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Protein aggregation occurs when the cell is exposed to extreme conditions like intense heat or exposure to the protein denaturants that may lead to cell death. However, protein aggregation can be minimized significantly if the cell is first exposed to moderate stress before encountering extreme conditions. This is a kind of acquired tolerance to the extreme conditions called a Heat-shock response. Heat-shock response is a result of the protective mechanism developed by the organism in response to the stress.
Heat-shock response includes the production of some special types of proteins called heat-shock proteins (HSPs) or molecular chaperones. These proteins prevent the protein aggregation and assist the aggregated protein to attain the natural 3D structure (protein folding) and also promote the degradation of aggregated proteins that may not be able to regain the native 3D structure.
Heat-shock response also promotes the synthesis of some small biomolecules that may also prevent the protein aggregation at elevated temperatures. Microorganisms such as Saccharomyces cerevisiae, are found to contain Heat-shock protein (HSP104) and trehalose, a disaccharide. These molecules contribute to the survival of the organism in extreme conditions by preventing aggregation of the proteins.
Initially, HSP104 is present in a very low amount, but its expression increases significantly when an organism is exposed to the stressed conditions and tolerance to the stressed conditions is greatly affected in the organism with HSP104 mutation. HSP104 does not suppress the aggregation of proteins in response to the heat but helps to regain the 3D structure of the protein that has already been aggregated.
Trehalose is a disaccharide that was previously considered as a reserved carbohydrate. However, it also promotes stress tolerance in the organism. Trehalose is produced in response to the extreme conditions where it protects from stresses. Furthermore, mutation of the tps1 gene that encodes a subunit of trehalose synthase affects the production of trehalose as a result of which organism becomes sensitive to the heat.
Researchers have reported that trehalose not only stabilizes the native structure of the proteins but also prevents aggregation of the proteins that have been denatured already and, therefore, it assists the function of the Heat-shock proteins. In fact, at higher concentrations, trehalose inhibits the reactivation of the denatured proteins by heat-shock proteins and itself helps the full recovery of the denatured proteins from heat shock.
Effect of trehalose and some other small organic molecules on protein stabilization
The effect of trehalose on protein stabilization had also been studied in vitro. However, no such studies had been carried out in vivo. So, to confirm whether the trehalose helps protein stabilization during heat shock in vivo, the researcher selected firefly luciferase. Luciferase is an enzyme that is heat-sensitive and gets denatured at high temperature. When luciferase-expressing cells with tps1 mutation were treated to heat-shock, the activity of the luciferase enzyme was found to be declined significantly while, in the organism of wild type, the luciferase activity was declined only slightly.
Not only trehalose but some other small organic molecules are also found to affect the protein structure. Researchers performed an in vitro study in which they analyzed the effect of some small organic molecules on the denatured rhodanese enzyme at elevated temperature. They found that sucrose and maltose suppress the aggregation, while glucose and sorbitol has a smaller effect. In addition, glycine, mannitol, proline, and betaine did not affect the denaturation of rhodanese enzyme.
In conclusion, organisms not only produce Heat-shock proteins to maintain the balance of protein aggregation and proper folding of the denatured proteins but also produce some organic molecules that equally contribute to this balance. Trehalose stabilizes the protein aggregates that are reactivated spontaneously. However, the higher concentration of trehalose inhibits the reactivation of denatured proteins. Therefore, trehalose is rapidly degraded during the recovery of an organism from the heat-shock.
Reference: Molecular Cell
Article DOI: 10.1016/S1097-2765(00)80064-7