Abstract
Chaperones protect other proteins against misfolding and aggregation, a key requirement for maintaining biological function. Experimental observations of changes in solubility of amyloid proteins in the presence of certain chaperones are discussed here in terms of thermodynamic driving forces. We outline how chaperones can enhance amyloid solubility through the formation of heteromolecular aggregates (co-aggregates) based on the second law of thermodynamics and the flux towards equal chemical potential of each compound in all phases of the system. Higher effective solubility of an amyloid peptide in the presence of chaperone implies that the chemical potential of the peptide is higher in the aggregates formed under these conditions compared to peptide-only aggregates. This must be compensated by a larger reduction in chemical potential of the chaperone in the presence of peptide compared to chaperone alone. The driving force thus relies on the chaperone being very unhappy on its own (high chemical potential), thus gaining more free energy than the amyloid peptide loses upon forming the co-aggregate. The formation of heteromolecular aggregates also involves the kinetic suppression of the formation of homomolecular aggregates. The unhappiness of the chaperone can explain the ability of chaperones to favour an increased population of monomeric client protein even in the absence of external energy input, and with broad client specificity. This perspective opens for a new direction of chaperone research and outlines a set of outstanding questions that aim to provide additional cues for therapeutic development in this area.
Highlights
A large fraction of the proteins produced in the human body are chaperones that prevent other proteins from misfolding and aggregating (Bukau et al, 2006; Hartl et al, 2011, Balchin et al, 2016)
We present a thermodynamic analysis of different scenarios in systems composed of amyloid peptide and chaperone and discuss the experimental observations of changes in apparent solubility of amyloid proteins modulated by initial a b time equilibrium Pm Pma Pmo c d
A change in the solubility of the amyloid peptide can only be achieved, in the absence of external energy input, by a particular class of chaperones that are very unhappy on their own. This class includes for example several of the DNAJB proteins and αB crystallins. The action of these chaperones in the suppression of aggregation and promotion of disaggregation may be understood in terms of the second law of thermodynamics and the equal chemical potential in all phases of a compound at thermodynamic equilibrium
Summary
A large fraction of the proteins produced in the human body are chaperones that prevent other proteins from misfolding and aggregating (Bukau et al, 2006; Hartl et al, 2011, Balchin et al, 2016). Such roles are key for maintaining biological function, and chaperones are critical components of organisms ranging from bacteria to human. The direction of change of a system is always towards lower free energy and we argue here that passive ATP-independent mechanisms are able to alter the effective protein solubility and discuss such mechanisms from a thermodynamic perspective, assuming in the following a constant temperature and pressure
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