Abstract
BackgroundThe nature of the protein molecular clock, the protein-specific rate of amino acid substitutions, is among the central questions of molecular evolution. Protein expression level is the dominant determinant of the clock rate in a number of organisms. It has been suggested that highly expressed proteins evolve slowly in all species mainly to maintain robustness to translation errors that generate toxic misfolded proteins. Here we investigate this hypothesis experimentally by comparing the growth rate of Escherichia coli expressing wild type and misfolding-prone variants of the LacZ protein.ResultsWe show that the cost of toxic protein misfolding is small compared to other costs associated with protein synthesis. Complementary computational analyses demonstrate that there is also a relatively weaker, but statistically significant, selection for increasing solubility and polarity in highly expressed E. coli proteins.ConclusionsAlthough we cannot rule out the possibility that selection against misfolding toxicity significantly affects the protein clock in species other than E. coli, our results suggest that it is unlikely to be the dominant and universal factor determining the clock rate in all organisms. We find that in this bacterium other costs associated with protein synthesis are likely to play an important role. Interestingly, our experiments also suggest significant costs associated with volume effects, such as jamming of the cellular environment with unnecessary proteins.
Highlights
The nature of the protein molecular clock, the protein-specific rate of amino acid substitutions, is among the central questions of molecular evolution
In this study we investigated whether the toxicity of misfolded proteins or other costs associated with protein synthesis make a dominant contribution to cellular fitness, and constrain the molecular clock in Escherichia coli
Single amino acid substitutions should serve as a good model for translational errors because only rarely, in about 10% of the proteins that contain translation errors, two or more residues will be simultaneously mistranslated in the same protein
Summary
The nature of the protein molecular clock, the protein-specific rate of amino acid substitutions, is among the central questions of molecular evolution. It has been suggested that highly expressed proteins evolve slowly in all species mainly to maintain robustness to translation errors that generate toxic misfolded proteins. Orthologous proteins accumulate substitutions at an approximately constant rate over long evolutionary intervals This observation suggests that one can use available protein sequences as a molecular clock to estimate divergence times between different species [3]. Adaptive pressure will maintain sequences of highly expressed proteins robust to translation errors, which will in turn slow the amino acid substitution rate, that is, the protein molecular clock. The misfolding toxicity hypothesis was supported by the results of computer simulations [22], but to the best of our knowledge, it has never been tested experimentally
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