Oligomers of Heat-Shock Proteins: Structures That Don’t Imply Function

Most proteins must remain soluble in the cytosol in order to perform their biological functions. To protect against undesired protein aggregation, living cells maintain a population of molecular chaperones that ensure the solubility of the proteome. Here we report simulations of a lattice model of interacting proteins to understand how low concentrations of passive molecular chaperones, such as small heat-shock proteins, suppress thermodynamic instabilities in protein solutions. Given fixed concentrations of chaperones and client proteins, the solubility of the proteome can be increased by tuning the chaperone–client binding strength. Surprisingly, we find that the binding strength that optimizes solubility while preventing irreversible chaperone binding also promotes the formation of weakly bound chaperone oligomers, although the presence of these oligomers does not significantly affect the thermodynamic stability of the solution. Such oligomers are commonly observed in experiments on small heat-shock proteins, but their connection to the biological function of these chaperones has remained unclear. Our simulations suggest that this clustering may not have any essential biological function, but rather emerges as a natural side-effect of optimizing the thermodynamic stability of the proteome.Author Summary: The vast majority of living cells express molecular chaperones that suppress protein aggregation by inhibiting illicit protein–protein interactions. We refer to this class of chaperones as ‘passive molecular chaperones,’ since they do not require an external energy source in order to function. We use simulations of a minimal model of passive chaperones and aggregation-prone client proteins to show how these chaperones increase the solubility of the proteome as a whole. This anti-aggregation mechanism is surprisingly effective, even when the chaperones are expressed in very low concentrations. Most importantly, we predict that passive chaperones that are optimized to stabilize the proteome while avoiding irreversible aggregation are likely to cluster in chaperone-only oligomers. This behavior is not functional per se—that is, it is not required for these chaperones to perform their anti-aggregation function—but nevertheless emerges as a side-effect of this optimization. Our analysis thus provides an explanation for an unusual behavior that is commonly observed in experiments on passive molecular chaperones.