Abstract
A subset of the proteome is prone to aggregate formation, which is prevented by chaperones in the cell. To investigate whether the basic principle underlying the aggregation process is common in prokaryotes and eukaryotes, we conducted a large-scale aggregation analysis of ~500 cytosolic budding yeast proteins using a chaperone-free reconstituted translation system, and compared the obtained data with that of ~3,000 Escherichia coli proteins reported previously. Although the physicochemical properties affecting the aggregation propensity were generally similar in yeast and E. coli proteins, the susceptibility of aggregation in yeast proteins were positively correlated with the presence of intrinsically disordered regions (IDRs). Notably, the aggregation propensity was not significantly changed by a removal of IDRs in model IDR-containing proteins, suggesting that the properties of ordered regions in these proteins are the dominant factors for aggregate formation. We also found that the proteins with longer IDRs were disfavored by E. coli chaperonin GroEL/ES, whereas both bacterial and yeast Hsp70/40 chaperones have a strong aggregation-prevention effect even for proteins possessing IDRs. These results imply that a key determinant to discriminate the eukaryotic proteomes from the prokaryotic proteomes in terms of protein folding would be the attachment of IDRs.
Highlights
Most proteins must fold into their native structure to exert their function[1]
The histogram of the differences in the solubility between the homologous pairs indicated that the S. cerevisiae counterparts tended to have higher solubility than those of E. coli (Fig. 4A, upper panel). This tendency was observed only in the low disorder group, whereas an opposite trend was observed in the high disorder group (Fig. 4A, middle and lower panel). These results suggest that S. cerevisiae proteins that did not have long intrinsically disordered regions (IDRs) tended to be more soluble than E. coli homologous counterparts, while S. cerevisiae proteins that have long IDRs showed a stronger tendency to aggregate than the E. coli counterparts
These results suggest that the solubility difference between S. cerevisiae and E. coli homologous pairs has some relationship with the structural properties such as the Structural Classification of Proteins (SCOP) folds
Summary
Most proteins must fold into their native structure to exert their function[1]. protein folding is a highly complicated process, and many nascent proteins synthesized at the ribosomes are exposed to the risk of forming protein aggregation because of the difficulty of their folding under the physiological conditions[2,3]. To fill the significant gap in our understanding on folding and aggregation, we previously conducted a comprehensive analysis of protein aggregation by using a chaperone-free reconstituted translation system of Escherichia coli, called the PURE system[7,8]. Most eukaryotes have multiple sets of Hsp70/40 chaperones, Hsp[90] chaperones, and group II chaperonin CCT in the cytosol[3,12,13,14] They are thought to maintain protein homeostasis in the cell by acting cooperatively on the nascent proteins and proteins destabilized by certain environmental changes. Another major difference between prokaryotic and eukaryotic proteins is assumed to be the existence of intrinsically disordered regions (IDRs). The fundamental roles of these IDRs for the eukaryotic organisms are not fully elucidated, they are known to constitute a highly complex protein-protein interaction network by their unique binding manner, including the ability to bind multiple binding partners[22,23]
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