Protein folding is essential for function. Newly synthesized proteins require chaperone proteins and chaperonins to fold correctly to prevent aggregation. Misfolded proteins are associated with diseases like Alzheimer's and Parkinson's. Chaperones assist folding in cellular compartments like the cytosol and mitochondria. Misfolding can occur through mutations, defective chaperones, or external agents and lead to nonfunctional or toxic protein aggregates associated with neurodegenerative diseases.

1. Folding of Protein and
Chaperons and various protein
folding diseases and function
of Protein
Mohmmad Amil Rahman
S.R.

2. Protein Folding
• If a correct primary structure has been formed, the
nascent protein will fold spontaneously and attain
higher orders of structure and the correct
conformation.
• However, spontaneous folding is a slow process.

3. • Most proteins must fold
into defined three-
dimensional structures to
gain functional activity.
• But in the cellular
environment, Newly
synthesized proteins are
at great risk of aberrant
folding and aggregation,
potentially forming toxic
species.

4. •Rapid and correct folding of the newly-
synthesised protein is ensured by:
Some enzymes
Protein factors known as chaperone
proteins and chaperonins
• Aberrant behavior of some of these metastable proteins, such as
tau and α-synuclein, can give rise to the formation of fibrillar
aggregates that are associated with dementia and Parkinson’s
disease.
Proteostasis

5. •The enzymes are:
• Protein disulphide isomerase – This
enzyme ensures that the disulphide bonds
are formed between the correct cysteine
residues.
• Peptidyl prolyl cis-trans isomerase – This
enzymes ensures that the bonds involving
proline residues are cis or trans as
required.

6. •The chaperone proteins include:
1. Heat shock proteins 40 and 70 (HSP 40 and HSP
70) in cytosol
2. Heat shock proteins 10 and 60 (HSP 10 and HSP
60) in mitochondria
3. Calnexin and calreticulin in endoplasmic
reticulum

7. The HSP70 chaperone cycle.
HSP70 is switched between
high- and low-affinity states for
unfolded and partially folded
protein by ATP binding and
hydrolysis. Unfolded and
partially folded substrate
(nascent chain or stress-
denatured protein), exposing
hydrophobic peptide segments,
is delivered to ATP-bound
HSP70 (open; low substrate
affinity with high on-rates and
off-rates) by one of several
HSP40 cofactors.

9. •The chaperonins include:
A. BiP
B. TriC
• These enzymes and protein factors are also required
to refold the proteins after they have passed through
a membrane in the unfolded form.

10. Organization of chaperone pathways in the
cytosol

11. • Proteome maintenance and the proteostasis network.
 Protein fates in the proteostasis
network. The proteostasis network
integrates chaperone pathways for the
folding of newly synthesized proteins,
for the remodelling of misfolded states
and for disaggregation with the protein
degradation mediated by the UPS and
the autophagy system.

12. Misfolding of proteins
• Misfolding can occur due to :
Change in primary structure
Defects in molecular chaperones
Exogenous agents
 Proteins that are not able to achieve the native state, due either to an unwanted
mutation in their amino acid sequence or simply because of an error in the folding
process, are recognized as misfolded and subsequently targeted to a degradation
pathway.

13.  The formation of oligomers and aggregates occurs in the cell when a critical
concentration of misfolded protein is reached. Aggregated proteins inside the
cell often lead to the formation of an amyloid-like structure, which eventually
causes different types of degenerative disorders and ultimately cell death.
 A ‘chaperone overload’hypothesis, which explains that with aging, there is an
overburden of accumulated misfolded protein that prevents molecular
chaperones from repairing phenotypically silent mutations which might cause
disease.
 It has been shown that the yield of correctly folded protein obtained from in
vitro refolding is low due to the formation of thermodynamically stable folding
intermediates. These conformations are called ‘dead-end’ conformations and are
‘off-pathway’intermediates, they generally lead to the formation of insoluble
aggregates that may eventually causes different degenerative diseases. Classic
examples of these degenerative diseases are CF, which is caused by the deletion
of a single residue phenylalanine in the CFTR protein, and sickle cell anemia,
which originated due to a mutation in hemoglobin.

14. • A misfolded protein is usually degraded.
• Some misfolded proteins are resistant to degradation
e.g. amyloid protein
• Misfolded proteins :
• May be non - functional
• May not reach their destination
• May be toxic

15. Diseases due to Misfolding
 Misfolding of proteins can cause disease
 Examples are :
 Scrapie in sheep
 Mad cow disease in cattle
 Alzheimer’s disease and Creutzfeldt - Jacob
disease in human beings

17. Alzheimer’s disease
 Misfolded amyloid b-protein is deposited in brain
 Resistant to degradation
 Results in neuropsychiatric abnormalities

19. Creutzfeldt - Jacob Disease (CJD)
 Misfolded prion protein is deposited in brain
 Results in neuropsychiatric abnormalities
 May be :
 Inherited
 Due to spontaneous mutation
 Acquired

20. Acquired CZD
 One form of transmissible CZD occurred in UK
 Meal made from sheep having prion disease (Scrapie)
was fed to cows
 Cows developed bovine spongiform encephalopathy
(mad cow disease)

21.  Human beings who consumed beef from these cows
developed a variant of CZD
 Abnormal prion protein caused misfolding of normal
prion protein also