Protein Folding, Misfolding, Aggregation, and Disease Flashcards Preview

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Flashcards in Protein Folding, Misfolding, Aggregation, and Disease Deck (86):
1

Can form aggregates that interfere with other cellular functions

Unfolded Proteins

2

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

Proteins

3

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

Neurodegenerative conditions

4

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

The sequence of amino acid residues

5

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

Frameshifting

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Can occur spontaneously, or be induced by environmental stresses

Post-translational misfolding

7

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

Protein folding

8

What interactions promote protein folding?

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

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What are some agents that promote unfolding?

Temperature, pH, pressure, urea, etc

10

Key information for protein folding is present in the

Polypeptide sequence

11

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

Linus Pauling

12

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).

Anfinsen experiment

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

1% of activity of protein to be recovered

14

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

Almost full activity

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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

Polypeptide sequence

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

Amino acid sequence

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

Chaperones

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

Levinthal's Paradox

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

Molecular chaperones

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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).

Bryngelson and Wolynes Principal of Minimal Frustration

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

Linear manner

22

The ΔG between unfolded and folded/native protein is very

Small

23

The average stability per residue is

0.1 kcal/mole

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

Chaperone proteins

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

Non-specific

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

Highly specific to a particular task

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

Hydrophobic core

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

Electrostatic interactions and van der Waals interactions

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Have a significant impact on a folded proteins stability

Disulfide bonds

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

Metal coordination

31

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

Zinc Finger (RING motif)

32

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

Hydrophobic amino acid residues

33

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

Renatured following denaturation

34

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

Vulnerability to the denaturant

35

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

-A measure of the thermodynamic stability of the protein

Transitional melting Temperature (Tm)

36

The Tm can be affected by

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

37

What are four agents that can promote folding?

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

38

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

Molecular chaperones

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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

Mature structure

40

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

Sequential folding model

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The sequential folding model is improbable since

Intermediates have never been detected

42

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

Continuum folding model

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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

Molten Globule

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

-Can be represented as U M N

Molten Globule

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The driving force in the molten globule is

Water exclusion

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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

The need for Chaperones

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

Molecular chaperones

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

Proteosome and GroEL chaperone

49

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

14 ATP

50

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

Chaperones

51

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

Degraded

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

Proteosome

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

Zymogens

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Consumed in proteosome formation

UMP 1

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What are the three modules in protein folding?

Hierarchical, Nucleation-condensation, and Hydrophobic collapse

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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

Hierarchical module

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

Nucleation-Condensation module

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

Hydrophobic collapse module

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Cleaves insulin into it's final conformation

Carboxypeptidase e

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

Cytosolic Hsp70 proteins

61

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

Non-productive endpoints

62

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

Chaperones

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

Protein disulfide isomerase and prolyl isomerase

64

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

Cytosolic Chaperones (Hsp70's)

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

Chaperones

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

Disulfide isomerases

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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.

CFTRΔ508

68

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.

eEF1A

69

In order to form, the proteosome requires

4-5 chaperones

70

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

Endoplasmic Reticulum Associated protein Degredation (ERAD)

71

Promotes the assembly of components of the mitochondrial energy generating pathway

-Can be inhibited by geldenamycin

Hsp90

72

The ribosome error rate is

1 out of every 10^4 aminos incorporated

73

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

GroEL chaperone

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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

Unfolded Proteins

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

-Prevents premature release of the substrate

GroES complex

76

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

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

77

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

Insoluble proteins (Aggregates)

78

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

Prion Diseases

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Prion diseases can be caused by a mutation in the

PRNP gene

80

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

Kuru

81

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

Stress-induced protein damage

82

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

Aggresome

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

β-pleated sheet aggregates

84

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

Prions

85

Characterized by the accumulation of aberrant Aβ peptide in the plaques

Alzheimer's Disease

86

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

Trinucleotide expansion diseases

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