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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
What is the function of chaperones?
Chaperones prevent misfolded or incompletely assembled proteins from exiting the ER.
26
What is the unfolded protein response?
Maintains the balance of protein folding in the endoplasmic reticulum.
27
What is the unfolded protein response caused by?
Caused by an increase in misfolded proteins in the ER.
28
What reversible covalent modifications affect protein function?
Phosphorylation Acetylation Glycosylation Ubiquitination
29
Why do undesirable protein modification occur?
Due to reactive oxygen or reactive nitrogen species.
30
What are the 2 major classes of oxidative damage within protein?
Conformational Covalent.
31
What is conformational damage?
The unfolding of proteins.
32
What is conformational damage caused by?
Heating, attack by free radicals, chemicals, pH changes.
33
What is covalent damage?
A chemical change in the amino acids that make up the protein.
34
What is covalent damage caused by?
Spontaneous or may be induced and/or accelerated by environmental factors.
35
When does the AGEs pathway begin?
When proteins are exposed to sugar.
36
What is the basic process of the AGEs pathway?
Activates a stress response which leads to the chemical attachment of sugar to amino acids.
37
How may protein homeostasis fail?
Every step of this process can go wrong.
38
Draw the process of protein synthesis.
39
What do you think the effect of DNA damage will be on protein synthesis?
Incorrect protein is synthesised.
40
What does the repair of protein damage depends on?
The ability to recognise a change in a protein as abnormal. A means of reversing the change.
41
Why do unsuccessful proteins need to be removed?
To prevent cellular dysfunction and protein aggregation.
42
What are molecular chaperones?
Known as heat shock proteins, they are in cells.
43
What is the function of molecular chaperones?
Folding/refolding Prevent protein aggregation Assist in targeting proteins for degradation
44
What is the function of small heat shock proteins?
prevents protein aggregation
45
What is the function of molecular chaperone Hsp40?
Prevents protein aggregation. Interacts with Hsp70
46
What is the function of molecular chaperone Hsp60?
Protein folding. Anti-apoptotic.
47
What is the function of molecular chaperone Hsp70?
Protein folding/refolding. Stress response. Protein degradation.
48
What is the function of molecular chaperone Hsp90?
Protein folding/refolding. Stress response. Protein degradation. Interacts with steroid receptors.
49
What is the function of heat shock factor 1 (HSF1?
Regulates the transcription of heat shock genes.
50
What is HSF1 usually present as?
Inactive monomers.
51
What happens to HSF1 in stressed cells?
Forms homotrimers.
52
What then happens with the trimers HSF1 forms under stress conditions?
Trimers are activated by phosphorylation Translocated to the nucleus. Bind to the heat shock element (HSE).
53
What happens when trimers bind to the heat shock element (HSE)?
This results in the synthesis of heat shock proteins.
54
What constitutes the negative feedback mechanisms during HSF1-mediated heat shock response?
Triggers the unfolding of proteins. Misfolded proteins bind to displace chaperones from HSF1 and that displacement allows the proteins to trimerize.
55
How do chaperones prevent the aggregation of proteins?
Chaperones bind to the hydrophobic region to prevent misfolding proteins from “sticking” together.
56
Why do proteins aggregate?
Misfolded proteins expose hydrophobic regions which tend to “stick” together.
57
How are chaperones involved in protein degradation?
* Chaperone-mediated autophagy * Target some proteins for degradation via ubiquitin-proteasome system
58
What kinds of proteins do Hsp70 an Hsp90 interact with?
Nuclear hormone receptors Protein kinases Cell cycle regulators Cell death regulators
59
Why does the heat shock response decline with ageing?
Possibly due to decline in HSF1 transcriptional response with age.
60
What is the chaperone overload hypothesis?
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
What are the 5 protein degardation pathways?
Macroautophagy Microautophagy Chaperone-mediated autophagy Ubiquination Proteasome
62
What is macroautophagy?
Release cell which is degraded by lysosome.
63
What is microautophagy?
Pinch into lysosome.
64
What is chaperone-mediated autophagy?
More of a transport pathway.
65
What are proteasome?
A large protein complex.
66
Where is the proteasome?
Located in the nucleus and cytoplasm.
67
What is the function of proteasomes?
proteolysis.
68
What is proteolysis?
A chemical reaction that breaks peptide bonds.
69
What is the product of proteolysis?
Yields peptides about 7-8 amino acids long.
70
What happens to the product of proteolysis?
Further degraded into amino acids.
71
What is the function of the proteasomal pathway?
Regulates concentration of particular proteins and removes misfolded proteins.
72
What is the function of the alpha subunit of the 20s proteasome?
Maintain a gate through which substrates enter.
73
What is the function of the beta subunit of the 20s proteasome?
Maintain a gate through which substrates enter.
74
What is the function of 20S proteasome?
Protein spins through the middle.
75
What is the requirement for 20S proteasome interactions with proteins?
Proteins must be unfolded.
76
Is the function of 20S proteasome specific?
No. There is no recognition machinery present.
77
What are 26S proteasomes?
The alpha subunits bind to the regulatory cap of the 19S subtype.
78
What is the function of the 19S proteasome subtype?
The 19S cap contains ATPase active sites and ubiquitin-binding sites.
79
What is the importance of the 20S and 19S subtypes binding to form 26S?
Substates must be tagged by ubiquitin to be recognised. This gives the recognition 20S lacks.
80
What does the S stand for in 20S?
The Svedberg sedimentation coefficient which is used to characterise the behaviour of a particle type in ultracentrifugation.
81
What is the function of Ubiquitin?
Serves as a marker for degradation.
82
What is ubiquitin?
Small regulatory protein.
83
How big is ubiquitin?
8.5kDa
84
What is the process of ubiquination?
Single chains of Ub are added to the substrate protein. Those chains are then recognised as a signal.
85
What happens to the substrate after Ub is attached to it?
– Degradation – Change in cellular location – Change in protein activity
86
What are E1 enzymes?
It activates ubiquitin (ATP-dependent reaction).
87
What are E2 enzymes?
Ubiquitin-conjugating enzymes, they bind to activated ubiquitin.
88
What are E3 enzymes?
Ubiquitin ligases, each enzyme has a specific substrate protein.
89
Draw a rough sketch of the process of ubiquitination?
90
Why are de-ubiquitinating enzymes (DUBs) important?
Because Ub isn't degraded.
91
What are De-ubiquitinating enzymes (DUBs)?
The majority are cysteine proteases.
92
What are USPs?
Ubiquitin-specific protease family.
93
What are UCHs?
Ubiquitin C-terminal hydrolases.
94
What is function of DUBs?
Reverse the action of ubiquitination. Recycling ubiquitin.
95
What happens with Ub with ageing?
No change in ubiquitin levels or ubiquitin enzymes with age.
96
What happens to the proteasome with age?
Some proteasomal components may decline with age.
97
What happens when aggregated proteins contain ubiquitin?
Increases in the ageing retina.
98
What is macroautophagy?
Considered to be a cell survival mechanism.
99
What is macroautophagy controlled by?
ATG genes and phosphoinositide 3-kinase (PI3K).
100
Why is basal autophagy?
It is the quality control for proteins and organelle.
101
What happens to macroautophagy during ageing?
Oxidised and aggregated proteins accumulate in lysosomes. Damaged mitochondria.
102
What is the effect of reduced autophagy?
Increase in damaged protein Increase in ROS Increase in inflammation
103
What is lipofuscin?
Lysosomal damage which is used as a marker for ageing.
104
What are the steps of Chaperone-mediated autophagy?
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
What happens to chaperone-mediated autophagy with age?
A decline in LAMP-2A receptors with age and mutant proteins can block those present.
106
Do autophagy and the UPS functionally interact with each other and how?
They regard each other in compensation.
107
What is the Garbage catastrophe theory of ageing?
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
What is a protein aggregate?
* Change in structure. * Poor solubility. * Aberrant localisation
109
What does the proteins ability to aggregate depend on?
The secondary structure Stability of the tertiary structure Degree of disorder
110
What is the function of the aggresome?
Formation of inclusion bodies by active retrograde transport of misfolded proteins along microtubules.
111
What determines protein structure?
DNA sequence
112
What secondary structure would you expect in a protein that is prone to aggregate?
Beta sheets.

Biology Of Ageing Year2 (23 decks)

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