Proteostasis is adaptive: Balancing chaperone holdases against foldases

Adam MR de Graff, David E Mosedale, Tilly Sharp, Ken A Dill and David J Grainger

PLOS Computational Biology, 2020, vol. 16, issue 12, 1-15

Abstract: Because a cell must adapt to different stresses and growth rates, its proteostasis system must too. How do cells detect and adjust proteome folding to different conditions? Here, we explore a biophysical cost-benefit principle, namely that the cell should keep its proteome as folded as possible at the minimum possible energy cost. This can be achieved by differential expression of chaperones–balancing foldases (which accelerate folding) against holdases (which act as parking spots). The model captures changes in the foldase-holdase ratio observed both within organisms during aging and across organisms of varying metabolic rates. This work describes a simple biophysical mechanism by which cellular proteostasis adapts to meet the needs of a changing growth environment.Author summary: Cells must maintain low levels of protein unfolding to avoid deleterious outcomes such as protein aggregation, oxidative damage, or premature degradation. The proteins responsible for this, called chaperones, come in two main varieties: ATP-consuming “foldases” that help clients fold and ATP-independent “holdases” that hold unfolded proteins until a foldase arrives. While foldases are necessary for folding, they are expensive to have in high quantities. Given that chaperones are abundant and costly, cells are under strong selective pressure to find economical combinations of foldases and holdases for maintaining low levels of unfolded protein. Yet, it is presently unclear what the ideal combination is and how it varies with growth conditions. By examining a toy model of chaperone function and minimizing the total cost of folding at different rates of protein synthesis, we find that while foldases are necessary at fast growth, holdases become increasingly effective at slow growth. Unexpectedly, total chaperone requirements were predicted to increase as synthesis slows, consistent with observations across age in worms, as well as across species with varying metabolic rates. This work thus provides a general framework for understanding the chaperone requirements of a proteome in terms of an energy minimization principle.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1008460

DOI: 10.1371/journal.pcbi.1008460

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