“Defective the most important biological macromolecules. There are

“Defective protein folding as a
basis of human diseases ”

 

Abstract: protein is the most important
biological macromolecules, which is composed of polypeptide chains of specific
amino acid sequences. It is the structural and functional unit of living cells.

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To function properly in a cell a protein must achieve its proper conformation
and location within the crowded environment of the cell. Multiple cell system
called chaperons and also other cell environmental conditions such as pH and
thermodynamics system of the cell and the activities of different enzymes help
proteins to get a stabilized in its three dimensional structures and folded in
a way that can perform its function properly in a living system. An error in
these system can lead to an improper folding in protein’s amino acid sequences
which can accumulate and cause toxicity in cells that can introduce improper
functions of protein which can lead to different diseases known as protein
misfolding diseases. There are several reasons that can cause protein-misfolding
diseases in human. The most important factors are improper degradation; mutation
in protein coding genes, mislocalization; dominant negative mutations,
structural alternations. Oxidative stress; trafficking error that introduce
improper functions of proteins and established toxicity in tissue. For example
different neurological disorders like Alzheimer’s diseases, Parkinson’s
diseases, prion diseases and amylo lateral sclerosis are caused by deposit of
amyloid fibrils, which is a result of misfolded proteins. Many genetics
experiment shows that protein misfolding is a underlying cause of many human
diseases. Now a day by experimenting these conditions several treatments
strategies and drugs are discovered to prevent and cure the misfolding protein
functions. In these paper the factors and the mechanisms those are the
underlying causes of misfolding proteins are described and also the therapeutic
interventions are taken under consideration to fight these protein misfolded
diseases.

Introductions: proteins are the
most important biological macromolecules. There are four different levels of
protein structures. The basic unit of protein structure is amino acid
sequences, which are linked together by peptide bonds. The secondary structures
of proteins are defined by localized conformation of the polypeptide backbone.

The three dimensional structure of protein is not accurately known yet. So any
small change in the amino acid sequences led to the protein misfolding. There
are several factors that can affect the amino acid sequences of protein. The
molecular chaperons system and enzymes catalyzing reactions help proteins to
stabilized in its three dimensional structure. The proper folding of protein
into its functional structure is a complex processes. The calnexin and the heat
shock proteins Hsp60 and Hsp70 and two additional enzymes peptidyl-prolyl
isomerase (PPI) and protein disulfide isomerase (PDI) play important role in
folding of protein into the cells. Hsp70 binds to the unstructured newly
synthesized protein polypeptides and released it into the solution of Hsp60.

The Hsp60 binds to unfolded polypeptide and helps it to fold in its functional three-dimensional
structures and transfers it to different organelles where they form different oligomer
complexes. Hsp chaperon partially folded the polypeptide chain. Besides these
protein binding molecular system in the endoplasmic reticulum of the  cell there is another chaperon system called
calnexin. This is an Ca+ binding integral membrane phosphoprotein which
interacts   with newly synthesized glycoprotein in the ER.

Any kind of error in this system can give rise to misfolding in proteins. These
misfolded or partially unfolded intermediates aggregate and enhanced at
equilibrium conditions of cell. The surfaces of these partially unfolded
proteins are normally hydrophobic. For this reason they aggregate more easily
than the normal folded proteins which posses hydrophobic amino acid that
situated at interior portion of the protein. The partially folded protein
interacted with normal proteins that form fibrils and protofibrils. This
aggregation is the origin of toxicity in the cell that leads to
neurodegenerative diseases in human. Various factors can also change the
conformation of different proteins, which can then aggregate and cause toxicity
in human cell. One of the example of conformation change in protein causes
toxicity is the Tau protein which then cannot properly paired with the
microtubules and causes Alzheimer’s diseases in human.

Factors and mechanism for protein
misfolding:

The mechanism of misfolding of
proteins and the diseases caused by them are discussed below:

1)   Changes
in environmental factors: Various environmental conditions of cell such as
changes in ionic strengths, pH, temperature and also protein concentration
affect the rate and extent of amyloid formation. Experimentally it was proved
that the fibril formation and their structure is mainly pH dependent. At pH
about 2.5 the fibrils fragments are formed with 60-80 A in diameter. But in
higher pH at 5.5 the fibrils does not form any branch and become numerous in
length. At pH 8 these fibrils are mostly become amorphous materials. In a
similar way aggregation of beta amyloid protein (A?1-42) is dependent on the pH of
the solution. Acidic condition is favorable for the formation of larger and
complex structure of these beta fibrils but at pH of 5.8 these aggregation
causes apoptosis death of the cell. Similarly the kinetics of formation
aggregation of amyloid ? peptide depends on ionic strength of the cell solution. By many-researched
information it was proved that the increased in ionic strength enhanced the
atomic fluctuation of the hydrophobic core and it destabilized the ?sheet
structure of protein. This causes the amyloid ? to aggregate and causes the
neurotransmitter degradation diseases Alzheimer.

The
temperature also has some affect on the aggregation formation. For example the
transition of solid Abeta (1-28)and Abeta (1-42) from ?helix to beta sheets structure
occurred at 40-45 degree celcius. In fact this Abeta (1-42) does not contain
alpha helix and random coil structure and thus it aggregate highly at this
temperature. Like temperature the high concentration of Abeta peptide also
influence the formation of aggregation of these fibrils. Recent studies shows
that the amyloid precursor protein get high in concentration due to age related
matter which also influence the processing of aggregation in the tissue of CSF.

2)   Dominate
negative mutation, loss of function and gain of toxic function: the dominant
negative mutation occurs when a mutation in any gene adversely effects the
function of wild type gene even in the presence of heterozygote condition. It
usually block the function of the wild type gene and aggregate to exits toxic
effect which can lead to death. For example the mutation in the insulin gene
produced diabetic mellitus diseases. The mutation occurs in all domains of the
gene which causes addition or removal of cysteine thus enhances the odd number
of potential pairing sites for disulfide bonds that causes the aggregation of
misfolded protein and roots the diseases. Another example of negative dominant
mutation factor is mutation in the homotetrameric transcription factor p53.

This is a phosphorylated protein that plays an important role in preventing
cancer diseases. Under cytological stress p53 enhances the cell cycle arrest or
apoptosis. So mutation in this gene disrupts the vital role of p53 and causes
the cancer diseases. The p53 aggregation into oligomers and fibrils has already
been demonstrated by Silva et al(2014). Furthermore in tumor tissue both
aggregations of mutant and wild type p53 has been observed.

3)   Error in posttranslational
modification: usually after transcription of a protein encoded gene the
translation the translated protein goes several modification. This is a very
highly controlled process and plays an important role in cellular processes.

But stressed or diseased condition effect the regulation of this important
process and the excessive or differential modifications causes the protein to
aggregate and causes different diseases. The enzymatic PTMs that causes the
misfolding of proteins are glycation, sulfation and phosphorylation.

i)             
Glycation: glycation is also known as no
enzymatic glycosylation. It is the process by which a sugar molecule such as
glucose or fructose covalently bonded with a protein molecule without
activation of any enzyme. Several reports have demonstrated that there is a
direct link between protein glycation and amyloidosis fibrils. For example A?
is a suitable substrate for glycation. The advanced glycation end product
(AGEs) can elevate the aggregation of simple A? accumulation that causes Alzheimer’s
diseases. Another example is that the glycation of ?-synuclein also causes the
aggregation of toxicity which causes Parkinson’s diseases. Similarly D ribosylation
of ?-synuclein promotes molten globule like aggregation that produce high
toxicity in the cell.

ii)            
Phosphorylation: