Fitness Costs of Minimal Sequence Alterations Causing Protein Instability and Toxicity

Tomala, K.; Pogoda, Elzbieta; Jakubowska, Agata; Korona, Ryszard

doi:10.1093/molbev/mst264

Cited by 10 publications

(12 citation statements)

References 33 publications

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“…5). Despite the previously reported associations between increased protein stability and lower aggregation rates, higher soluble abundance and a greater capacity to evolve (DePristo et al 2005;Bershtein et al 2012;Tomala et al 2014;Bloom et al 2006), we found no statistically significant correlation, either positive or negative, between the measures of LeuB stability (T opt and DG z NÀU ) and organism fitness (Fig. 5).…”

Section: In Vivo Fitness Is Not Correlated With Stability or Catalyticontrasting

confidence: 99%

“…In turn, soluble protein abundance was positively correlated with organism fitness. Tomala et al (2014) also showed that overexpression of destabilised mutants of two yeast proteins was associated with decreased fitness. Thirdly, increased protein stability has been associated with mutational robustness, or a greater capacity to sample sequence space in the course of evolution (Bloom et al 2005(Bloom et al , 2006.…”

Section: Introductionmentioning

confidence: 97%

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Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

et al. 2015

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Ancestral sequence reconstruction has been widely used to study historical enzyme evolution, both from biochemical and cellular perspectives. Two properties of reconstructed ancestral proteins/enzymes are commonly reported-high thermostability and high catalytic activity-compared with their contemporaries. Increased protein stability is associated with lower aggregation rates, higher soluble protein abundance and a greater capacity to evolve, and therefore, these proteins could be considered ''superior'' to their contemporary counterparts. In this study, we investigate the relationship between the favourable in vitro biochemical properties of reconstructed ancestral enzymes and the organismal fitness they confer in vivo. We have previously reconstructed several ancestors of the enzyme LeuB, which is essential for leucine biosynthesis. Our initial fitness experiments revealed that overexpression of ANC4, a reconstructed LeuB that exhibits high stability and activity, was only able to partially rescue the growth of a DleuB strain, and that a strain complemented with this enzyme was outcompeted by strains carrying one of its descendants. When we expanded our study to include five reconstructed LeuBs and one contemporary, we found that neither in vitro protein stability nor the catalytic rate was correlated with fitness. Instead, fitness showed a strong, negative correlation with estimated evolutionary age (based on phylogenetic relationships). Our findings suggest that, for reconstructed ancestral enzymes, superior in vitro properties do not translate into organismal fitness in vivo. The molecular basis of the relationship between fitness and the inferred age of ancestral LeuB enzymes is unknown, but may be related to the reconstruction process. We also hypothesise that the ancestral enzymes may be incompatible with the other, contemporary enzymes of the metabolic network.

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Section: In Vivo Fitness Is Not Correlated With Stability or Catalyticontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

et al. 2015

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“…Various studies have reported diverse and often conflicting effects in terms of the beneficial and detrimental effects of protein deposit formation on cell fitness (Maji et al , ; Geiler‐Samerotte et al , ; Sanchez de Groot et al , ; Escusa‐Toret et al , ; Tomala et al , ). These differences are understandable if one considers the complexity of deposit formation, the differences in the dynamic nature of the deposit, biochemical function of the protein forming the deposit, and the diversity in the experimental conditions in which the studies have been carried out.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we measure and disentangle the effects of phase separation of a model protein. To trigger the phase separation process, instead of mutating an endogenous protein to destabilize it as has been done before (Geiler‐Samerotte et al , ; Tomala et al , ), we designed a modular system that allows us to disentangle and quantify the cost/benefit of protein phase separation while tuning different roles influencing this process (e.g., the essentiality/non‐essentiality/toxicity of a protein). The model protein phase‐separates from a mainly soluble, functionally active state into a primarily insoluble, functionally less active state (Materials and Methods, Figs 5 and EV1, and Appendix Fig S2).…”

Section: Resultsmentioning

confidence: 99%

“…The overall fitness effect (cost/benefit) of protein phase separation is not only determined by the loss or gain of the biochemical activity of the protein, but also due to the cost of deposit formation (e.g., amino acid sequestration in deposits, sequestration of ATP‐dependent chaperone activity and other proteins, toxicity of the assembly; Maji et al , ; Olzscha et al , ;; Gsponer & Babu, ; Sanchez de Groot et al , ; Suraweera et al , ; Tomala et al , ; Patel et al , ); Fig A, equation ). To infer the impact of these effects, we considered that the measured selection coefficient ( S ) is determined by a combination of three factors: (i) the cost of deposit formation, (ii) the cost of losing the essential Ura3p biochemical activity, and (iii) the benefit of gaining a protective function against the toxic activity by sequestering Ura3p into deposits (Fig A, equation ).…”

Section: Resultsmentioning

confidence: 99%

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The fitness cost and benefit of phase‐separated protein deposits

Groot

Torrent

Ravarani

et al. 2019

Molecular Systems Biology

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Phase separation of soluble proteins into insoluble deposits is associated with numerous diseases. However, protein deposits can also function as membrane‐less compartments for many cellular processes. What are the fitness costs and benefits of forming such deposits in different conditions? Using a model protein that phase‐separates into deposits, we distinguish and quantify the fitness contribution due to the loss or gain of protein function and deposit formation in yeast. The environmental condition and the cellular demand for the protein function emerge as key determinants of fitness. Protein deposit formation can influence cell‐to‐cell variation in free protein abundance between individuals of a cell population (i.e., gene expression noise). This results in variable manifestation of protein function and a continuous range of phenotypes in a cell population, favoring survival of some individuals in certain environments. Thus, protein deposit formation by phase separation might be a mechanism to sense protein concentration in cells and to generate phenotypic variability. The selectable phenotypic variability, previously described for prions, could be a general property of proteins that can form phase‐separated assemblies and may influence cell fitness.

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Using yeasts for the studies of nonfunctional factors in protein evolution

Potera,

Tomala

2024

Yeast

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The evolution of protein sequence is driven not only by factors directly related to protein function and shape but also by nonfunctional factors. Such factors in protein evolution might be categorized as those connected to energetic costs, synthesis efficiency, and avoidance of misfolding and toxicity. A common approach to studying them is correlational analysis contrasting them with some characteristics of the protein, like amino acid composition, but these features are interdependent. To avoid possible bias, empirical studies are needed, and not enough work has been done to date. In this review, we describe the role of nonfunctional factors in protein evolution and present an experimental approach using yeast as a suitable model organism. The focus of the proposed approach is on the potential negative impact on the fitness of mutations that change protein properties not related to function and the frequency of mutations that change these properties. Experimental results of testing the misfolding avoidance hypothesis as an explanation for why highly expressed proteins evolve slowly are inconsistent with correlational research results. Therefore, more efforts should be made to empirically test the effects of nonfunctional factors in protein evolution and to contrast these results with the results of the correlational analysis approach.

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Fitness Costs of Minimal Sequence Alterations Causing Protein Instability and Toxicity

Cited by 10 publications

References 33 publications

Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

Reconstructed Ancestral Enzymes Impose a Fitness Cost upon Modern Bacteria Despite Exhibiting Favourable Biochemical Properties

The fitness cost and benefit of phase‐separated protein deposits

Using yeasts for the studies of nonfunctional factors in protein evolution

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