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BMS > Protein Folding, Misfolding, Aggregation, and Disease > Flashcards

Protein Folding, Misfolding, Aggregation, and Disease Flashcards

1
Q

Can form aggregates that interfere with other cellular functions

A

Unfolded Proteins

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2
Q

Regulatory mechanisms that promote correct folding are balanced by proteolytic pathways that degrade persistantly damaged

A

Proteins

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3
Q

Increased levels of misfolded proteins can lead to a number of disease, including

A

Neurodegenerative conditions

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4
Q

Can play a significant role in guiding the correct folding of the polypeptide chain, to generate the structural and catalytic properties of the protein

A

The sequence of amino acid residues

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5
Q

While genetic mutations affect all the polypeptide chains produced from a specific mRNA, errors can also arise from inserting incorrect amino acid in the growing chain, and by slippage of the ribosome on the mRNA template resulting in

A

Frameshifting

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6
Q

Can occur spontaneously, or be induced by environmental stresses

A

Post-translational misfolding

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7
Q

Can occur co-translationally or post-translationally and can confer alternate biochemical fates

A

Protein folding

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8
Q

What interactions promote protein folding?

A
  1. ) Hydrophobic
  2. ) Electrostatic
  3. ) van der Waals
  4. ) Disulfide bonds
  5. ) Metal coordination
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9
Q

What are some agents that promote unfolding?

A

Temperature, pH, pressure, urea, etc

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10
Q

Key information for protein folding is present in the

A

Polypeptide sequence

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11
Q

Based on a fundamental understanding of the physical and chemical properties of amino acids, proposed the formation of α-helices and β-sheets

A

Linus Pauling

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12
Q

Showed that bovine pancreatic ribonuclease could be fully denatured by treatment with β-mercaptoethanol (β-Me reduces disulfide bonds) and 8M urea (which unfolds proteins by disrupting non-covalent interactions and solubilizing non-polar residues).

A

Anfinsen experiment

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13
Q

In the Anfinsen experiment, rapid removal of β-Me and urea only allowed

A

1% of activity of protein to be recovered

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14
Q

In the Anfinsen experiment, slow removal of β-Me and urea by step-wise dialysis restored

A

Almost full activity

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15
Q

The conclusion from the Anfinsen experiment was that the information for generating the secondary and tertiary structure in a protein is intrinsically available in the

A

Polypeptide sequence

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16
Q

All the information necessary to assemble and generate full enzymatic activity is present in the

A

Amino acid sequence

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17
Q

Small proteins may fold rapidly and spontaneously, however, large proteins tend to require

A

Chaperones

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18
Q

States that particular folding pathways must be favored by a specific protein because otherwise it would take too long for proteins to fold

A

Levinthal’s Paradox

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19
Q

Do not enhance correct folding, rather they prevent non-productive routes

A

Molecular chaperones

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20
Q

Posits that evolution has selected polypeptide chains in which the individual amino acids are positioned so that they maximize correct folding events, and minimize structural barriers (through their side chains).

A

Bryngelson and Wolynes Principal of Minimal Frustration

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21
Q

Bryngelson and Wolynes Principal of Minimal Frustration basically says that the folding pathway for a polypeptide does not proceed in a

A

Linear manner

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22
Q

The ΔG between unfolded and folded/native protein is very

A

Small

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23
Q

The average stability per residue is

A

0.1 kcal/mole

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24
Q

Can promote folding of specific proteins, or participate in general quality control mechanisms

A

Chaperone proteins

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25
Q

Chaperone proteins that promote the folding of proteins emerging from the ribosome are likely to be

A

Non-specific

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26
Q

Chaperone proteins that assist in the assembly of large multi-subunit complexes are typically

A

Highly specific to a particular task

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27
Q

Has a significant impact on the global structure of the folded protein

A

Hydrophobic core

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28
Q

Have a significant impact on the local environment of a folded protein

A

Electrostatic interactions and van der Waals interactions

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29
Q

Have a significant impact on a folded proteins stability

A

Disulfide bonds

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30
Q

Has a significant impact on the structure and stability of a folded protein

A

Metal coordination

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31
Q

A common DNA binding domain present in many enzymes and nucleic acid binding proteins

A

Zinc Finger (RING motif)

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32
Q

Water molecules around a hydrophobic protein structure are constrained because certain hydrogen bonds resist pointing towards the

A

Hydrophobic amino acid residues

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33
Q

Larger proteins that achieve 3-D conformation with help from a chaperonetypically can not be

A

Renatured following denaturation

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34
Q

Protein denaturation is not concentration dependent (zero order kinetics) and is simply a function of protein

A

Vulnerability to the denaturant

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35
Q

The temperature at which 50% of the proteins molecules are unfolded

-A measure of the thermodynamic stability of the protein

A

Transitional melting Temperature (Tm)

36
Q

The Tm can be affected by

A

Mutation, post-translational modification, and association with other proteins

37
Q

What are four agents that can promote folding?

A

Co-factors, disulfide bond, chaperones, and physiological partners

38
Q

Help to shield the hydrophobic cores of proteins until they are released from the ribosome and can fold into their final conformations

A

Molecular chaperones

39
Q

The chaperones stabilize the nascent chain, prevent deleterious interactions with other constituents in the cell, and provide an opportunity for the protein to achieve its

A

Mature structure

40
Q

Predicts that folding resembles a simple chain reaction with reactants and products

-Each sub-step culminates in a folded intermediate that can then proceed into the next folding event

A

Sequential folding model

41
Q

The sequential folding model is improbable since

A

Intermediates have never been detected

42
Q

Posits that a polypeptide chain can enter multiple folding pathways, although only one path leads to a productive native structure

A

Continuum folding model

43
Q

A polypeptide chain that has achieved a near-final secondary structure (i.e. alpha helices & beta sheets), but is maintained in a less ordered 3-D structure that is ‘looser’ and more ‘open’ than the final structure

A

Molten Globule

44
Q

Not a defined structure, but refers to a family of related structures that are fluid and interchangeable

-Can be represented as U M N

A

Molten Globule

45
Q

The driving force in the molten globule is

A

Water exclusion

46
Q

Related to the observation that ‘off-pathway’ folding events are not energetically prohibited. In fact, the energy difference between an on-pathway structural intermediate and an off-pathway structure is only -10 kcal/mol

A

The need for Chaperones

47
Q

Increase the likelihood of guiding ‘on-pathway’ folding intermediates, ultimately leading to mature and
functional proteins

A

Molecular chaperones

48
Q

Very similar in structure, each containing a barrel with four rings

A

Proteosome and GroEL chaperone

49
Q

Chaperones use ATP hydrolysis to generate energy and turn it into torque to refold the protein. This requires the hydrolysis of

A

14 ATP

50
Q

Protect the nascent chain and give guidance during folding to prevent kinetic dead ends

A

Chaperones

51
Q

Chaperones sitting by the ribosome decide if a protein is folding properly or if it needs to be

A

Degraded

52
Q

Structurally similar to the chaperone, but its hydrophobic channel is much more narrow, which prevents folded proteins from entering

A

Proteosome

53
Q

The proteosome is made up of four rings, 2 α and 2 β, and three of these subunits are made up of

A

Zymogens

54
Q

Consumed in proteosome formation

A

UMP 1

55
Q

What are the three modules in protein folding?

A

Hierarchical, Nucleation-condensation, and Hydrophobic collapse

56
Q

Secondary structures form first, and then through intramolecular interactions promote the assembly of the 3-dimensional structure. In the absence of the 3-dimensional interactions, the secondary structure is not stable

A

Hierarchical module

57
Q

Local sites of structural nucleation results in rapid propagation of the structure motif, which coalesce and stabilize the final native structure

A

Nucleation-Condensation module

58
Q

The molten globule forms as a result of tertiary hydrophobic interactions that initiate secondary structure maturation and the 3-D structure

A

Hydrophobic collapse module

59
Q

Cleaves insulin into it’s final conformation

A

Carboxypeptidase e

60
Q

Initially interact with short hydrophobic patches in nascent polypeptide chains, and form a stronger binding with the hydrolysis of ATP.

A

Cytosolic Hsp70 proteins

61
Q

These cycles of binding and release are coupled to improve folding of the emerging chain, in part by preventing

A

Non-productive endpoints

62
Q

Do NOT increase the rate of folding reactions, but DO improve the yield of successfully folded products

A

Chaperones

63
Q

Overcome energetic barriers that slow specific folding steps and can thereby increase folding rates

A

Protein disulfide isomerase and prolyl isomerase

64
Q

Can transiently bind unfolded segments during the translocation of proteins to the ER and mitochondria, which requires partial unfolding.

A

Cytosolic Chaperones (Hsp70’s)

65
Q

Also present in the lumen of the ER to facilitate refolding and complex assembly

A

Chaperones

66
Q

Fix improperly formed disulfide bonds and ensure that the correct cysteine residues are paired together

A

Disulfide isomerases

67
Q

This mutation in the cystic fibrosis transmembrane receptor proteins causes slow folding into the 3D structure. The protein is thus captured by the proteolytic system and degraded.

A

CFTRΔ508

68
Q

Plays a critical role in recruiting charged
tRNA’s to the ribosome, and in ensuring that the correct anticodon::codon pairing ensues. However, when a polypeptide chain fails to fold correctly, it facilitates the degradation of the unfolded chain.

A

eEF1A

69
Q

In order to form, the proteosome requires

A

4-5 chaperones

70
Q

Plays an important role in targeting unfolded ER proteins to the cytosolic protein degredation pathway

A

Endoplasmic Reticulum Associated protein Degredation (ERAD)

71
Q

Promotes the assembly of components of the mitochondrial energy generating pathway

-Can be inhibited by geldenamycin

A

Hsp90

72
Q

The ribosome error rate is

A

1 out of every 10^4 aminos incorporated

73
Q

A multi-subunit cylindrical particle consisting of four rings that can bind unfolded proteins in large hydrophobic cavities present at both ends of the cylinder

-Hydrolyzes 14 ATP per protein

A

GroEL chaperone

74
Q

The GroEL chaperonin consists of seven identical subunits, which have three distinct domains, termed equatorial, intermediate, and axial. The axial domain forms a large cavity lined with hydrophobic residues that bind

A

Unfolded Proteins

75
Q

Once the unfolded protein has been captured, the GroEL cavity is covered by the

-Prevents premature release of the substrate

A

GroES complex

76
Q

When GroEL hydrolyzes ATP, it turns, exposing hydrophilic residues in the cavity which cause

A

Hydrophobic aminos of the protein to be buried in the center (promoting folding)

77
Q

Most neurodegenerative conditions (including Parkinson’s, Alzheimer’s, and Amyotrophic Lateral Sclerosis) are associated with high levels of

A

Insoluble proteins (Aggregates)

78
Q

Protein folding also plays a key role in diseases such as mad cow disease and Creutsfeldt-Jakob Disease (CJD), which are both

A

Prion Diseases

79
Q

Prion diseases can be caused by a mutation in the

A

PRNP gene

80
Q

A form of transmissible prion disease, which is acquired through ritual cannibalistic activities

A

Kuru

81
Q

Proteosome substrates can come from co-translational protein misfolding, short-lived regulatory proteins, and

A

Stress-induced protein damage

82
Q

A large clump of damaged, unfolded proteins all in one area

A

Aggresome

83
Q

The amyloid diseases share a common feature of accumulating fibrous plaques containing mostly

A

β-pleated sheet aggregates

84
Q

Protein infectious units that can cause chain reactions of unfolding amongst wild type proteins

A

Prions

85
Q

Characterized by the accumulation of aberrant Aβ peptide in the plaques

A

Alzheimer’s Disease

86
Q 
CAG repeats (glutamine) that undergo extensive
expansion to cause altered function or aggregation. Ex: Huntington’s Disease, Machado Joseph Disease
A

Trinucleotide expansion diseases

BMS (62 decks)

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