
40
Q

What is the structure of the 20s catalytic core of the proteosome?

A
  • composed of 2 x 7 membered rings of alpha subunits and 2 x 7 membered rings of beta subunits
41
Q

Which beta subunits of the catalytic core of the proteasome are active?

A

B1, B2, and B5

42
Q

What is unique about the proteasome protease mechanism?

A

Depends on nucleophilic attack by the N-temrinal threonine

43
Q

How does the proteasome process proteins?

A
  • 19s caps recognise ubiquinated protein and unfold it and feed it into central cavity using ATP (from ATP binding domains)
  • 19s caps release the ubiquitin for reuse
44
Q

What does the proteasome do to polyubiquinated proteins?

A

Hydrolyses them into small peptides

45
Q

What happens to peptides leaving the proteasome?

A
  • They are reused, and digested by cytosolic peptidases to amino acids for use in protein synthesis
  • deaminated and used for different functions
46
Q

Why is the unique protease mechanism in the proteasome useful?

A

Makes the beta units a good target for cancer as the proteasome can help maintain cell proliferation

MCB (28 decks)

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