![]() ![]() It consists of Hsp70 protein, a cooperating DnaJ protein (Hsp40) and a nucleotide exchange factor. The remaining polypeptides interact with the Hsp70 chaperone system ( Deuerling et al, 1999 Teter et al, 1999). ![]() In prokaryotes, where most proteins are rather small, it is estimated that 65–80% of them fold immediately after synthesis. The first line of defense is drawn at the ribosome, where prokaryotic trigger factor, or NAC protein in the case of eukaryotic organisms, associates with a nascent peptide to hold it in a folding-competent state. To minimize the risk of protein aggregation, the cells evolved a system of protecting nascent proteins during folding. Additionally, the hydrophobic stretches that are normally hidden inside the three-dimensional structure of a properly folded protein are not shielded from the environment and increase the tendency to form non-native contacts. During translation, since all the interacting residues are not yet present prior to chain termination, it is not possible for the new polypeptide chain to form all the proper amino-acid contacts that determine the protein's native structure. In a native protein, the interacting amino-acid residues are often dispersed along the polypeptide sequence, and only folding of the polypeptide chain brings them in proximity. Under physiological conditions, proteins are threatened with aggregation from the very first moments of their existence. Here, we focus on the specific mechanisms by which chaperones from three unrelated families, namely heat-shock protein 70 (Hsp70), Hsp100 and the small Hsps, act on protein aggregates to liberate and refold the polypeptides trapped inside the aggregates. Either constitutively expressed or induced under stress conditions, they are essential for proper functioning of the cell and are found in every living organism. The chaperones are a large and diverse group of unrelated proteins that assist in correct noncovalent assembly and/or disassembly of other polypeptide-containing structures, but which are not permanent components of these structures when they are performing their normal biological functions ( Ellis, 1997). A special class of proteins, called molecular chaperones, has evolved to counteract this process. Loss of native conformation not only leads to depletion of functional proteins, but also leads to another problem in the cell, namely aggregation of polypeptides. Molecular crowding and rapidly changing environmental factors interfere with the process of folding of newly synthesized chains or promote loss of native conformation in mature polypeptides. The situation inside a living cell is much more complex than under idealized test-tube conditions of low protein concentration and a carefully chosen temperature. The level of expression of human genes shows an astonishingly tight inverse correlation with aggregation rates of the corresponding proteins measured in vitro, suggesting that there is hardly any margin of safety to respond to factors that decrease protein solubility ( Tartaglia et al, 2007). Thus, native proteins have a low margin of stability and are always more or less on the verge of denaturation. However, interactions stabilizing the unique conformation of energetic minimum combined with proper functioning are counterbalanced by a large decrease in entropy. The idea of an ‘energy landscape' (reviewed in Dobson, 2004) helped us to understand how it is possible to overcome the Levinthal paradox in protein folding. One of the most prominent qualities of proteins is their ability to find their native folded conformation within a vast conformational space. Here, we focus on the molecular mechanisms by which heat-shock protein 70 (Hsp70), Hsp100 and small Hsp chaperones liberate and refold polypeptides trapped in protein aggregates. Elimination of aggregates can be achieved by solubilization of aggregates and either refolding of the liberated polypeptides or their proteolysis. With massive protein aggregation occurring in response to heat exposure, the cell needs chaperones to control and counteract the aggregation process. Stress imposed by high temperature was one of the first aggregation-inducing factors studied and remains one of the main models in this field. Many factors leading to unfolding and misfolding of proteins eventually result in protein aggregation. Chaperones also play a role in a post-translational quality control system and thus are required to maintain the proper conformation of proteins under changing environmental conditions. Although the native structure of a protein is principally encoded in its amino-acid sequence, the process of folding in vivo very often requires the assistance of molecular chaperones. The chaperone protein network controls both initial protein folding and subsequent maintenance of proteins in the cell. ![]()
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