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BMS-I > Protein Misfolding/Diz > Flashcards

Protein Misfolding/Diz Flashcards

1
Q

What was so damn special about Linus Pauling?

A

Alpha helix and beta sheet.

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2
Q

What did Anfinsen do?

A

Denatured pancreatic ribonuclease fast and slow.

Added b-mercaptoethanol (denatures disulfide bonds) & 8M urea(disrupts non-covalent bonds and solubilizes r grps)

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3
Q

What is Levinthal’s paradox?

A

AA has 2 potential confirmations. So AA-100 would habe 2^99 potential folds.

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4
Q

Who postulated the principle of minimal frustration?

A

Bryngelson + Wolynes => AA want to maximize correct folding events

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5
Q

How are energy barriers in protein folding overcome?

A

Chaperones.

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6
Q

What is a molcular chaperone (5)?

A
  1. Matchmaker (complex assembly)
  2. Trafficking (secretion via ER)
  3. Quality control (protein syn.)
  4. Molecular cpr
  5. Wrecking ball
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7
Q

What are the needs of a chaperone (3)?

A
  1. Protein synthesis (protection of chain, guidance, avoiding kinetic dead ends)
  2. Protein unfolding (degradation required polypeptide unfolding)
    PH in gut/lysosome
  3. Complex assembly
    (Step-wise assembly to promote correct interactions)
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8
Q

What molecular chaperone is required for proteosome formation?

A

UMP-1

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9
Q

What type of interactions promote folding?

A
  1. Hydrophobic core -> global structure
  2. Electrostatic interactions -> local environment
  3. Van der Waals interactions -> local environment
  4. Disulfide bonds -> protein stability (insulin)
  5. Metal coordination -> co-factor in catalysis (zn finger)
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10
Q

What is a molten globule?

A

Polypeptide chain w/ near final 2’ structure. Looser and more open.

Not any 1 structure. More of an amalgamation

This structure is trying to condense and get rid of excess H20.

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11
Q

What is the Zinc finger generally composed of?

A

Cys2His2.

Alpha helix and antiparallel beta sheet that coordinate a zinc ion

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12
Q

What are conditions that promote protein unfolding?

A
  1. Temperature
  2. PH
  3. Pressure
  4. Urea
  5. Guanidine
  6. Organic solvents
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13
Q

What enzymes break and correct sulfide bonds?

A

Sulfide protein isomerases

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14
Q

Do chaperones increase the rate of folding reactions?

A

No, but they increase the yield.

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15
Q

How is the maturation of proteins facilitated by ER chaperones?

A

CHaperones (Hsps) and folding stimulants (PDIs and PIs) found in ER and help protein fold correctly.

Irreversible damaged proteins will be guided out of Er and into proteosome thru ERAD (endoplasmic-reticulum associated degredation)

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16
Q

How does a mutations in CFTRdelta508 implicated in diz?

A

Protein folding goes very slow, so it is easier to get caught in proteolytic system.

There is still some levels tho.

Mutation depletes intracellular levels of a critical transporter.

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17
Q

What role does eEF1A have in degradation?

A

While it recruits tRNAs to ribosome, if a polypeptide chain is folding incorrectly it can facilitate chain degradation.

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18
Q

What is pathogenesis of:

  1. Alzhiemers
  2. ALS
  3. Prion
  4. Trinucleotide expansion
A
  1. Aberrant AB peptide plaques.
  2. Aggregaiton of SOD
  3. Protein conformational change
  4. CAG repeats (glutamine)
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19
Q

Are proteosomes ATP dependent?

A

Yes!

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20
Q

How many lysine residues are present on the surface of Ub? How many aa are there?

A

7

76 AA

Small hydrophobic patches on surface.

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21
Q

What is the structure of Ub’s reactive terminus?

A

ARG-GLY-GLY-COO(-)

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22
Q

Why are Ubs expressed as a fusion protein?

A

Protect reactive carboxy terminal hydrolase.

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23
Q

What enzyme breaks down Ub fusion proteins?

A

Ub carboxy terminal hydrolase (deficiencies seen in PD)

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24
Q

What step in the Ub cascade is ATP-dependent?

A

E1 (Ub activating enzyme)

Binds 2 Ubs as ubiquitin-adeynlate via thioester bond.

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25
Q

What kind of bond is formed when a Ub attaches to a substrate?

A

Isopeptide (usually via a lysine residue on protein)

26
Q

Why are Ub chains so important for function of proteosome system? How is the chain formed?

A

Hydrophobic stripe is what is recognized. 1 ub is not enough, usually need at least 4-5.

Lysine-29 & lysine-48 interactions

27
Q

Why are K-63 Ub chains important?

A

Not for proteosome recognition.

These chains get regulated to lysosome for degradation (important for DNA repair too)

28
Q

What is combinational diversity?

A

Different E2 (50) and E3(800) coming together to recognize a plethora of different substrates

29
Q

Will E3 always have a Ub attached?

A

No, but E2 always will!

30
Q

What is the difference between HECT-E3s and RING E3s?

A

Hect-E3 have ability to form thioester bond with Ub.

RING - does not.

31
Q

What is Rad23?

A

Shuttles substrate over to proteosome (via Rpn10)

DNA repair protein.

Typically binds Xpc in NER repair pathway. Mutations in NER => Xeroderma Pigmentosum (XP)

32
Q

What 3 distinct proteolytic activities does the 20S core contain?

A
  1. Chymotrypsin like activity (cleaves large AA or hydrophobic side chains)
  2. Trypsin-like = cleaves basic residues
  3. PGPH -> post-glutamyl activity
33
Q

What part of the proteosome contains the ATP dependent structure

A

19S regulatory subunit.

34
Q

How many B subunits in the ring have hydrolytic activity

A

3/ring. So 1 proteosome would have 6

35
Q

How many ATPases are found in the 19S subunit?

36
Q

How is HPV pathogenic?

A

HPV introduces a viral protein E6 into the ubiquinating system.

E6 associates with E3 (E6AP in this case) and changes target for substrate to p53 instead of some other target.

Degradation of p53 leads to loss of growth control

37
Q

What unit in the E3 is required for Ub conj. In the Von Hippel-Lindau tumor pathway?

38
Q

If VHL is mutated, which substrate does it now fail to recognize?

A

Hif-1.

Induces hypoxia proteins even in non-hypoxic states.

39
Q

What protein could potentially be deficient in Xeroderma Pigmentosum? Why is this important for protein folding?

A

Xpc is a DNA damage-binding protein that is degraded by proteosome.

40
Q

What is the non-covalent step of the ubiquination process?

A

Forms a Ub-adenylate and binds non-covalently with E1.

2nd step is ATP required (release adenylate, conjugates G76 of Ub to catalytics cysteine residue.

41
Q

What type of E3 is involved in Hif-1 Ubiquinitation?

A

RING
E3: three conserved subunits (cullin2/elongin c (SKP), F-box)

E2: Ubc3

42
Q

How is the inflammatory response mediated by proteosomes? What are the key players?

A

NFkB - transcription factor

  • > proteosome processes NFkB and produces p65 which dimerizes with p50 -> p50/65.
  • > p50/65 is usually sequestered in the cell by IkBa

Cell INJURY

  • > IkK activated & phosphorylates IkBa
  • > E2/E3 factors now recognizes phosphorylated IkBa and gets ubq and degraded
  • > p50/65 can now enter nucleus and activate stress-responsive genes.
  • > Auto regulated b/c IkBa is a gene that gets transcribed and pathway will self-terminate.
43
Q

What are the three phases of altitude acclimatization? What are they mediated by?

A
  1. Immediate
  2. Intermediate
  3. Long term

Mediated by Hif-1

44
Q

How do Hif transcription factors compensate for hypoxic conditions?

A

Activate genes that promote angiogenesis, anaerobic metabolism, and resistance to apoptosis

45
Q

What is the structure of HIFs?

A

Heterodimers

  1. 3 types of alpha units (Hif-1a/2a/3a) - these are oxygen labile
  2. Constitutive Hif-1b present in nucleus
46
Q

How are Hif1 levels regulated?

A
  1. Transcriptional:
    MTOR/s6 kinase => syntehesis
    VHL/VDU => Degradation
  2. Translational
3. Post-translational:
Prolyl hydroxylation (proline hydroxyl) - degradation
Lysyl acetylation (acetyl at lysine) - degradation

Cystine nitrosylation -> promotes transcription

47
Q

How does VHL recognize HIf1? What is VHL?

A

VHL is a component of an E3 complex.

Recognizes hydroxylation on HIF-1 put there by PDH

48
Q

What enzyme can dismantle a Ub-chain on Hif-1?

49
Q

What are PHD1-3s?

A

Prolyl hydroxylase (makes residue visible to VHL, component of E3 Ub cascade)

50
Q

What enzyme can put PHDs1-3 up for ubiquination? Thus hampering Hif1a degradation?

How else can PHDs be inhibited?

A

Siah1/2 (E3ligase)

Mitochondrial failure of processing ROS -> Fe2+

51
Q

What is PHD1-3 role in Hif1a degradation?

A

Substrate modification

52
Q

Can VHL/E3ligase be be ubiquinated?

A

Yes.

Process thru Hdm2 (e3 ligase) + p53 (oxygen independent pathway)

53
Q

How does VDU play in this cascade of Hif1a ubiq.?

A

VDU can de-ubiquinate Hif1a

54
Q

What factor can Hif1a activate that is associated with inflammation?

A

IkKb

Remember IkKb is usually activated in response to cell stress. It phosphorylates IkB releasing it from p50/65 allowing those things to go increase transcription

55
Q

After a Hif1 molecule dimerizes in the nuclease, how does it affect the cell?

A

Increases transcription via HRE.

Induces Transcription activation (expression) of miRNA210 (shuts down expression of normoxia genes)

-> Angiogenesis, nrg metabolism, inflammation

56
Q

How does oxygen dependent activation [typical Ub pathway] of Hif1a affect energy metabolism?

A
  1. Accelerate glycolysis
  2. Activate conversion of pyruvate to lactic acid
  3. Block pyruvate to acetyl CoA
57
Q

How is Hif1a syn. Independently from 02?

A

MTOR & S6-kinase => increase translation of Hif1a

58
Q

Where does the oxygen independent control of Hif1a take place?

59
Q

Where does the Hif1a/b heterodimer exert it’s effects?

60
Q

What are the mTOR inhibitors?

A

Rapamycin

Everolimus

61
Q

What are the proteosome inhibitors?

A

Bortezomib

Carfilzomib

BMS-I (17 decks)

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