Proteinis the most important molecule in a creatures’ life (Schwartz, Snapp andKenworthy, 2001). The word protein is a Greek word which means ‘of firstimportance’. Proteins perform the most biological functions in living cells (Schwartz,Snapp and Kenworthy, 2001) and there are numerous proteins in organisms whichdiffer from one another. An important molecule, Deoxyribonucleic acid (DNA), isa long polymer made up of four different nucleotides and is the vehicle ofgenetic information responsible for making the proteins found in cells. Thegenetic information is then converted from four different bases of nucleotidesin DNA to amino acid in proteins by a process called translation. Therefore, aminoacid is the basic unit which builds the protein. These amino acids are thenjoined by peptide bonds to create a polypeptide chain.
However, amino acid canbe folded into many shapes to create diverse components that are important inliving cells. The majority of proteins in living cells are made up of just 20different types of amino acids that arrange in a practical order (Jayaram,2008) and have either acidic, basic, neutral, or hydrophobic side chains. The primary structure of a protein is a linearamino acid chain that determines the properties and the shape of the proteinand hence, any change in just a single amino acid in the sequence can lead to achange in properties of the protein which may stop it from function effectively(Schaefer& Rost, 2012). In other words, a protein is very specific to itsfunction. This essay will look at the role of misfolding protein in disease andthe mechanisms of protein misfolding and if there is relationship with aging.Firstly, it will discuss the mechanisms involved in protein folding and theforces that drive this process.
The folding of protein in three-dimensionalstructure is important to how a protein functions. The 3-D shape allows eachprotein to be recognised by other molecules and then it could interact withthem in a very specific way (Alberts, Johnson et al, 2002). In order for a primaryprotein to become functional, the protein has to be folded into its nativeconformation. To create a native conformation, molecular chaperones in the cellare required to assist the synthesized polypeptide. While, some chaperones arevery specific to their function, others are very general and they help most of theglobular protein to fold. The process of protein folding is very complicatedand understanding the molecular mechanisms involved in protein assembly is theone of most open questions in biochemistry (Herczenik& Gebbink, 2008).
Accordingto Englander et al (2008), the debate on whether proteins followed multipleroutes controlled principally by the downhill nature of the folding pathway ora distinct pathway which organised proteins respectively created problems inunderstanding the protein folding mechanism. However, the first theory of energy landscape proposedby Joseph Bryngelson and Jose´ N. Onuchic (1995) , which states that proteins do not have aspecific folding pathway; but rather, a compound series of mechanisms whichoccur through ‘routes down a folding funnel’ and which can be seen in figure 1clearly clarifies this issue. In addition to this, Leopold et al (1992)inaugurated a kinetic method for understanding the principle of ‘proteinfolding funnels’ by listing some basic considerations which include; (i) proteinsfold from indiscriminate places by doubling up and reshaping (ii) this process happensdiffusively and occurs when one system moves from higher to lower energy and(iii) the reconfiguration occurs between conformation and conformation(). Figure1: energy state of a protein folding under physiological and morphologicalconditions (). According to the graph, the protein is in the process ofacquiring its native conformation. The shape of the graph also explains theenergy states of the protein as it tries to attain this native conformationusing multiple inter- andintramolecular contacts (). Thereare many reasons for the existence of misfolded proteins.
The first reason isthe somatic mutation. This means that if there is a somatic mutation in thesequence of the gene, it will result in the protein being incapable ofattaining it’s the native conformation ( Gonzalez & soto, 2011). Another reason for misfolding, according to (Herczenik & Gebbink, 2008) is the environmental factors associated with aprotein; immediately changes such as high temperature, increase in PH orglucose levels affects a protein, lossof the natural or native state may occur.
In addition to this, it has beendiscovered that neurotoxicity of certain fibrillar forms are accountable forthe appearance of misfolded proteins (Papadimitriou et al, 2004). Furthermore,errors in transcription or translation process which occur cannot let theproteins fold well (Gonzalez & soto, 2011). As a result of the fairly highprobability of acquiring misfolded proteins, molecules known as chaperones arepresent in the cell to assist in proper protein folding (Muchowski ,2002). Someof the basic functions of these chaperones include; protecting hydrophobicregions and helping enzyme to reach its activity (Vishwas et al, 2000). Similarmolecules known as chaperonins help to provide a separate environment in whichfolding can take place, unhindered by intermolecular forces between non-nativeproteins (Gonzalez & soto, 2011).
However, even with the intervention ofthese protein-folding aiding molecules, misfolded proteins are still commonwhich have been found to be linked to many diseases today (Gonzalez & soto,2011). As a result of the failure of chaperones to effectively aid proteinsfold correctly, the existing environmental factors and mutations; it isimportant to carefully understand the mechanism of misfolded proteins as theyundoubtedly play a role in diseases. Moreover, mistakes which occurred on thepost translation modification or trafficking process of the proteins are also abig reason of protein misfolding. A very astonishing reason though is theenvironmental change which can has a great impact on the protein misfolding.Seeding and cross seeding mechanism is another reason for induction proteinmisfolding.
Inthe last ten years, there have been many conformational diseases reported to belinked to protein misfolding and these diseases are caused by the aggregation ofmisfolded protein structures into intermolecular ? sheet (Gonzalez & soto,2011). The interaction of these ? sheetsaccounts for the formation of oligomersand fibrils, which then come together to form amyloid deposits in affected regions such as tissues(Gonzalez & soto, 2011). As, mutation leads non-functional, misfoldedprotein to accumulate (Valastyan&Lindquist, 2014), there is a cellulardegradation in the cell such as autophagy, which is necessary for preventingnon-functional and misfolded protein to accumulate (). However, sometimesautophagy can cause diseases by being overactive (). Therefore inappropriatedegradation of protein could be a fundamental reason of developing severediseases. The diseases related to protein misfolding canbe found in table 1().
They may either be related to the central nervous systemor the peripheral nervous system (). General examples of these diseasesinclude; Table1: list of some diseases associated with misfolded proteins and theirrespective proteins (). Tosum up, formation and accumulation of incorrectly folded proteins causesseveral diseases such as that have no cure. Despite this, significant progresshas been made in regard to understanding the mechanism of protein misfolding , althoughso far, researchers and biologists do not understand the origin of thesediseases and the mechanisms that lead to misfolding to impair cell function anddamage tissue ().
Most of the misfolded proteins that cause diseases share thesame misfolding mechanisms.