Type: Process Essays
Sample donated: Maria Haynes
Last updated: September 29, 2019
“Defective protein folding as abasis of human diseases ” Abstract: protein is the most importantbiological macromolecules, which is composed of polypeptide chains of specificamino acid sequences. It is the structural and functional unit of living cells.To function properly in a cell a protein must achieve its proper conformationand location within the crowded environment of the cell. Multiple cell systemcalled chaperons and also other cell environmental conditions such as pH andthermodynamics system of the cell and the activities of different enzymes helpproteins to get a stabilized in its three dimensional structures and folded ina way that can perform its function properly in a living system. An error inthese system can lead to an improper folding in protein’s amino acid sequenceswhich can accumulate and cause toxicity in cells that can introduce improperfunctions of protein which can lead to different diseases known as proteinmisfolding diseases. There are several reasons that can cause protein-misfoldingdiseases in human. The most important factors are improper degradation; mutationin protein coding genes, mislocalization; dominant negative mutations,structural alternations.
Oxidative stress; trafficking error that introduceimproper functions of proteins and established toxicity in tissue. For exampledifferent neurological disorders like Alzheimer’s diseases, Parkinson’sdiseases, prion diseases and amylo lateral sclerosis are caused by deposit ofamyloid fibrils, which is a result of misfolded proteins. Many geneticsexperiment shows that protein misfolding is a underlying cause of many humandiseases. Now a day by experimenting these conditions several treatmentsstrategies and drugs are discovered to prevent and cure the misfolding proteinfunctions. In these paper the factors and the mechanisms those are theunderlying causes of misfolding proteins are described and also the therapeuticinterventions are taken under consideration to fight these protein misfoldeddiseases. Introductions: proteins are themost important biological macromolecules. There are four different levels ofprotein structures.
The basic unit of protein structure is amino acidsequences, which are linked together by peptide bonds. The secondary structuresof proteins are defined by localized conformation of the polypeptide backbone.The three dimensional structure of protein is not accurately known yet. So anysmall change in the amino acid sequences led to the protein misfolding. Thereare several factors that can affect the amino acid sequences of protein. Themolecular chaperons system and enzymes catalyzing reactions help proteins tostabilized in its three dimensional structure. The proper folding of proteininto its functional structure is a complex processes.
The calnexin and the heatshock proteins Hsp60 and Hsp70 and two additional enzymes peptidyl-prolylisomerase (PPI) and protein disulfide isomerase (PDI) play important role infolding of protein into the cells. Hsp70 binds to the unstructured newlysynthesized 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-dimensionalstructures and transfers it to different organelles where they form different oligomercomplexes. Hsp chaperon partially folded the polypeptide chain.
Besides theseprotein binding molecular system in the endoplasmic reticulum of the cell there is another chaperon system calledcalnexin. This is an Ca+ binding integral membrane phosphoprotein whichinteracts with newly synthesized glycoprotein in the ER.Any kind of error in this system can give rise to misfolding in proteins. Thesemisfolded or partially unfolded intermediates aggregate and enhanced atequilibrium conditions of cell. The surfaces of these partially unfoldedproteins are normally hydrophobic. For this reason they aggregate more easilythan the normal folded proteins which posses hydrophobic amino acid thatsituated at interior portion of the protein.
The partially folded proteininteracted with normal proteins that form fibrils and protofibrils. Thisaggregation is the origin of toxicity in the cell that leads toneurodegenerative diseases in human. Various factors can also change theconformation of different proteins, which can then aggregate and cause toxicityin human cell.
One of the example of conformation change in protein causestoxicity is the Tau protein which then cannot properly paired with themicrotubules and causes Alzheimer’s diseases in human. Factors and mechanism for proteinmisfolding:The mechanism of misfolding ofproteins and the diseases caused by them are discussed below:1) Changesin environmental factors: Various environmental conditions of cell such aschanges in ionic strengths, pH, temperature and also protein concentrationaffect the rate and extent of amyloid formation. Experimentally it was provedthat the fibril formation and their structure is mainly pH dependent.
At pHabout 2.5 the fibrils fragments are formed with 60-80 A in diameter. But inhigher pH at 5.5 the fibrils does not form any branch and become numerous inlength.
At pH 8 these fibrils are mostly become amorphous materials. In asimilar way aggregation of beta amyloid protein (A?1-42) is dependent on the pH ofthe solution. Acidic condition is favorable for the formation of larger andcomplex structure of these beta fibrils but at pH of 5.8 these aggregationcauses apoptosis death of the cell. Similarly the kinetics of formationaggregation of amyloid ? peptide depends on ionic strength of the cell solution. By many-researchedinformation it was proved that the increased in ionic strength enhanced theatomic fluctuation of the hydrophobic core and it destabilized the ?sheetstructure of protein.
This causes the amyloid ? to aggregate and causes theneurotransmitter degradation diseases Alzheimer. Thetemperature also has some affect on the aggregation formation. For example thetransition of solid Abeta (1-28)and Abeta (1-42) from ?helix to beta sheets structureoccurred at 40-45 degree celcius. In fact this Abeta (1-42) does not containalpha helix and random coil structure and thus it aggregate highly at thistemperature. Like temperature the high concentration of Abeta peptide alsoinfluence the formation of aggregation of these fibrils. Recent studies showsthat the amyloid precursor protein get high in concentration due to age relatedmatter which also influence the processing of aggregation in the tissue of CSF.
2) Dominatenegative mutation, loss of function and gain of toxic function: the dominantnegative mutation occurs when a mutation in any gene adversely effects thefunction of wild type gene even in the presence of heterozygote condition. Itusually block the function of the wild type gene and aggregate to exits toxiceffect which can lead to death. For example the mutation in the insulin geneproduced diabetic mellitus diseases. The mutation occurs in all domains of thegene which causes addition or removal of cysteine thus enhances the odd numberof potential pairing sites for disulfide bonds that causes the aggregation ofmisfolded protein and roots the diseases. Another example of negative dominantmutation factor is mutation in the homotetrameric transcription factor p53.This is a phosphorylated protein that plays an important role in preventingcancer diseases. Under cytological stress p53 enhances the cell cycle arrest orapoptosis.
So mutation in this gene disrupts the vital role of p53 and causesthe cancer diseases. The p53 aggregation into oligomers and fibrils has alreadybeen demonstrated by Silva et al(2014). Furthermore in tumor tissue bothaggregations of mutant and wild type p53 has been observed.3) Error in posttranslationalmodification: usually after transcription of a protein encoded gene thetranslation the translated protein goes several modification. This is a veryhighly controlled process and plays an important role in cellular processes.
But stressed or diseased condition effect the regulation of this importantprocess and the excessive or differential modifications causes the protein toaggregate and causes different diseases. The enzymatic PTMs that causes themisfolding of proteins are glycation, sulfation and phosphorylation.i) Glycation: glycation is also known as noenzymatic glycosylation. It is the process by which a sugar molecule such asglucose or fructose covalently bonded with a protein molecule withoutactivation of any enzyme. Several reports have demonstrated that there is adirect 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’sdiseases. Another example is that the glycation of ?-synuclein also causes theaggregation of toxicity which causes Parkinson’s diseases. Similarly D ribosylationof ?-synuclein promotes molten globule like aggregation that produce hightoxicity in the cell. ii) Phosphorylation: