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Biochemistry > Exam 2 Lecture 18 > Flashcards

Exam 2 Lecture 18 Flashcards

1
Q

Where does transcription take place?

A

In the nucleus

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2
Q

What happens during translation?

A

mRNA is translated into amino acid sequences

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3
Q

What are the 4 major steps after DNA replication?

A
  1. transcription
  2. translation
  3. protein folding → where a lot of things can go wrong
  4. protein processing, subcellular targeting, and posttranslational modifications (PTMs) → can be permanent or transient
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4
Q

What do molecular chaperones do?

A

They assist in the covalent folding or unfolding of proteins and they can also play a role in the assembly or disassembly of other macromolecular structures such as protein oligomerization and protein aggregates

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5
Q

What are some examples of molecular chaperones?

A
  1. HSP60 - GroEL/GroES complex in E. coli
  2. HSP70 - DnaK in E. coli
  3. HSP90 - HtpG in E. coli
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6
Q

What are the most abundant kind of molecular chaperones?

A

heat shock proteins (HSPs)

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7
Q

What is aggregation?

A

Partially folded or misfolded proteins in which there are exposure of hydrophobic residues and unstructured polypeptide backbone

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8
Q

Aggregation is driven by what?

A

Hydrophobic forces → results in amorphous structures

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9
Q

Formation of aggregates is restricted by what?

A

Chaperone machinery (but more widespread under stress or when protein quality control fails)

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10
Q

Fibrillar aggregates are commonly accompanies by the formation of what?

A

Soluble oligomeric states → have key roles in diseases of aberrant folding

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11
Q

Once it is folding or an aggregate forms, why are molecular chaperones unable to do anything?

A

It takes a lot of energy for it to disassemble or go back to being partially or fully unfolded

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12
Q

What type of posttranslational modifications involves a recognition signal?

A

Glycosylation

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13
Q

What type of posttranslational modifications involve histone/DNA modifications?

A

Methylation and acetylation

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14
Q

What type of posttranslational modifications involve transient activity regulation?

A

Phosphorylation

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15
Q

What type of posttranslational modifications involve protein degradation?

A

Ubiquitination → if a protein gets ubiquitinated, it doesn’t necessarily get degraded

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16
Q

Posttranslational modifications add what to the proteome?

A

Complexity

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17
Q

What is the mechanism and function for the different PTMs?

A
  1. proteolytic processing and conformational change (cleaving protein) → activation
  2. PTM-dependent proteolysis (attaching ubiquitin chain on protein for the recognition to degrade) → degradation
  3. PTM-dependent recognition (adding a phosphate group) → activation, interaction, localization, and secretion
  4. Reversible multi-site PTMs (multiple PTMs on the protein) → dynamic regulation or modulation of protein activity and protein-protein and protein-DNA interactions
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17
Q

What is the mechanism and function for the different PTMs?

A
  1. proteolytic processing and conformational change (cleaving protein) → activation
  2. PTM-dependent proteolysis (attaching ubiquitin chain on protein for the recognition to degrade) → degradation
  3. PTM-dependent recognition (adding a phosphate group) → activation, interaction, localization, and secretion
  4. Reversible multi-site PTMs (multiple PTMs on the protein) → dynamic regulation or modulation of protein activity and protein-protein and protein-DNA interactions
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18
Q

If degradation increases, what happens to protein levels?

A

decreases

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19
Q

If degradation decreases, what happens to protein levels?

A

Increases

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20
Q

What is the purpose of protein degradation?

A
  1. Misfolded proteins
  2. Dietary proteins to supplement essential amino acids (must come from the diet)
  3. Regulation of cellular processes (transcription, signal transduction)
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21
Q

What are threats to cell function?

A

Protein misfolding, aggregation, and other types of damage

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22
Q

What is the proteostasis network?

A

It monitors proteins throughout their life cycle (synthesis, folding, refolding, transport, and degradation)

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23
Q

Molecular chaperones facilitate the folding of what types of proteins?

A

Both preexisting and developing proteins

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24
What processes can be controlled by protein degradation?
1. blood clotting 2. processing pro-forms of proteins 3. cell matrix proteolysis for cell movement/growth 4. replication and transcription → once licensing factors are released (Cdc6 and Cdt1), can degrade
25
What does protein degradation get rid of?
1. misfolded or unfolded proteins and protein fragments (cells don't need anymore) 2. damaged proteins: oxidation, proteolysis, translation errors 3. large aggregates that disrupt normal function, kill the cell, and can cause disease (Alzheimer's, Parkinson's, Huntington's, ALS)
26
What are the 3 routes of protein degradation?
1. proteasomal degradation 2. lysosomal digestion 3. autophagy → all recognize proteins in different ways
27
What are the 5 types of protein degradation processes?
1. ubiquitin-proteasome proteolysis: proteins that are targeted for degradation as part as cellular regulation 2. ERAD: misfolded protein in the ER lumen is translocated to the cytoplasm by chaperones where it enters the ubiquitin-proteasome pathway 3. lysosomal digestion: membrane bound organelles containing proteases that can degrade exogenous proteins or aged/damaged organelles 4. autophagy: maintains normal cellular functioning by protein degradation and turnover of damaged organelles → turned up during stress 5. apoptosis: part of programmed cell death is the activation of caspases (cytosolic proteases)
28
What is the difference between lysosomal digestion and autophagy between ubiquitin-proteasome proteolysis?
Lysosomal digestion and autophagy recognize proteins that we don't need anymore (like damaged or worn out organelles) but ubiquitin-proteasome proteolysis is more fine tuned and recognizes proteins that have structures that get targeted.
29
Who won the Nobel Prize in Chemistry in 2004?
Ciechanover, Hershko, and Rose for the discovery of ubiquitin-mediated protein degradation
30
Who won the Nobel Prize in Physiology or Medicine in 2016?
Ohsumi for his discoveries of mechanisms for autophagy.
31
What does autophagy mean?
Can degrade proteins/organelles that come from outside the cell or damaged organelles that are resident in the cell → "self eating"
32
What is the endosomal pathway?
Uptake and recycling of nutrients and transmembrane receptors, proteins get degraded in lysosomes, merges with the autophagic pathway
33
What is the mechanism of autophagy?
a double membraned structure forms by vesicle nucleation around cytoplasmic contents and becomes an autophagosome → fusion of autophagosome with the lysosome produces the autolysosome (also double membraned) → cytoplasmic substrates are degraded → degradation products can be recycled
34
Where is A𝛽 generated and where is it degraded?
It is generated in autophagosomes and degraded in the autophagosome → but keeps accumulating since it has not fused with the lysosome yet
35
What happens if lysosomal digestion is defective or impaired?
Can lead to increased A𝛽 oligomers which is bad → the over formation of autophagosomes (too much autophagy) can lead to Alzheimer's disease
36
How does the ubiquitin system recognize proteins?
It recognizes proteins based on specific sequences (part of normal cell function)
37
Why is the ubiquitin-proteasomal system (UPS) important?
It is important for cell cycle control, cell differentiation, and stress responses
38
What is the first step in covalently modifying a lysine on a degraded protein?
E1 (activating): ATP hydrolysis to add ubiquitin to a cysteine (uses ATP)
39
What is the second step in covalently modifying a lysine on a degraded protein?
E2 (conjugating): receives ubiquitin on a cysteine → ubiquitin is now activated
40
What is the third step in covalently modifying a lysine on a degraded protein?
E3 (ligase): have specific recognition of protein to be degraded, catalyzes transfer from E2 to substrate, need at least 4 ubiquitin molecules
41
How many E1, E2, and E3 do humans have?
E1: 9 E2: 25 E3: 500-1000
42
What role does the ubiquitin chain serve?
Serves as recognition for degradation by the proteasome (attached to the lysine) → ubiquitin can also be a posttranslational modification in signal transduction
43
What is the 20S proteasome?
It is a core complex that consists of rings made up of 𝛼 and 𝛽-subunits and has a channel in the middle of the complex
44
What can the 20S proteasome do?
Able to degrade short unfolded non-ubiquitinated peptides
45
What is the 19S cap?
Is a regulatory cap that consists of multiple subunits
46
What is the 19S cap responsible for?
Deubiquitination, protein unfolding, and "feeding the proteasome" → recognizes proteins and unfolds them so that a single chain of amino acids can go through the core → chain gets cleaved in the core and can then be further degraded
47
What 3 activities does the proteasome possess?
1. trypsin activity 2. caspase activity 3. chymotrypsin activity
48
What does the proteasome consist of?
20S proteasome + 2 19S cap = 26S proteasome
49
Oxidized proteins are what?
Unfolded
50
What happens under oxidative stress?
1. ECM29 sequesters 19S cap 2. HSP70 acts as a holdase to keep 19S sequestered 3. More 20S is available to degrade oxidized proteins
51
What is the key difference between autophagy/lysosome and UPS?
Target specificity
52
What is a dregon?
A recognition sequence of structure for an E3 ligase
53
What are 3 examples of dregons?
1. N-end rule: the N terminal sequence of a protein is recognized in which the second residue can be 'destabilized" → destabilizing residues include Arg, Leu, and Phe 2. PEST sequences: rich in proline (P), glutamic acid (E), serine (S), and threonine (T) 3. Posttranslational modification: phosphorylation can create or destroy a degron
54
Unregulated cell division requires what?
Increased protein synthesis → increased synthesis is typical for numerous proteins in metabolism and growth processes
55
Cancer cells are susceptible to what kind of drugs?
Drugs that disrupt proteostasis (inhibit protein degradation)
56
Cancer cells also depend on what?
Proteolysis that saturates the protein degradation process → cancer cells more sensitive to inhibitors of proteolysis
57
What drugs target HSP90 (a chaperone inhibitor)?
Geldanamycin and Gamitrinib → increases misfolded protein stress
58
What is Bortezomib?
It is the first proteasome inhibitor to be used in humans for blood cancers such as multiple myeloma and mantle cell lymphoma
59
What is the significance of MDM2?
It is an E3 ligase which means that when p53 is bound to MDM2, p53 is inactive (or gets degraded)
60
What is the idea behind induced protein degradation using proteolysis targeting chimera (PROTAC)?
Have a known ligand that binds to E3 ligand and couple to a ligand that will recognize a specific protein to degrade
61
What is an example of induced protein degradation using proteolysis-targeting chimera (PROTAC)?
Thalidomide: anti-cancer, graft-versus-host, binds to the E3 ligase Cereblon (CRBN) BRD4 ligand: contains 2 bromodomains that recognize acetylated lysine residues, required for expression of myc and other tumor activating oncogenes in hematologic cancers
62
What disease states are attributed to accumulation of aggregated proteins?
Alzheimer's disease (A𝛽) and Huntington's disease
63
How does the ubiquitin-proteasome system work together to degrade proteins in a targeted fashion?
- E1, E2, and E3 attaches ubiquitin chains to lysine residues on target proteins - E3 ligases confer specificity and recognizes dregons on their substrates

Biochemistry (18 decks)

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