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Cell Biology > Degradation and Lysosome > Flashcards

Degradation and Lysosome Flashcards

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1
Q

why do proteins need to be degraded?

A
  • incomplete or missense proteins
  • damaged proteins
  • unwanted proteins
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2
Q

what are incomplete/missense proteins?

A
  • cellular errors
  • proteins with disruptive mutations
  • premature termination
  • proteolytic cleavage
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3
Q

what is post synthetic damage?

A
  • misfolded proteins
  • protein ageing
  • denaturation
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4
Q

what are unwanted proteins?

A
  • inactive or ‘used’ proteins
  • free subunits or multimeric complexes
  • other proteins made in excess
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5
Q

what are the two sites for degradation?

A
  • Lysosome

- Proteasome

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6
Q

what is degraded in the proteasome?

A

soluble proteins (in the cytoplasm)

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7
Q

what is degraded in the lysosome?

A

soluble proteins/organelles (autophagy)/pathogens/membrane

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8
Q

what is the lysosome?

A
  • membrane bound organelle
  • contains 63 acidic hydrolases
  • capable of degrade DNA, RNA, protein, carbohydrate, lipid
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9
Q

what is common to the proteasome and lysosome?

A

ubiquitin - which targets protein for degradation

- a protein will become ubiquinated and is then sent to the proteasome or lysosome

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10
Q

what is autophagy?

A
  • when you eat yourself
  • some material that is taken up for autophagy is ubiquinated
  • autophagosome circularises the material
  • devilvered to the lysosome
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11
Q

what is ubiquitin?

A
  • 76 amino acid polypeptide that labels proteins
  • attached by C terminus to tag the protein onto lysine residues
  • very common in cells
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12
Q

how is ubiquitin added?

A

ubiquitin conjugating enzymes

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13
Q

what is E1?

A

ubiquitin activating enzyme: uses ATP to activate the ubiquitin
- passed from E1 to E2

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14
Q

what is E2?

A
  • ubiquitin conjugating enzymes: passes the ubiquitin via E3 (ubiquitin ligase) to the substrate
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15
Q

what is E3?

A
  • has a ring domain = ubiquitin is passed directly from E2 to substrate
  • has a hect domain = ubiquitin is passed from E2 to the E3 to the substrate
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16
Q

what does ubiquitin attach to?

A

lysine residues

- ubquitin itself has lysine residues so ubiquitin can be added to ubiquitin

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17
Q

what is mono ubiquitin?

A

one ubiquitin

  • one can be added to each lysine
  • so can get multiple mono ubiquination
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18
Q

what is poly ubiquitin?

A
  • ubiquitin in a chain

- ubiquitin itself can be ubiquinated

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19
Q

what does ubiquination determine?

A
  • produces different structures which determines where and how its degraded
  • cell recognises the differences
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20
Q

is ubiquitin reversible?

A

yes

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21
Q

what are DUBs?

A
  • de-ubiquitnases
  • ubiquitin is removed and recycled
  • not generally degraded
  • can save a protein from degradation with a DUB
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22
Q

what happens when you degraded the protein?

A

cell wants to use the Ub again, so its removed just before degradation
-requires DUB

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23
Q

what other signal can Ub provide?

A
  • can have a non-degradation signal
  • protein editing
  • remove the signal
  • requires DUB
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24
Q

where are ubiquitin synthesized and processed?

A
  • synthesized on cystolic ribosomes

- rapidly processed into mature ubiquitin by DUBs

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25
Q

what is ubiquitin protein targeting?

A
  • different Ub conformations will give a molecular tag

- enables Ub binding proteins to target the protein for degradation

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26
Q

how are proteins targeted to the proteasome?

A
  • RPN10 and RPNB

- Shuttling receptors

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27
Q

what are RPN10 and RPNB?

A
  • intrinsic receptors
  • these are proteasomal proteins
  • directly bind Ub cargo
  • have Ub bidning domains
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28
Q

what are shuttling receptors?

A
  • domains to the proteasome
  • they have domains that bind Ub
  • bring proteins to the proteasome
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29
Q

what are the majority of substrates for the proteasome?

A
  • polyubiquinate (lys48)
  • traditionally 4xlys48 are the minimal targetting motif
  • LysII, Lys63 and mono ubiquitin epitopes can also be potential substrate
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30
Q

what are the target proteins in degradation via the proteasome?

A
  • fed into the cap proteins
  • denatured
  • feed through proteolytic core
  • short peptides then released
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31
Q

what are unfolding proteins?

A
  • AAA_ATPase ‘cap’ proteins unfold proteins
  • allows access to the proteolytic core
  • hydrolysing ATP to unfold
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32
Q

what is an example of targetting proteins to the proteasome?

A
  • tumour suppressor protein p53
  • gene transcription of MDM2 and MDMx
  • MDM2 –> E3 Ub ligase
  • p53 gets degraded in the proteasome
  • if you have less p53 you have less MDM2 which gives less degradation so p53 increases
  • MDMX works in a similar loop
  • auto inhibitory loop
  • cell can regulate the levels of p53
  • polyubuitination can cause targeting to the proteasome
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33
Q

what is the function of the lysosome?

A

degradation, autophagy, phagocytosis, disease

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34
Q

what is EGF receptor degradation?

A
  • receptor mediated andocytosis and receptor binds ligand
  • conformational change and phosphorylation
  • receptor is ubiquinated
  • in the early endosome you can still get signalling from this active receptor bound to ligand
  • need to internalise the receptor so it can be degraded
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35
Q

what do you need to totally degrade a receptor?

A

-need to have all parts of the receptor available to the lysosomal hydrolases

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36
Q

what happens if the receptor isnt internalised when the endosome and lysosome fuse?

A

only degrades part of the protein

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37
Q

what is a MVB?

A
  • a multivesicular body (a late endosome)
  • invagination of the endosome surface
  • end up with a vesicle inside the endosome itself
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38
Q

what happens when the late endosome and the lysosome fuse?

A

they can degrade absolutely everything and have stopped the signalling

39
Q

how do you get internalisation of the limiting membrane?

A
  • endosomal sorting complexes required for transport (ESCRT)

- proteins recognise membrane bound ubiquinated cargo and aids in their sorting into MVBs

40
Q

what is the role of ESCRTs?

A
  • Ub causes the binding of the different ESCRTs
  • activation of the ESCRT complex proteins binds to Ub cargo causing membrane invagination and the cargo to be internalised
41
Q

what does autophagy mean?

A
  • process of self-cannibalisation
  • cells capture their own cytoplasm and organelles and deliver them to the lysosome for nutrient release
  • selective autophage often caputres ubiquinated cargo
42
Q

what is autophagy a response to?

A

nutrient deprivation

- start eating ourselves for energy

43
Q

what is the process of autophagy?

A
  • proteins and carbohydrates in the cytoplas,
  • double membrane surrounds the cytoplasm
  • forms the autophagosome
  • nucleation and extension
  • closure
  • fusion with lysosomes
  • digestion
44
Q

what is macro autophagy?

A

PAS - phagophore - autophagosome - autolysosome

45
Q

mitophagy?

A

eating mitochondria

46
Q

what is aggrephagy?

A

protein aggregate

47
Q

what is pexophagy?

A

peroxisome

48
Q

what does autophagy regulate?

A

energy homeostasis

49
Q

what are the initiators of autophagy?

A

stagnantion, ammonia stress, damage, developmental cues

- material is degraded to the building blocks to regulate energy

50
Q

what are the consequences of impaired autophagy?

A
  • lack of nutrients
  • aggregate formation
  • immune activation
  • ROS accumulation
  • chronic infection
51
Q

what happens if you dont have mitophagy?

A
  • can remove damaged mitochondria
  • get an increase in reactive oxygen species
  • creates oxidative damage
52
Q

what can not being able to remove aggregates lead to?

A

neurodegenerative disease

53
Q

where can you find apoptosis?

A
  • cytotoxic T cells (cause killing)
  • during development
  • removal of damaged cells
  • tissue homeostasis
  • elimination of pre-maligmant cells eg p53 pathway
  • skin cells (always renewing)
  • outer cells of eyes (renewal)
54
Q

what is apoptosis?

A

regulated and rpogrammed cell death

- a controlled non-inflammatory event

55
Q

what is necrosis?

A
  • cell death following injury and results in inflammation
  • contents of the cell bursts out
  • body recognises that the cell contents shouldnt be out of the cell
56
Q

what are the different processes of apoptosis?

A
  • nuclear fragmentation
  • cell fragments
  • apoptotic body
  • phagocytosis of the apoptotic bodies
57
Q

what does apoptosis depended on?

A

intracellular proteolytic cascade that is mediated by caspases

58
Q

what are the 3 types of caspases?

A
  • intiators
  • executioners
  • inflammatory
59
Q

what are the properties of initiators capsase?

A
  • caspase 8,9
  • have a large and a small subunit (protease domain)
  • exists as an inactive domain
  • when they bind/get a signal it causes the inactive monomers to dimerise
  • have proteolytic activity (cleave each other)
  • creates a conformational change and the protein folds up
  • becomes an active caspase
  • they go on to cleave the executioner caspases
60
Q

what are executioner caspases?

A
  • also have proteolytic activity
  • cleave substrates inside the cell eg DNA and the cytoskeleton
  • induces apoptosis
61
Q

what is the structure of caspases?

A
  • adaptor-binding domain
  • 2 cleavage sites
  • protease subunits (large and small)
62
Q

what are caspases 8 and 10?

A

extrinsic pathway (have a Ded domain)

63
Q

what are caspses 9 and 2?

A

intrinsic pathway (have a Card domain)

64
Q

what do 8, 10, 9 and 2 caspases cleave?

A

the executioner caspases 3,6 and 7

65
Q

what are caspases activated by?

A
  • dimerization (initiators)

- proteolysis (effectors)

66
Q

what happens when executioners are activated?

A
  • apoptosis is virtually guaranteed
  • only way to stop it is to digest caspases
  • happens at the end of apoptosis
67
Q

what is CAD?

A

an endonuclease

68
Q

how is DNA fragmented?

A
  • inactive CAD has an inhibitor (iCAD) bound to it (in normal cells)
  • an executioner caspase cleaves the inhibitor releasing the CAD
  • endonuclease can fragment the DNA
  • CAD cleaves DNA between nucleosomes
69
Q

How do caspases cause amplification?

A
  • caspase activation leads to a caspase cascade which amplifies to apoptotic signal
  • caspases cleave nuclear and cytoskeletal proteins
  • caspases cleave and activate gelsolin including actin severing
70
Q

what is the result of amplification?

A

nuclear fragmentation, disruption of the cytoskeleton, membrane blebbing and cell fragmentation

71
Q

what is procaspase?

A

inactive form

72
Q

what are the two pathways that lead to degradation?

A

intrinsic and extrinsic pathway

73
Q

what is the extrinsic pathway?

A
  • the cell recieves a signal from the extracellular environment to initiate apoptosis
  • ligand binds to a receptor
  • e.g. death ligands and receptors
74
Q

what are the death receptors in the extrinsic pathway?

A
  • initiate apoptosis following ligand binding
  • fas
  • TNF-RI
75
Q

what are the ligands of the extrinsic pathway?

A
  • FasL
  • TNF alpha
  • TRAIL
76
Q

what do the death receptors contain?

A

a death domain

- which interact with adaptor proteins through mutual death domains

77
Q

how is Fas an example of the extrinsic pathway?

A
  • FasL binds to Fas
  • Fas interacts with adaptor proteins via the FADD
  • FAD complexes with pro-caspase 8 (a DED caspase)
  • domains interact with each other
  • forms DISC
  • turns into active caspase 8 as more caspases are recruited
  • leads to apoptosis
78
Q

what is FADD?

A

Fas-assocaited death domain

79
Q

what is DED?

A

death effector domain

80
Q

what is DISC?

A

death inducing signal complex

81
Q

how is Fas involved in influenza defence?

A
  • infected cell presents a virus peptide on its cell surface with the histocompatability complex
  • CTL induces apoptosis by binding FasL to Fas on target cell
82
Q

how does HIV affect Fas?

A
  • results in the loss of CD4+ T cells
  • HIV gene causes overexpression of FasL
  • allows it to interact with Fas on CD4 T cells
  • induces non-infected cells to commit suicide
  • failure in response of immune response
83
Q

what is the intrinsic pathway?

A
  • normally involves the release of cytochrome c from mitochondria
  • induced by stress, damage or developmental cues
  • involves Bcl-2 proteins
84
Q

what stimulates the intrinsic pathway?

A
  • cytochrome c is released
  • binds Apaf-1
  • Apaf-1 has an apoptotic domain the CARD domain
  • causes the Apaf1 to assemble the apoptosome which recruits pro-caspase9 via its CCARD domain binding to the CAR domain of Apaf1
  • binding of CARD domains allows the recruitment of procaspase 9 which also has a CARD domain
  • causes dimerization, activation and apoptosis
85
Q

what is the role of Bcl2 proteins?

A

regulation of the intrinsic pathway

86
Q

what is the Bcl2 family?

A
  • there are pro-apoptotic (BH3 and sometimes BH1 and BH2)
  • there are anti-apoptotic members (BH4)
  • there are activators, suppressors and depressors
  • they have BH = Bcl2 homology domain
  • balance between these proteins that determines apoptosis
87
Q

what is the role of the BH3-only proteins?

A

thought to promote apoptosis by inhibiting anti-apoptosis Bcl2 family proteins

88
Q

what is the role of inactivity in the intrinsic pathway?

A
  • have active anti-apoptotic protein that inhibits proteins such as Bax and Bak
  • found in the membrane
  • means the cytochrome c is contained in the mitochondrial membrane
89
Q

what happens when these proteins are activated?

A
  • activated BH3 only proteins
  • Bcl2 proteins form a pore in the membrane
  • cytochrome c is released and can bind to Apaf1
90
Q

what can inhibit apoptosis?

A
  • extracellular survival factors
  • growth/topic factor
  • trophic factors
91
Q

what are grow/trophic factors?

A
  • they are transmembrane binding
  • activation of PI-3 and AKT (PkB)
  • this phosphorylates a Bcl2 protein called Bad
  • causes it to bind a molecular chaperone
  • therefore no longer binding to Bcl2 or BcIXL
  • no longer have the open pore
92
Q

what are trophic factors?

A

factor inducing differentiation/survival

93
Q

how is there cross-over between the two pathways?

A

extrinsic pathway can activate the intrinsic pathway

94
Q

how can the extrinsic pathway activate the intrinsic pathway?

A

• FasL  Fas  FAD  caspase 8 activation  executioner  death
- This active caspase 8 can cleave a Bcl2 protein (Bid) and it becomes tBid
o This inhibits Bcl2 on the mitochondrial membrane to cause the release of cytochrome c
o Activates caspase 9 via apoptosome formation

Cell Biology (10 decks)

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