Proteins are one of the most important and are the most diverse of macromolecules as they carry out multiple functions, such as acting as enzyme catalysts and being used for transport (Alberts et al. , 2009). They are composed of polypeptides, which are long chains of amino acids held together by peptide bonds (Alberts et al. , 2009). The process whereby proteins form their 3-D conformation is known as protein folding. It is essential that proteins fold correctly as the shape of the protein determines its function and severe consequences can result if they are misfolded.
A common thought was that protein folding was spontaneous, however, it has been realized that some proteins need assistance to form into their native state (Hartl, Hlodan, & Langer, 1994). Special proteins that aid in protein folding are known as molecular chaperones. The main role of molecular chaperones is to prevent misfolding and aggregation of proteins, however, they also help with refolding denatured proteins (Hartl, Hlodan, & Langer, 1994). In addition, they focus on reducing chances of off-pathway reactions to produce functional proteins (Hartl & Martin, 1993).
Furthermore, hydrophobic portions of proteins are usually embedded in the centre of a folded protein, but are uncovered in partially folded polypeptide chains (Hartl, Hlodan, & Langer, 1994). Consequently, protein aggregates can be formed through the interaction of the hydrophobic portions on unfolded proteins (Hartl, Hlodan, & Langer, 1994). Thus, to avoid such interactions and allow proteins to fold correctly, chaperones shield the exposed hydrophobic surface, and isolate the unfolded protein from the cell surroundings (Hartl, Hlodan, & Langer, 1994).
One main issue with protein folding is that misfolded proteins and protein aggregation are affiliated with diseases such as Huntington disease and Alzheimer disease (Alberts, et al. , 2009). In recent studies, activation of the heat shock response was tested to see whether it would benefit those with Huntington disease (Labbadia, et al. , 2011). The heat shock response is stimulated when there is stress in the cytoplasm (e. g. excessive heat), and it causes genes, that result the production of molecular chaperones, to be turned on (Jackrel & Shorter, 2011).
Subsequently, the chaperones produced are able to help proteins maintain their native form or assist in their degradation (Jackrel & Shorter, 2011). In this study, the heat shock response was triggered by the activation of the transcription factor, HSF1 through HSP90 inhibitor (Labbadia et al. , 2011). It was conducted by using a mouse a model of Huntington disease. At first, it was observed that using the drug HSP990 (HSP90 inhibitor), did work as a therapeutic benefit as the amount of mutant huntingtin decreased in the mice; unfortunately, the effects wore off as time progressed (Labbadia et al. 2011). It was discovered that it was harder for the heat shock response to be activated as cells with Huntington disease had altered chromatin architecture that impaired the response (Labbadia et al. , 2011). Thus, treating these diseases is harder and more complex than anticipated which it is why it is important to have properly folded proteins. In conclusion, molecular chaperones in protein folding are necessary in order for them to function and reach their native states. Misfolded proteins can turn into aggregates and lead to untreatable diseases.
Although probable ways to cure these diseases are to either take a drug that stabilizes the native form of a protein or find a molecule that interferes with the pathway leading to the misfolded protein, it is hard to do. Thus, having chaperones there for assistance is vital. Bibliography Alberts, B. , Bray, D. , Hopkin, K. , Johnson, A. , Lewis, J. , Raff, M. , et al. (2009). Essential Cell Biology . New York: Garland Science. Hartl, F. -U. , Hlodan, R. , & Langer, T. (1994). Molecular chaperones in protein folding: the art of avoiding sticky situations. Trends in Biochemical Sciences, 19(1), 20-25.
Jackrel, M. E. , & Shorter, J. (2011). Shock and awe: unleashing the heat shock response to treat Huntington disease. The Journal of Clinical Investigation, 121(8), 2972-2975. Labbadia, J. , Cunliffe, H. , Paganetti, P. , Bates, G. P. , Weiss, A. , Katsyuba, E. , et al. (2011). Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. The Journal of Clinical Investigation, 121(8), 3306–3319. Martin, J. , & Hartl, F. -U. (1993). Protein folding in the cell: molecular chaperones pave the way. Structure, 1(3), 161-164.