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Proteins and Proteomics BCEM 431 > Chaperones. > Flashcards

Chaperones. Flashcards

1
Q
  • When is the earliest contiguous domains can be folded?
  • When is the earliest non-contiguous domains can be folded?
A
  • co-translationally as the linear sequence emerges from the ribosome
  • Post-translationally as the entire chain comprising the domains must be completely translated before folding can occur.
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2
Q

Name a substrate-specific chaperone

A

PapD which is involved in pilus formation

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3
Q

Name some General chaperones

A
  • Trigger factor, NAC (nascent-polypeptide associated complex)
  • PFD (Prefoldin)
  • Hsp70 family
  • Hsp60 family (chaperonin)
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4
Q

Explain how the chaperone PapD works in pilus formation

A
  • PapD temporarily binds to the PapK molecule to prevent it from aggregating prior to pilus assembly.
  • When PapK is in the right position, PapD donates a beta sheet strand to PapK.
  • This change exposes hydrophobic residues on PapK that causes it to aggregate to form the pilus.
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5
Q

What molecules does FimC (a PapD-like chaperone) bind to. What would happen if it was not present?

A

FimC binds to FimH, FimG, FimF and FimA. Without FimC, all those molecules would aggregate in a non-specific way and not form a proper pilus.

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6
Q

Why are general chaperone systems highly conserved in all organisms?

Hint: why is it useful to move unfolded proteins in the cell?

A

They are conserved because different subcellular compartments have different protein compositions and environments, and creating holes large enough in the membrane for fully folded proteins to travel though could prevent proper partitioning of these compartments, especially those with different proton or salt gradients. They are also required for the proper functioning of a variety of proteins.

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7
Q
  • Where is trigger factor located?
  • What does TF do to nascent polypeptides which emerge from the ribosome?
  • In prokaryotes, what percentage of proteins are folded only be trigger factor?
A
  • On the exit tunnel of the large ribosomal subunit.
  • It assists with folding, reducing misfolding.
  • 70%
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8
Q

What three ribosomal proteins does trigger factor ribosomal binding protein attach to?

A

L29, L23, L19.

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9
Q

How does trigger factor help protein folding

A

It’s domains project out around the ribosome, protecting the nascent protein from proteases and aggregation.

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10
Q

What are the prokaryotic counterparts of:

Hsp70
Hsp40
TRiC

A

DnaK
DnaJ + GrpE
GroEL-GroES

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11
Q

How does the Hsp70/ DnaK system work?

A
  1. DnaJ (Hsp40) binds to the nascent protein
  2. DnaJ + unfolded protein binds to ATP-bound form of DnaK.
  3. Hydrolysis of ATP into ADP makes it close around the unfolded protein and release DnaJ and a Pi.
  4. GrpE induces the release of ADP from DnaK.
  5. a new ATP will bind to DnaK and cause it to take on the open conformation and release the protein.
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12
Q

How many residues do DnaK and DnaJ bind to?

A

roughly 7 residues or the peptide.

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13
Q
  • What size of protein does DnaK associate with?
  • Do the proteins immediately fold when released by DnaK?
A
  • 20-30 kDa
  • some fold rapidly, others will need multiple cycles of binding and release.
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14
Q

In what life domain(s) is Prefoldin found in?

A

the Archaea and the Eukaryota

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15
Q

Describe the structure of Prefoldin

A

2 alpha subunits and 4 beta subunits which meet at one end forming a jellyfish like appearance. Hyrdophobic patches exist on the distal end of the subunits.

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16
Q

Describe how the Prefoldin complex prevents neurodegenerative diseases.

A

Alzheimers:
Prefoldin inhibits A beta fibril formation and facilitates non-toxic A beta aggregation.

Parkinson’s:
prevents aggregation of alpha-synuclein which forms the disease causing Lewy bodies.

Huntington’s:
Prefoldin complexes help Huntington proteins form non-toxic oligomers, The absence of prefoldins leads to the proteins forming toxic oligomers and inclusion bodies

17
Q

What protein does prefoldin bind to to release its unfolded protein?

A

TRiC

Different conformations of the TRiC-PFD complexes exist, with PFD binding to some area on the top of TRiC

18
Q

What is the name given to chaperonin proteins for the three life domains?

A

Bacteria: GroEL, GroES
Archaea: Thermosome
Eukaryota: TRiC/ CCT

19
Q

What is GroES?

A

It is a heptameric Cap protein which cycles on and off to allow unfolded proteins into the barrel of GroES

is has seven 10kDa subunits.

20
Q

What is GroEL?

A

It is two heptameric rings, comprised of 3 domains:

Equatorial domain: ATP-binding
Intermediate domain
Apical domain: hydrophobic.

21
Q

How does the GroEL-GroEs complex facilitate protein folding?

A
  1. Non-native substrate protein binds to the hydrophobic open trans heptamer ring of GroEL.
  2. GroES and 7 ATP bind to GroEL to trigger a conformational change that results in the protein being released into the interior compartment of GroEL to be folded in isolation with exposed hydrophilic residues. Trans ring becomes the new Cis ring
  3. The time it takes the new cis ring ATP to hydrolyses into ADP is the time it the protein has to properly fold in the compartment.
  4. When a GroES and ATP bind to the new trans ring on the other side of the GroEL, the protein will be released from the side it entered.
  5. If the protein did not have time to properly fold and still has some exposed hydrophobic residues, it will associate with a prefoldin or Hsp70 which will bring it back to the GroEL so that the process can be repeated.
22
Q

How do GroEL and DnaK/ Hsp70 prevent proteins from permanently falling into kinetic intermediate traps?

A

They promote or accelerate the rate of correct folding. Reducing aggregation and smoothing the folding funnel.

-> Confinement

23
Q

How do folding enzymes like PPlase and PDI prevent proteins from permanently falling into kinetic intermediate traps?

A

PPlase reshuffles incorrectly placed disulfide bridges, saving the protein from the kinetic intermediate traps

-> Iterative annealing

24
Q

Name two ways understanding protein folding can be used practically.

A
  • Biotechnology: production of recombinant proteins in GMOs is limited by the protein folding efficiency. For instance, the antibodies which are produced in organisms like horses or mice might not fold properly or be able to use.
  • Medicine: Protein misfolding can cause or improve serious diseases. For instance, a working Prefoldin complex can help prevent the misfolding of Alpha - synuclein
25
Q

Are all misfolded states similar or greater in energy than the native protein? if not provide an example to the contrary.

A

Some protein misfolded states are actually lower in energy than the native state. For instance, the amyloid Beta fibrils which cause Alzhiemer’s are far lower in energy.

26
Q

In humans, what percentage of proteins fail to fold properly?

A

10-30%

27
Q

Why might a misfolded protein be worse than useless?

A

The change in form may cause the protein to exhibit an entirely new function which is harmful to the organism.

28
Q

How can proteasome affect protein misfolding?

A

It can degrade the misfolded proteins so they can’t cause problems and their components can be reused

29
Q

What are the three main pathways for misfolded protein degradation?

A
  • CMA (chaperone mediated autophagy) delivers misfolded proteins one-by-one to the lysosome.
  • Macroautophagy delivers aggregates of misfolded proteins to the lysosome.
  • UPS (ubiquitination proteasome system) marks proteins for degradation
30
Q

Where is the cystic fibrosis transmembrane regulator folded?

A

In the ER. It is then exported to the surface membrane.

31
Q
  • What kind of folding does the CFTR require to be functional?
  • What percentage of CFTRs are targeted to the proteasome for degradation normally?
  • What percentage of CFTRs are targeted to the proteasome for degradation with the ΔF508 mutation?
A
  • C-translational folding and Post-translational folding (Hsp70 & 90), Domain assembly (sec23 & 24 pathway)
  • 10-25%
  • 98%
32
Q

Name three infections caused by misfolded proteins and the animals they predominantly affect.

A
  • Scrapie (Sheep)
  • BSE (Bovine spongiform encephalopathy) (Cows)
  • Variant Creutzfeld-Jakob disease (humans)
33
Q

How many people died from Bovine Spongiform Encephalopathy (BSE) in the 1980s? Why did the disease spread so easily?

A
  • 175 people died
  • Cows were being feed left-over animal parts.
34
Q

Name 3 diseases which are associated with toxic amyloid fibrils.

A
  • Parkinson’s
  • Alzheimer’s ?????
  • Prions (BSE)
  • Type II diabetes
35
Q

What is the dominant effect of misfolded proteins?

A

The protein gains a new function which can kill the cell and even be infectious. It is especially effective against neurons.

36
Q

What is the structure of amyloid fibrils?

A

They are composed of cross- beta sheet structures. These are found in both mice and humans suffering from AA amyloidosis

37
Q

What is a way in which different states of Alzheimer’s disease could be distinguish?

A

Different strucutes of Tau filaments exist for the disease: Paired helical filaments (PHF) and Straight filaments (SF).

Proteins and Proteomics BCEM 431 (13 decks)

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