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Biology Of Ageing Year2 > Protein homoeostasis > Flashcards

Protein homoeostasis Flashcards

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1
Q

What is homeostasis?

A

Homeostasis is the property of an open system, especially living organisms, to regulate their internal environment to maintain a stable, constant condition by means of multiple feedback controls, regardless of external conditions.

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2
Q

What are the steps of a negative feedback loop?

A
  1. Body conditions change from a set point.
  2. Detection of change in body conditions from a set point.
  3. Corrective mechanisms activated
  4. Conditions returned to the set point
  5. Corrective mechanisms deactivated.
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3
Q

What is protein homeostasis also known as?

A

Proteostasis

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4
Q

What is the function of protein homeostasis?

A

maintaining the correct amount of functional proteins within and outside the cell.

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5
Q

Why is protein so important?

A

It is the main component of the body.

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6
Q

How are protein levels maintained?

A

Protein turnover.

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7
Q

What is protein turnover?

A

Amino acids released by by the breakdown of proteins can be reused for protein synthesis with very little loss.

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8
Q

What is p53?

A
  • Transcription factor
  • Tumour suppressor
  • Involved in the cell cycle arrest, DNA repair and apoptosis
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9
Q

Why is p53 kept at a low basal rate?

A

Can trigger apoptosis so increased levels can stop the cell cycle.

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10
Q

What is Mdm2?

A

An E3 ligase.

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11
Q

What is the function of mdm2?

A

Binds to p53 which marks it for degradation by the proteasome via ubiquitination.

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12
Q

What happens to the levels of p53 during cellular stress?

A

Increased levels of p53.

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13
Q

How is the maintenance of p53 a negative feedback?

A

P53 is a transcription factor for Mdm2. High levels of p53 lead to an increase in Mdm2. High levels of Mdm2 lead to a decrease in p53.

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14
Q

When does the negative feedback loop of p53 and Mdm2 stop?

A

Goes through cycles till the system stabilises to low levels of both molecules.

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15
Q

What is the life cycle of a protein?

A
  • Synthesis
  • Folding
  • Transport
  • Modifications
  • Function
  • Degradation
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16
Q

What is the AGES pathway?

A

Oxidative stress-induced pathways.
AGEs induce oxidative stress through the activation of NADPH oxidases.

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17
Q

What is the end result of the AGEs pathway?

A

Produces deleterious effects on cells.

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18
Q

What is transcription regulated by?

A

Transcription is regulated by transcription factors which can either promote or inhibit transcription.

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19
Q

What causes changes i translation of proteins?

A

Dysregulation in signalling pathways.

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20
Q

What happens to translation factors with age?

A

Activity declines.

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21
Q

What is important about protein structure regarding function and stability?

A

Each level of complexity within the structure must be perfect otherwise the protein is considered misfolded and will not function properly, therefore will be degraded very quickly.

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22
Q

What are the 3 types of folding?

A

Chaperone-independent folding.
Hsp70-assisted protein folding.
Folding assisted by HSP70 and chaperonin complexes.

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23
Q

What is chaperone-independent folding?

A

The protein folds as it is synthesized on the ribosome.

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24
Q

What is hsp70-assisted protein folding?

A

Hsp70 binds to nascent polypeptide chains as they are synthesized and help folding.

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25
Q

What is the function of chaperones?

A

Chaperones prevent misfolded or incompletely assembled proteins from exiting the ER.

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26
Q

What is the unfolded protein response?

A

Maintains the balance of protein folding in the endoplasmic reticulum.

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27
Q

What is the unfolded protein response caused by?

A

Caused by an increase in misfolded proteins in the ER.

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28
Q

What reversible covalent modifications affect protein function?

A

Phosphorylation
Acetylation
Glycosylation
Ubiquitination

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29
Q

Why do undesirable protein modification occur?

A

Due to reactive oxygen or reactive nitrogen species.

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30
Q

What are the 2 major classes of oxidative damage within protein?

A

Conformational
Covalent.

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31
Q

What is conformational damage?

A

The unfolding of proteins.

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32
Q

What is conformational damage caused by?

A

Heating, attack by free radicals, chemicals, pH changes.

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33
Q

What is covalent damage?

A

A chemical change in the amino acids that make up the protein.

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34
Q

What is covalent damage caused by?

A

Spontaneous or may be induced and/or accelerated by environmental factors.

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35
Q

When does the AGEs pathway begin?

A

When proteins are exposed to sugar.

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36
Q

What is the basic process of the AGEs pathway?

A

Activates a stress response which leads to the chemical attachment of sugar to amino acids.

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37
Q

How may protein homeostasis fail?

A

Every step of this process can go wrong.

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38
Q

Draw the process of protein synthesis.

A
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39
Q

What do you think the effect of DNA damage will be on protein synthesis?

A

Incorrect protein is synthesised.

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40
Q

What does the repair of protein damage depends on?

A

The ability to recognise a change in a protein as abnormal.
A means of reversing the change.

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41
Q

Why do unsuccessful proteins need to be removed?

A

To prevent cellular dysfunction and protein aggregation.

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42
Q

What are molecular chaperones?

A

Known as heat shock proteins, they are in cells.

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43
Q

What is the function of molecular chaperones?

A

Folding/refolding
Prevent protein aggregation
Assist in targeting proteins for degradation

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44
Q

What is the function of small heat shock proteins?

A

prevents protein aggregation

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45
Q

What is the function of molecular chaperone Hsp40?

A

Prevents protein aggregation.
Interacts with Hsp70

46
Q

What is the function of molecular chaperone Hsp60?

A

Protein folding.
Anti-apoptotic.

47
Q

What is the function of molecular chaperone Hsp70?

A

Protein folding/refolding.
Stress response.
Protein degradation.

48
Q

What is the function of molecular chaperone Hsp90?

A

Protein folding/refolding.
Stress response.
Protein degradation.
Interacts with steroid receptors.

49
Q

What is the function of heat shock factor 1 (HSF1?

A

Regulates the transcription of heat shock
genes.

50
Q

What is HSF1 usually present as?

A

Inactive monomers.

51
Q

What happens to HSF1 in stressed cells?

A

Forms homotrimers.

52
Q

What then happens with the trimers HSF1 forms under stress conditions?

A

Trimers are activated by phosphorylation

Translocated to the nucleus.

Bind to the heat shock element (HSE).

53
Q

What happens when trimers bind to the heat shock element (HSE)?

A

This results in the synthesis of heat shock proteins.

54
Q

What constitutes the negative feedback mechanisms during HSF1-mediated heat shock response?

A

Triggers the unfolding of proteins.
Misfolded proteins bind to displace chaperones from HSF1 and that displacement allows the proteins to trimerize.

55
Q

How do chaperones prevent the aggregation of proteins?

A

Chaperones bind to the hydrophobic region to prevent misfolding proteins from “sticking” together.

56
Q

Why do proteins aggregate?

A

Misfolded proteins expose hydrophobic regions which tend to “stick” together.

57
Q

How are chaperones involved in protein degradation?

A
  • Chaperone-mediated autophagy
  • Target some proteins for degradation via ubiquitin-proteasome system
58
Q

What kinds of proteins do Hsp70 an Hsp90 interact with?

A

Nuclear hormone receptors
Protein kinases
Cell cycle regulators
Cell death regulators

59
Q

Why does the heat shock response decline with ageing?

A

Possibly due to decline in HSF1
transcriptional response with age.

60
Q

What is the chaperone overload hypothesis?

A

Emphasizes the need for efficient ways to enhance chaperone capacity in ageing subjects, and will hopefully lead to the identification and ‘repair’ of silent mutations.

61
Q

What are the 5 protein degardation pathways?

A

Macroautophagy
Microautophagy
Chaperone-mediated autophagy
Ubiquination
Proteasome

62
Q

What is macroautophagy?

A

Release cell which is degraded by lysosome.

63
Q

What is microautophagy?

A

Pinch into lysosome.

64
Q

What is chaperone-mediated autophagy?

A

More of a transport pathway.

65
Q

What are proteasome?

A

A large protein complex.

66
Q

Where is the proteasome?

A

Located in the nucleus and cytoplasm.

67
Q

What is the function of proteasomes?

A

proteolysis.

68
Q

What is proteolysis?

A

A chemical reaction that breaks peptide bonds.

69
Q

What is the product of proteolysis?

A

Yields peptides about 7-8 amino acids long.

70
Q

What happens to the product of proteolysis?

A

Further degraded into amino acids.

71
Q

What is the function of the proteasomal pathway?

A

Regulates concentration of particular proteins and removes misfolded proteins.

72
Q

What is the function of the alpha subunit of the 20s proteasome?

A

Maintain a gate through which substrates enter.

73
Q

What is the function of the beta subunit of the 20s proteasome?

A

Maintain a gate through which substrates enter.

74
Q

What is the function of 20S proteasome?

A

Protein spins through the middle.

75
Q

What is the requirement for 20S proteasome interactions with proteins?

A

Proteins must be unfolded.

76
Q

Is the function of 20S proteasome specific?

A

No. There is no recognition machinery present.

77
Q

What are 26S proteasomes?

A

The alpha subunits bind to the regulatory cap of the 19S subtype.

78
Q

What is the function of the 19S proteasome subtype?

A

The 19S cap contains ATPase active sites and ubiquitin-binding sites.

79
Q

What is the importance of the 20S and 19S subtypes binding to form 26S?

A

Substates must be tagged by ubiquitin to be recognised.
This gives the recognition 20S lacks.

80
Q

What does the S stand for in 20S?

A

The Svedberg sedimentation coefficient which is used to characterise the behaviour of a particle type in ultracentrifugation.

81
Q

What is the function of Ubiquitin?

A

Serves as a marker for degradation.

82
Q

What is ubiquitin?

A

Small regulatory protein.

83
Q

How big is ubiquitin?

A

8.5kDa

84
Q

What is the process of ubiquination?

A

Single chains of Ub are added to the substrate protein.
Those chains are then recognised as a signal.

85
Q

What happens to the substrate after Ub is attached to it?

A

– Degradation
– Change in cellular location
– Change in protein activity

86
Q

What are E1 enzymes?

A

It activates ubiquitin (ATP-dependent reaction).

87
Q

What are E2 enzymes?

A

Ubiquitin-conjugating enzymes, they bind to activated ubiquitin.

88
Q

What are E3 enzymes?

A

Ubiquitin ligases, each enzyme has a specific substrate protein.

89
Q

Draw a rough sketch of the process of ubiquitination?

A
90
Q

Why are de-ubiquitinating enzymes (DUBs) important?

A

Because Ub isn’t degraded.

91
Q

What are De-ubiquitinating enzymes (DUBs)?

A

The majority are cysteine proteases.

92
Q

What are USPs?

A

Ubiquitin-specific protease family.

93
Q

What are UCHs?

A

Ubiquitin C-terminal hydrolases.

94
Q

What is function of DUBs?

A

Reverse the action of ubiquitination.
Recycling ubiquitin.

95
Q

What happens with Ub with ageing?

A

No change in ubiquitin levels or ubiquitin enzymes with age.

96
Q

What happens to the proteasome with age?

A

Some proteasomal components may decline with age.

97
Q

What happens when aggregated proteins contain ubiquitin?

A

Increases in the ageing retina.

98
Q

What is macroautophagy?

A

Considered to be a cell survival mechanism.

99
Q

What is macroautophagy controlled by?

A

ATG genes and phosphoinositide 3-kinase (PI3K).

100
Q

Why is basal autophagy?

A

It is the quality control for proteins and organelle.

101
Q

What happens to macroautophagy during ageing?

A

Oxidised and aggregated proteins accumulate in lysosomes.
Damaged mitochondria.

102
Q

What is the effect of reduced autophagy?

A

Increase in damaged protein
Increase in ROS
Increase in inflammation

103
Q

What is lipofuscin?

A

Lysosomal damage which is used as a marker for ageing.

104
Q

What are the steps of Chaperone-mediated autophagy?

A
  1. Recognition of substrates by hsc/chaperone cells in the cytosol.
  2. Binding of the substrate-chaperone complex to LAMP-2A monomer.
  3. Unfolding the substrate.
  4. LAMP-2a multimerized, substrate translocated, and degraded.
  5. LAMP-2A monomers degraded.
105
Q

What happens to chaperone-mediated autophagy with age?

A

A decline in LAMP-2A receptors with age and mutant proteins can block those present.

106
Q

Do autophagy and the UPS functionally interact with each other and how?

A

They regard each other in compensation.

107
Q

What is the Garbage catastrophe theory of ageing?

A

The imbalance between oxidative damage and renewal of biological structures may lead to a progressive loss of functionally effective elements and accumulation of waste products with age.

108
Q

What is a protein aggregate?

A
  • Change in structure.
  • Poor solubility.
  • Aberrant localisation
109
Q

What does the proteins ability to aggregate depend on?

A

The secondary structure
Stability of the tertiary structure
Degree of disorder

110
Q

What is the function of the aggresome?

A

Formation of inclusion bodies by active retrograde transport of misfolded proteins along microtubules.

111
Q

What determines protein structure?

A

DNA sequence

112
Q

What secondary structure would you expect in a protein that is prone to aggregate?

A

Beta sheets.

Biology Of Ageing Year2 (23 decks)

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