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MCP Unit 2 > Lecture 12: Protein Misfolding and Disease I > Flashcards

Lecture 12: Protein Misfolding and Disease I Flashcards

1
Q

What parts of proteins does Hsp70 bind to? In what conformation are the proteins in at this time?

A

hydrophobic patches

intermediate conformation - not native

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2
Q

What are the domains of Hsp60?

A

GroEL/GroES

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3
Q

When do chaperones come into play? About what percent of proteins need this?

A
  • cell is overwhelmed with misfolded proteins

- small percent of proteins require chaps

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4
Q

By what three mechanisms does GroEL/GroES seem to work?

A
  1. isolation (forms Anfinsen box)
  2. forced unfolding
  3. confinement (in box)
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5
Q

What is the function of GroEL/GroES?

A

help proteins fold/unfold

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6
Q

What is the function of E1?

A

activating enzyme
activates Ub
ATP driven
forms E1-Ub bond

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7
Q

What are the roles of E2 and E3?

A

E2 = conjugating enzyme
E3 = ligating enzyme
target protein is bound to E3
E2 transfers activated Ub to target protein +E3
E3 catalyzes final transfer step of Ub to protein

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8
Q

Where are Ub-tagged proteins degraded?

A

Proteasome

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9
Q

How many concatenated Ub molecules are needed for protein-proteasome binding?

A

4

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10
Q

What are the subunits of the proteasome?

A

20S core particle

19S regulatory particle caps

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11
Q

What immune response can proteins degraded by the proteasome activate? Where do the peptides pass through to do so?

A

MHC Class 1

ER

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12
Q

What are 4 diseases associaited with the Ub-proteasome pathway?

A

Cancer
Neurodegenerative diseases
Cystic Fibrosis
Autoimmune disease

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13
Q

How is the Ub-proteasome pathway associated with cancer?

A

faster growth makes cells more dependent on proteasome

ca have increased degradation of tumor supressors

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14
Q

How is the Ub-proteasome pathway associated with neurodegenerative diseases (Alzheimer’s, Parkinson, Huntington)?

A

accumulation of Ub-proteins has been seen in plaques

have found some disease-causing mutations in pathway

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15
Q

How is the Ub-proteasome pathway associated with Cystic fibrosis?

A

Ub-proteasome is supposed to clear delta-F508 CFTR

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16
Q

How is the Ub-proteasome pathway associated with autoimmune diseases?

A

improper processing of peptide antigens

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17
Q

What is the role of p53? How is it activated? What does it trigger? What does it prevent?

A

Txn factor
Activated by DNA damage
Triggers cell cycle arrest or apoptosis
Prevents accumulation of xs mutations

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18
Q

What are three aspects which can be altered by p53 mutation?

A
  1. DNA contact
  2. Stability
  3. Zinc binding
19
Q

What motifs and secondary structures are important in p53?

A

beta sheets –> beta clam
alpha helices and loops = DNA binding site
Zinc ion

20
Q

What is the most common outcome of missense mutations?

A

loss of thermodynamic stability

21
Q

How does loss of stability often affect the Ub-proteasome pathway?

A

leads to increased degredation

22
Q

How does loss of stability of p53 affect the Ub-proteasome pathway?

A

exhibits neg feedback with pathway

mutant p53 accumulates

23
Q

What is the molecular logic behind using crevice binders to stabilize stability mutants?

A

design small molecule
fits into solvent-accessible area
binds that protein only
take into account size/shape and chem complementarity

24
Q

What is the molecular logic behind using MDM2 blockers when p53 is mutated?

A

MDM2 blockers prevent p53 from binding E3
–> p53 accumulates
even if mutate, some might be functional
can reactivate p53 by other means

25
Q

What protein is missing from target tissues in Cystic fibrosis?

A

Delta-F508 CFTR

26
Q

What mutation characterizes Cystic fibrosis?

A

ABSENCE of F508 (not change in structure)

27
Q

Where is F508 located on the CFTR?

A

nucleotide binding domain 1 (NBD1)

28
Q

Of what family is CFTR? What does it do?

A

ABC membrane protein (ATP binding casette)

pumps solutes in and out

29
Q

What are treatment options for delta-F508 CFTR? Are any of them great?

A

Not great

25 degrees C, small organic molecules, overexpressing chaps, inhibiting Ub-proteasome, stimulating CFTR funcion

30
Q

What are the Z-type and S-type mutations in alpha1-antitrypsin deficiency?

A 
Z-type = Glu342 --> Lys
S-type = Glu342 --> Val
31
Q

What is the role of Alpha1-AT?

A

Serine protease inhibitor (serpin)

in plasma - wound healing

32
Q

Where is Alpha1-AT released?

A

sites of inflammation

33
Q

What diseases are characterized by Alpha1-AT deficiency?

A

lung diseases - emphysema

liver disease - cirrhosis, cancer

34
Q

What secondary structure forms the active, inhibitory reactive center of Alpha1-AT? Is this cleaved or uncleaved?

A

Beta-sheet (RCL inserted into Beta-sheet)

cleaved

35
Q

What secondary structure forms the inactive reactive center of Alpha1-AT? Is this cleaved or uncleaved?

A

alpha-helix far away from Beta-sheet

uncleaved

36
Q

What structure of Alpha1-AT acts as a molecular mousetrap?

A

Reactive center loop (RCL)

37
Q

Is the cleaved or uncleaved form of Alpha1-AT more stable why?

A

cleaved

RCL inserted into beta sheet

38
Q

When antithrombin is in the locked form, how does its function change?

A

Goes from protease inhibitor –> angiogenesis inhibitor

39
Q

What family is antithrombin a member of?

A

Serpin (serine protease inhibitor)

40
Q

What can go wrong with the serpin activation cycle of alpha1-AT involving structural weakness?

A

Beta sheet needs to be flexible enough to accept RCL, but at the right times to have inhibitory function
If beta sheet is structurally weakened, it might accept RCL too often

41
Q

What can go wrong with the serpin activation cycle of alpha1-AT at the shutter region?

A
  • Glu264-Tyr38 Hydrogen bond forms right under beta sheet

- removing H bond can weaken beta sheet

42
Q

In alpha1-AT, is insertion of RCL into beta sheet reversible?

A

No - permanent insertion, permanent inhibitory function

43
Q

What happens to alpha1-AT in liver disease?

A

beta sheet opens at abnormal time
RCL from second protein enters irreversibly
forms beads on strings which accumulate and cause failure

MCP Unit 2 (17 decks)

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