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BMS > Protein Degredation > Flashcards

Protein Degredation Flashcards

1
Q

Besides just mutated or erroneous proteins, the degradation of cellular proteins that are no longer required, and the elimination of certain regulatory proteins is essential for normal

A

Cellular function

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2
Q

The ubiquitin/proteasome pathway (UPP) is dependent on

A

Energy

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3
Q

in the UPP pathway, the targeted protein is marked for degredation by attachment to the protein

A

Ubiquitin

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4
Q

Degradation of the ubiquinated protein occurs in a compartmentalized protease called the

A

Proteasome

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5
Q

The most efficient way to terminate a biological effect is to degrade the protein that performs that

A

Function

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6
Q

Permits the removal of damaged proteins, facilitates growth and tissue remodeling, and offers a rapid response to stress and infection

A

Protein degradation

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7
Q

The breakdown of proteins that generates amino acids for use in new protein synthesis and intermediates for the synthesis of other metabolites

A

Proteolysis (protein turnover)

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8
Q

The proteolytic enzymes involved in specific and non-specific protein degradation share which two key features?

-saves intracellular proteins

A
  1. ) expressed as zymogens

2. ) compartmentalized

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9
Q

Compartmentalizing the proteolytic enzymes does what?

A

Spares other cellular proteins

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10
Q

Refers to the time it takes for a protein to lose 50% of activity

A

Functional half-life

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11
Q

The hydrolytic activities of the proteasome exist inside a chambered barrel that is assembled from a stack ofq

A

Four seven subunit protein rings

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12
Q

Before substrates enter the inner sanctum of the proteasome, they are first unfolded by an

A

ATP-dependent unfolding machine

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13
Q

Unlike digestive and lysosomal proteolysis, degradation by the proteasome is

A

Energy-dependent

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14
Q

Which three properties regulate proteolysis?

A
  1. ) Zymogen precursors
  2. ) Compartmentilization
  3. ) pH
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15
Q

Another restriction that ensures that some proteases are active only in the correct location is their strict requirement for

A

Low pH for optimal activity

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16
Q

A compartmentalized proteolytic organelle

A

Lysosome

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17
Q

A tumor suppressor protein that is degraded by the UPP

A

p53

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18
Q

Proteases that always degrade the same class of protein. The key feature is that the protein was not damaged, but it simply was no longer required by the cell

A

Specific degradation

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19
Q

A sporadic and unscheduled degradation of proteins, such as the dietary proteins, by proteases with a broad cleavage specificity

A

Non-specific Degredation

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20
Q

Since we want some proteins to only be active for a short amount of time, we could only express them when they are needed, or when they are not needed we could mark them for degradation with a

A

Post translational modification

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21
Q

A pathway for targeting proteins with a very high degree of specificity

A

The ubiquitin/proteasome system (UPS)

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22
Q

To mark them for degradation by the proteasome, substrates are post-translationally conjugated to a small protein called

A

Ubiquitin (Ub)

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23
Q

The most conserved protein known to man

-no known genetic mutations

A

Ubiquitin

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24
Q

Substrates are typically targeted by ubiquitin after a post-translational modification such as

A

Phosphorylation or hydroxylation

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25
Q

Substrate-specificity in the UPS is accomplished by forming unique combinations of targeting factors. The substrate-targeting factors are known as

A

Ub-conjugating enzymes (E2) and Ub-protein ligases (E3)

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26
Q

Refers to the distinct targeting complexes that can be assembled from this large set of proteins.

-Each unique E2/E3 complex is likely to have only one or a few substrates to which they attach Ub

A

Combinatorial Diversity

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27
Q

Has a highly compact structure (fist w/ extended thumb) and 7 lysine residues on the surface

-a highly reactive carboxy terminus is accessible

A

Ubiquitin

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28
Q

Ubiquitin is always expressed as a fusion protein (Ub’s in tandem, or fused to specific ribosomal proteins) and is inactive until it is

A

Hydrolyzed to mono-Ub

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29
Q

Ubiquitin has a compact structure with a reactive carboxy terminus that participates in all

A

Covalent interactions

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30
Q

The lysine residues on the surface of Ub can be ligated to additional

A

Ub’s

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31
Q

When multiple Ub’s are attached to a substrate in the form of a chain, it can form a high-affinity hydrophobic interaction with the

A

Proteasome

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32
Q

A single Ub does not bind the proteasome because the hydrophobic patch on its surface is not sufficient to form a

A

High-affinity interaction

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33
Q

Neighboring ubiquitins form intramolecular hydrophobic interactions that yield a highly compact multi-Ub chain with a large hydrophobic surface that forms a high-affinity interaction with the

A

Proteasome

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34
Q

A significant reason for expression Ub as a fusion protein is to block the

A

Reactive carboxy terminus

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35
Q

What are the three key enzymes that promote the attachment of ubiquitin to to proteolytic substrates?

A
  1. ) Ub activating enzyme (E1)
  2. ) Ub-conjugating enzyme (E2)
  3. ) Ub-protein ligase (E3)
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36
Q

Mediates the transfer of Ub from E1 to either E3 or substrate

A

E2

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37
Q

The Ub-protein ligase (E3) attaches the Ub to substrate via an

A

Isopeptide bond

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38
Q

The carboxy terminus of Ub is generated by proteolysis and ends with the covalent residues

A

RGG

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39
Q

Ub is released from the fusion protein following hydrolysis by

A

Ub-carboxy terminal hydrolases (UCH)

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40
Q

In the formation of a multi-Ub chain, a lysine residue in the first Ub becomes covalently linked to the carboxy-terminus of the second Ub by an

A

Isopeptide bond

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41
Q

The formation of the hydrophobic stripe, which is required to interact with the proteasome, requires a minimum of

A

4 linked Ubs

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42
Q

Ub contains 7 lysine residues. The resulting chain
of ubiquitins can target a substrate to the proteasome, if the linkage involves

-If it is attached to a different residue, the potential conformation and biological effect could be very different

A

Lysine-48

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43
Q

Free mono-Ub is activated in an ATP dependent reaction by an enzyme called

A

E1

44
Q

The bond between Ub and E1 is a

A

Thioester bond

45
Q

Ub is transferred from E1 to E2 and then to E3 in a

-Only the ubiquination of E1 requires ATP

A

Thioester cascade

46
Q

The difference between a peptide and an isopeptide bond is that while a peptide bond involves an α-amino group, an isopeptide bond involves an

A

ε-amino group

47
Q

Can cleave and release Ub from a substrate

A

Ub processing enzymes

48
Q

Activates the carboxy terminus of Ub, forms a noncovalent interaction with Ub-adenylate, and forms a thioester bond with Ub

A

E1

49
Q

Receives Ub via a trans esterification reaction from E1

-Associate with E3 enzymes

A

E2

50
Q

What are the two types of E3 enzymes?

A
  1. ) Ring E3’s

2. ) Hect E3’s

51
Q

Differ from RING E3’s because they have the ability to form a thioester bond with Ub and so they don’t have to bind E2

A

Hect E3’s

52
Q

Can cleave the isopeptide bonds that link Ub to protein substrates, and Ub that is assembled into multiubiquitin chains

A

Ub-processing proteases (Ubp)

53
Q

The bond between Ub and substrate is an

A

Isopeptide bond

54
Q

Following interaction with the proteasome, multi-ubiquinated proteins are de-ubiquinated and unfolded. This reaction is coupled, since failure to remove the Ub results in

A

Inhibition of degradation

55
Q

The formation of a hydrophobic stripe is the primary determinant for promoting interaction with the

A

Proteasome

56
Q

Important for DNA repair, but does not promote degradation by the proteasome

A

Multi-ubiquitination through lysine 63

57
Q

Short chains assembled through Lysine 63 promote translocation of plasma membrane proteins to the

A

Lysosome for degradation

58
Q

The recognition of the substrate and the degradation of the substrate are spatially and temporally separable events in the

A

UPS

59
Q

A multisubunit and multicatalytic chambered protease in which substrate binding and substrate degradation are carried out by specialized sub-complexes

A

Proteasome

60
Q

In the Proteasome, which complex:

  1. ) Recognizes the substrate
  2. ) Degrades the substrate
A
  1. ) 19S complex

2. ) 20S complex

61
Q

Contains three distinct proteolytic activities:

  1. ) Chymotrypsin-like
  2. ) Trypsin-like
  3. ) PGPH
A

20S subunit (The catalytic core particle)

62
Q

A barrel -like structure generated by a stack of four rings (α on top and bottom, 2β in middle)

A

20S subunit

63
Q

Identical, and contain the catalytic subunits

A

β -subunits

64
Q

Form a densely packed mat of overlapping loops that prevent entry into the 20S catalytic chamber

A

α-subunits

65
Q

Three proteins in the β-subunits have the hydrolytic activity and exist as

A

Zymogens

66
Q

Cellular proteins are not hydrolyzed unless they are first recognized by the

-unfolds and translocates the proteins (requires ATP)

A

19S subunit

67
Q

The α and β rings dimerize. One α/β dimer associates with another α/β dimer in a reaction that is mediated by a chaperone called

A

Ump1 (degraded upon activation of proteolytic sites)

68
Q

One of the key properties of the 19S particle is that it contains receptors that enabled it to only bind to particles containing

-Prevents unmarked proteins from being degraded

A

Multi-Ub chains

69
Q

The affinity between the proteasome and multi-Ub chains increases from

A

4Ub to 8UB (but not 8Ub to 16Ub)

70
Q

Associated with deubiquitinating enzymes that can dismantle multi-Ub chains from substrates

A

19S particle

71
Q

The 19S particle contains a ring of 6 non-redundant ATPases that

A

Unfold substrates to be degraded

72
Q

Regulates the axial channel and binds regulatory proteins

A

19S particle

73
Q

Two 19S particles attach to each end of the 20S complex to form a dumbbell-shaped complex called the

A

26S proteasome

74
Q

The efficiency of multi-step events is often improved by physically restricting the path of the reactants and products, through a mechanism termed

A

Channeling

75
Q

The specificity of the proteasome is conferred entirely by the

A

19S subunit

76
Q

A DNA repair protein that binds XPC in the nucleotide excision repair pathway

-mutations can lead to XP

A

Rad23

77
Q

Ub proteins do not bind the 20S particle. Instead, they bind the

A

19S regulatory particle

78
Q

Immune cells express a specialized proteasome, which generates fragments of proteins that can be expressed on MHC class I and II molecules, forming antigens. These are called

A

Immunoproteasome

79
Q

In the immunoproteasome, the 19S particle is replaced with

-contributes to recognition of distinct types of substrates

A

PA28

80
Q

In the immunoproteasome, the three beta with the hydrolytic activity are

A

Replaced

81
Q

Generates peptides of the correct length and hydrophobicity to be placed in a cleft present in the extracellular domain of MHC molecules.

A

Immunoproteasomes altered cleavage properties

82
Q

What are the four mechanisms of regulation from protein degradation?

A
  1. ) Allosteric control
  2. ( Role of ATP hydolysis
  3. ) Recycling and peptide release
  4. ) Combinatorial diversity
83
Q

The process of protein hydrolysis by the proteasome has been termed

A

‘bite-and-chew’

84
Q

Polypeptide chains that enter the 20S chamber are first attacked by the

-generates large fragments

A

Chymotryptic activity

85
Q

High concentration of the large chymotryptic fragments allosterically inhibits further translocation of the polypeptide into the

A

Catalytic chamber

86
Q

During this allosteric inhibition, what begins to chew up the chymotryptic fragments?

A

Trypsin and PGPH

87
Q

The process whereby the 26S proteasome dissociates into the 19S and 20S subunits after each cycle of protein degradation, releasing the degradation products

A

‘chew-and-spew’

88
Q

p53 tummor suppressor is degraded by the

-prevents cells from exercising proper checkpoint control during the cell cycle

A

Human Papilloma Virus (HPV) E6 protein

89
Q

The variant of HPV that causes cancer does so because it expresses an altered viral E6 protein that can alter the substrate targeting properties of

A

E3

90
Q

E6AP is termed a

A

Hect E3 ligase

91
Q

Form a thioester linkage with Ub, and also interacts with an E2 enzyme

A

Hect E3 ligase

92
Q

Constitutively degraded in normal oxygenated tissues

A

Hif1 transcription factor

93
Q

Required for activating expression of a number of genes that respond to hypoxia

-degraded in normal cells becayse the tissues are well oxygenated

A

Hif1

94
Q

Mutations in the F-box protein of the SCF E3 Ligase (a RING E3 ligase) can prevent

A

Hif1 degradation

95
Q

A major fraction of solid sarcomas in the kidney and pancreas are due to the stabilization of

A

Hif1 due to F-box substitution

96
Q

The inflammatory response defines a cellular reaction to insult and injury. The central player in this response is the transcription factor

-initially synthesized as a large precursor

A

NFκB

97
Q

The first role for the proteasome is to process NFκB. The resulting processed and mature polypeptide
(p65) assembles into a dimer with another protein p50/p65, to form the active

A

NFκB transcription factor

98
Q

However, p50/p65 can be sequestered in the cytoplasm by the inhibitory molecule

A

IκBα

99
Q

Cell injury results in the activation of a kinase, called the Iκ kinase (IκK), in a mechanism that requires a functional ubiquitin-conjugation pathway. The activated IκK phosphorylates IκBα, which prevents it from

A

Sequestering p50/p65

100
Q

Specific E2/E3 factors recognize phosphorylated IκBα and promote its degradation by the

A

Proteasome

101
Q

Specific E2/E3 factors recognize phosphorylated IκBα and promote its degradation by the proteasome. This results in the release of p50/p65, which can now enter the nucleus and activate transcription of

A

Stress-responsive genes

102
Q

Required for activating a DNA damage response

A

Proteasome

103
Q

A proteasome subunit that can bind multiubiquitin chains

A

Ataxin-3

104
Q

If ataxin-3 undergoes trinucleotide repeats, the result is

A

Machodo-Joseph disease

105
Q

Failure to degrade hypoxia inducible transcription factor Hif1 causes

A

Von hippel-Lindau (VHL) syndrome

106
Q

Under normoxia conditions, Hif1 is targeted by

-requires Rbx1

A

VHL

BMS (62 decks)

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