Abstract
In the last few years, hydrostatic pressure has been extensively used in the study of both protein folding and misfolding/aggregation. Compared to other chemical or physical denaturing agents, a unique feature of pressure is its ability to induce subtle changes in protein conformation, which allow the stabilization of partially folded intermediate states that are usually not significantly populated under more drastic conditions (e.g., in the presence of chemical denaturants or at high temperatures). Much of the recent research in the field of protein folding has focused on the characterization of folding intermediates since these species appear to be involved in a variety of disease-causing protein misfolding and aggregation events. The exact mechanisms of these biological phenomena, however, are still poorly understood. Here, we review recent examples of the use of hydrostatic pressure as a tool to obtain insight into the forces and energetics governing the productive folding or the misfolding and aggregation of proteins.
Highlights
Protein folding has evolved from a field of mere academic interest to an area of major biological and medical relevance
In the last few years, hydrostatic pressure has been extensively used in the study of both protein folding and misfolding/aggregation
Much of the recent research in the field of protein folding has focused on the characterization of folding intermediates since these species appear to be involved in a variety of diseasecausing protein misfolding and aggregation events
Summary
Protein folding has evolved from a field of mere academic interest to an area of major biological and medical relevance. Recent kinetic simulation studies have suggested a possible critical contribution of onpathway intermediates in the folding of a simple three-helix bundle motif [6] The fact that such intermediates are not usually detected in equilibrium or kinetic investigations of small, fast folding proteins suggests that they constitute metastable states that are very little populated under the conditions that are normally employed to study protein folding (typically involving the use of chemical denaturants, acidic pH or high temperatures). Pressure denaturation studies of both natural and de novo designed proteins in which the volumes occupied by internal cavities in the hydrophobic core were changed by amino acid substitutions indicate that the loss of internal void volumes plays a critical role in the unfolding of proteins induced by pressure [12,13]. Here we will focus on pressure studies of the folding of single domain de novo designed and natural proteins, as well as on the effects of pressure on protein misfolding and aggregation phenomena
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