Protein Folding in Health & Disease

Question 1

What factors restrict the number of conformations that an amino acid chain can fold in to?

Answer 1

1. the rigidity of the peptide bond limits the flexibility of the chain
2. the physical and chemical properties of the sidechains restricts the number of stable options

Question 2

In protein folding, what structures will form first?

Answer 2

Secondary structures

Stabilising forces then retain these

Question 3

What do the secondary structures form in protein folding?

Answer 3

They create a core structure from which the remaining process proceeds

Question 4

How does the process of protein folding lead to a more stable conformation forming?

Answer 4

Less stable structures unravel and alternative structures form in quick succession

This occurs until a more stable conformation occurs

Question 5

What conformation will the protein finally fold into?

Answer 5

The conformation that has the lowest energy level

In the unfolded form, the protein is in the highest energy level

Question 6

What contains all the information needed to ensure correct protein folding?

What is the problem with this?

Answer 6

The amino acid sequence

However, within cells high protein concentrations and the presence of other biomolecules can interfere

Question 7

What is the role of chaperone proteins?

What are the 2 types?

Answer 7

They are present in cells to facilitate protein folding

1. molecular chaperones
2. chaperonins

Question 8

What is the role of molecular chaperones?

Answer 8

They bind to short segments of protein and help that particular area to fold correctly

Question 9

What is the role of chaperonins?

Answer 9

They form folding chambers (protein barrels) which provide a stable environment to encourage correct folding

Question 10

What happens if proteins are not folded correctly?

Answer 10

They will not function normally, if at all

Question 11

What type of protein misfolding causes cystic fibrosis and phenylketonuria?

Answer 11

Mutations which cause proteins to be unable to fold into an active conformation

Lack of the proteins gives the symptoms of the disease

Question 12

What happens if misfolded proteins accumulate?

Answer 12

They may hinder normal cellular processes and damage cells

Question 13

How may a misfolded protein act as an infectious agent?

Answer 13

It causes conformational changes in other proteins

This damages previously normal cellular proteins

It may lead to a damaging accumulation of aggregated protein

Question 14

What do protein misfolding diseases result in?

What causes this?

Answer 14

Aggregation of proteins and cell death

They are caused by formation of insoluble aggregates, rich in B-pleat sheet, of previously soluble proteins

Question 15

What is an amyloid disease?

What happens?

Answer 15

Fragments of normal proteins produce amyloid fibres

The build up of abnormal protein amyloid makes it difficult for organs and tissues to function properly

Question 16

What is a prion disease?

Answer 16

This occurs when an infectious protein agent causes a conformational change in a normal protein

Question 17

What are examples of amyloid and prion diseases?

Answer 17

Amyloid: Alzheimer’s

Prion: Creutzfelt-Jacob, BSE and scrapie

Question 18

What is a prion?

Answer 18

A type of protein that can trigger normal proteins in the brain to fold abnormally

Question 19

What type of disease is Alzheimer’s disease?

How is it cured?

Answer 19

It is a progressive dementia

There is no cure and it eventually causes death

Question 20

What are some of the symptoms of Alzheimer’s disease?

Answer 20

1. memory loss
2. loss of language ability
3. loss of the ability to manipulate visual information
4. poor judgement
5. confusion
6. mood swings and restlessness

Question 21

When comparing the brain of an Alzheimer’s patient to a healthy patient, what is visible?

Answer 21

There is an obvious loss of neurones in the cerebral cortex

Question 22

What causes Alzheimer’s disease?

Answer 22

A fragment from a normal membrane protein accumulates after it is cleaved by proteases

This is the amyloid precursor protein

It forms A-beta once cleaved

Question 23

What is the structure of A-beta protein like?

Answer 23

It contains large amounts of B-pleated sheet structure

Question 24

What happens once the amyloid precursor protein is cleaved to A-beta?

Answer 24

The protein aggregates and forms insoluble fibrils of amyloid B protein in the brain

Question 25

What happens to the amyloid B protein fibrils in the brain?

Answer 25

The fibrils aggregate to form plaques

The plaques damage and destroy neurones

Question 26

When do symptoms first begin to appear in Alzheimer’s disease?

Answer 26

Significant damage has occurred to the brain before any symptoms are experienced by the patient

Question 27

What is the most common form of Creutzfelt-Jacob disease (CJD)?

Who does it affect?

Answer 27

The sporadic form

This arises at random and tends to affect older people

Question 28

What are the symptoms of CJD?

Answer 28

1. loss of neurological function
2. memory loss
3. loss of coordination and language ability
4. coma and eventual death

Question 29

Other than the hereditary forms, what causes CJD?

Answer 29

Ingestion of an infectious agent

This is the prion protein

Question 30

What determines the incubation period for prion diseases?

Answer 30

Genetic factors

Question 31

How does the prion protein affect the brain?

What is this called?

Answer 31

It creates vacuoles in the brain which resemble a sponge-like structure

This is spongioform encephalopathy

Question 32

How is CJD caused by the interaction of a Prion protein with a normal component?

Answer 32

The prion protein interacts with a normal membrane protein (soluble prion)

Question 33

What are the characteristics of the normal prion protein?

Answer 33

They are water soluble and can be broken down by proteases

They are mostly a-helical

Question 34

What happens when the normal prion protein interacts with abnormal prion protein?

Answer 34

It causes the normal prion protein to acquire the abnormal prion structure

This is mostly B-pleated sheet

Question 35

How does the abnormal prion protein differ to the normal?

Answer 35

It is insoluble and resistant to breakdown by proteases

Question 36

What happens once the abnormal proteins have been formed?

Answer 36

They form insoluble aggregated clumps of protein