Molecular chaperones and their denaturing effect on client proteins
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Molecular chaperones and their denaturing effect on client proteins Sebastian Hiller1 Received: 29 July 2020 / Accepted: 23 October 2020 © The Author(s) 2020
Abstract Advanced NMR methods combined with biophysical techniques have recently provided unprecedented insight into structure and dynamics of molecular chaperones and their interaction with client proteins. These studies showed that several molecular chaperones are able to dissolve aggregation-prone polypeptides in aqueous solution. Furthermore, chaperone-bound clients often feature fluid-like backbone dynamics and chaperones have a denaturing effect on clients. Interestingly, these effects that chaperones have on client proteins resemble the effects of known chaotropic substances. Following this analogy, chaotropicity could be a fruitful concept to describe, quantify and rationalize molecular chaperone function. In addition, the observations raise the possibility that at least some molecular chaperones might share functional similarities with chaotropes. We discuss these concepts and outline future research in this direction. Keywords Molecular chaperones · Protein folding · Protein structure · Proteins dynamics · NMR spectroscopy · Chaotropic denaturants · Thermal unfolding · Protein stability
Atomic resolution studies of chaperone– client systems Cells in all kingdoms of life possess helper proteins—the chaperones—to perform essential tasks in the genesis of biomacromolecular structure (Ellis 1993; Bukau et al. 2006; Horwich and Fenton 2009; Hartl et al.. 2011; Georgescauld et al. 2014; Schopf et al. 2017). Chaperones can be classified into two groups, based on the broadness of their substrate range, the clientome. “Specialized chaperones” are specific for a single client or a few clients, while “general chaperones” have large clientomes with up to 100s of members (Bose and Chakrabarti 2017). The functionality of general chaperones is typically transitive among homologues, across species and even between different chaperone types, such that their clientomes overlap at least partially. In vitro assays for chaperone activity, such as the prevention of aggregation of model proteins, frequently show that different general chaperones function similarly, including ATP-independent as well as ATP-dependent ones (Stenberg and Fersht 1997; Gray and Fersht 1993; Gray et al. 1993; Entzminger et al. * Sebastian Hiller [email protected] 1
Biozentrum, University of Basel, Klingelbergstr. 70, 4056 Basel, Switzerland
2012; Huang et al. 2016; Burmann et al. 2020). Overall, these notions suggest that common biophysical principles are shared between general chaperones. The best characterized general chaperones are arguable the ATP-dependent Hsp90, Hsp60 and Hsp70 from the Heat shock protein (Hsp) family (Schlecht et al. 2011; Barducci and De Los Rios 2015; Sontag et al. 2017; Wruck et al. 2018; Burmann et al. 2020; Sousa et al. 2016; Goloubinoff et al. 2018; Rebeaud et al. 2020; Schopf et al. 2017). These large molecular machines integrate with
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