Molecular chaperones accelerate the evolution of their protein clients in yeast

Abstract

Protein stability is a major constraint on protein evolution. Molecular chaperones, also known as heat-shock proteins, can relax this constraint and promote protein evolution by diminishing the deleterious effect of mutations on protein stability and folding. This effect, however, has only been stablished for a few chaperones. Here, we use a comprehensive chaperone-protein interaction network to study the effect of all yeast chaperones on the evolution of their protein substrates, that is, their clients. In particular, we analyze how yeast chaperones affect the evolutionary rates of their clients at two very different evolutionary time scales. We first study the effect of chaperone-mediated folding on protein evolution over the evolutionary divergence of Saccharomyces cerevisiae and S. paradoxus. We then test whether yeast chaperones have left a similar signature on the patterns of standing genetic variation found in modern wild and domesticated strains of S. cerevisiae. We find that genes encoding chaperone clients have diverged faster than genes encoding nonclient proteins when controlling for their number of protein-protein interactions. We also find that genes encoding client proteins have accumulated more intra-specific genetic diversity than those encoding nonclient proteins. In a number of multivariate analyses, controlling by other well-known factors that affect protein evolution, we find that chaperone dependence explains the largest fraction of the observed variance in the rate of evolution at both evolutionary time scales. Chaperones affecting rates of protein evolution mostly belong to two major chaperone families: Hsp70s and Hsp90s. Our analyses show that protein chaperones, by virtue of their ability to buffer destabilizing mutations and their role in modulating protein genotype-phenotype maps, have a considerable accelerating effect on protein evolution.

Genes vary greatly in their propensity for collateral fitness effects of mutations

“…For example, the cell’s chaperones and stress responses may be more capable of buffering the negative effects caused by CAT-I and NDM-1 mutations than those caused by TEM-1 and AadB mutations. Consistent with this theory, proteins that interact with chaperones in yeast have been noted to evolve more quickly than proteins that do not (Alvarez-Ponce et al 2019).…”

The interactions of molecular chaperones with client proteins: why are they so weak?

“…For example, some clients J o u r n a l P r e -p r o o f seem to be preferentially degraded by the ubiquitin-proteasome system when they remain bound to the Hsp70 complex for too long 103,104 , and a similar mechanism may underlie client degradation by Hsp90 complexes 105,106 . In addition to determining client fate, it is possible that weak interactions between chaperones and clients have far-reaching consequences for the evolution of client sequences and folds, because there is strong evidence that some chaperones, such as Hsp90, GroEL, and DnaK, can accelerate the sequence evolution of their clients 14,[107][108][109] .…”

Universal constraints on protein evolution in the long-term evolution experiment withEscherichia coli

“…Many other experimental directions are possible. First, a better understanding of how chaperones and other molecular mechanisms of protein quality control affect evolutionary rates and fitness (Chen, et al 2017;Alvarez-Ponce, et al 2019;Samhita, et al 2020) is needed. We also need to better understand purifying selection on synonymous mutations (Walsh, et al 2020).…”