Redefining Molecular Chaperones as Chaotropes

Abstract

Molecular chaperones are the key instruments of bacterial protein homeostasis. Chaperones not only facilitate folding of client proteins, but also transport them, prevent their aggregation, dissolve aggregates and resolve misfolded states. 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. 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. Based on these findings, we propose chaotropicity as a suitable biophysical concept to rationalize the generic activity of chaperones. We discuss the consequences of applying this concept in the context of ATP-dependent and -independent chaperones and their functional regulation.

A Proteome-Wide Map of Chaperone-Assisted Protein Refolding in the Cytosol

“…These observations are consistent with the prevailing idea that the proteostasis network is integrated (Santra et al, 2017) rather than compartmentalized, with a large amount of redundancy built in: there may be proteins that prefer to use DnaK (because it requires less energy), or prefer to use GroEL (because they bind to it more rapidly), but ultimately most clients can use either. This finding is consistent with an emerging view that most chaperones share a common mechanism that can be effective on many clients, namely, unfoldase activity on misfolded states (Figure 7A) (Lin et al, 2008; Balchin et al, 2020; Macošek et al, 2021; Imamoglu et al, 2020), thereby providing those molecules with further opportunities to refold properly (the iterative annealing mechanism (Thirumalai and Lorimer, 2001)).…”

Cryo-EM structure of acylpeptide hydrolase reveals substrate selection by multimerization and a multi-state serine-protease triad

“…It is a necessary addition to the S9 oligopeptidase build-up too, since beside functioning as an oligopeptidaseassisting the degradation of smaller peptidesmammalian AAP also removes terminal N-acetylated amino acids from intact proteins, 17,18 processing a considerably greater variety of substrates than the other family members do. The highly charged clusters of the exible gatekeeper loops, lining the outer pore together with the shielded interior of the tetramer, might add a chaperon-like function 60 to the entrance: enabling it to rst strip the substrate protein segments of their solvent shell and then stabilize the exposed hydrophobic residues, promoting the unfolding of the chain that will allow the substrate to reach the buried and gated active sites.…”

Dissecting aggregation and seeding dynamics of α-Syn polymorphs using the phasor approach to FLIM

“…To the best of our knowledge, we show for the first time in situ that processing by the cellular proteostasis network does generate distinct α-Syn species with high seeding capacity. Our data offer an explanation for the conundrum that is increasingly observed with protein quality control pathways, as being generally protective and mediating the degradation of toxic protein aggregates, but sometimes having the opposite effect (Macošek et al, 2021; Tittelmeier et al, 2020). Indeed, there is mounting evidence that their activity can promote amyloid propagation under certain circumstances (Heiseke et al, 2009; Sang et al, 2021; Tittelmeier et al, 2020).…”

“…Our data offer an explanation for the conundrum that is increasingly observed with protein quality control pathways, as being generally protective and mediating the degradation of toxic protein aggregates, but sometimes having the opposite effect (Macošek et al, 2021;. Indeed, there is mounting evidence that their activity can promote amyloid 12 propagation under certain circumstances (Heiseke et al, 2009;Sang et al, 2021;.…”