![]() The underlying mechanism allowing a single chaperone to perform functions with such drastically different outcomes remains unclear. For example, heat shock protein 70 (Hsp70, or DnaK in bacteria) participates in de novo protein folding, assembly of protein complexes and translocation across membranes to protein refolding, disaggregation, and degradation ( Mayer and Gierasch, 2019). Interestingly, a single chaperone can often perform several of these functions. Chaperones not only facilitate folding of proteins, but also transport them, prevent their aggregation, dissolve aggregates or unfold misfolded proteins ( Pelham, 1986 Ellis, 1987 Hemmingsen et al., 1988 Goloubinoff et al., 1989 Walter and Buchner, 2002 Hartl and Hayer-Hartl, 2009 Balchin et al., 2016 Goloubinoff, 2016 Wentink et al., 2019 Balchin et al., 2020 Burmann et al., 2020). ![]() While UPS and the autophagy system play their functional role in degradation of expired proteins, chaperones are the key instrument of protein homeostasis. They comprise of different molecular chaperones, as well as the ubiquitin-proteasome system (UPS) and the autophagy system. To tackle this challenge, protein homeostasis networks have evolved in all kingdoms of life ( Hipp et al., 2019). Folding intermediates or unfolded proteins are dysfunctional, prone to aggregation and may lead to fatal conditions that are a threat to the health of the cell ( Knowles et al., 2014 Tittelmeier et al., 2020). In addition, even proteins that are capable of spontaneously reaching their native conformation may unfold under stress conditions. Folding via such intermediate states is considered to be the rule for proteins larger than 100 amino acids ( Brockwell and Radford, 2007). Thus, proteins can easily become trapped in local folding minima, from where they need to overcome free energy barriers to reach the correct native conformation. While small proteins can fold efficiently, the vast majority of nascent protein chains needs to navigate a rugged potential energy surface, driven by the hydrophobic collapse and constrained by the crowded environment of the cell ( Levinthal, 1968 Bryngelson and Wolynes, 1987 Wolynes et al., 1995 Onuchic and Wolynes, 2004 Bartlett and Radford, 2009). Most proteins need to fold into a three-dimensional structure to perform their function, as encoded in their amino acid sequence ( Anfinsen et al., 1961 Haber and Anfinsen, 1962 Anfinsen, 1973). We discuss the consequences of applying this concept in the context of ATP-dependent and -independent chaperones and their functional regulation. ![]() Based on these findings, we propose chaotropicity as a suitable biophysical concept to rationalize the generic activity of chaperones. Numerous recently elucidated structures of bacterial chaperone–client complexes show that dynamic interactions between chaperones and their client proteins stabilize conformationally flexible non-native client states, which results in client protein denaturation. Despite this seemingly large variety, single chaperones can perform several of these functions even on multiple different clients, thus suggesting a single biophysical mechanism underlying. Chaperones not only facilitate folding of client proteins, but also transport them, prevent their aggregation, dissolve aggregates and resolve misfolded states. Molecular chaperones are the key instruments of bacterial protein homeostasis.
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