Abstract
Solubility is a requirement for many cellular processes. Loss of solubility and aggregation can lead to the partial or complete abrogation of protein function. Thus, understanding the relationship between protein evolution and aggregation is an important goal. Here, we analysed two deep mutational scanning experiments to investigate the role of protein aggregation in molecular evolution. In one data set, mutants of a protein involved in RNA biogenesis and processing, human TAR DNA binding protein 43 (TDP-43), were expressed in S. cerevisiae. In the other data set, mutants of a bacterial enzyme that controls resistance to penicillins and cephalosporins, TEM-1 beta-lactamase, were expressed in E. coli under the selective pressure of an antibiotic treatment. We found that aggregation differentiates the effects of mutations in the two different cellular contexts. Specifically, aggregation was found to be associated with increased cell fitness in the case of TDP-43 mutations, as it protects the host from aberrant interactions. By contrast, in the case of TEM-1 beta-lactamase mutations, aggregation is linked to a decreased cell fitness due to inactivation of protein function. Our study shows that aggregation is an important context-dependent constraint of molecular evolution and opens up new avenues to investigate the role of aggregation in the cell.
Highlights
The majority of proteins function as monodispersed ordered species dissolved in intra- or extracellular aqueous fluids
We focused on molecular evolution data of human TAR DNAbinding protein 43 (TDP-43) exogenously expressed in yeast and bacterial TEM-1 beta-lactamase endogenously expressed in E. coli
This study aimed to investigate the influence of protein aggregation on molecular evolution
Summary
The majority of proteins function as monodispersed ordered species dissolved in intra- or extracellular aqueous fluids. The interfaces through which proteins interact are often highly aggregation prone, so that their engagement in interactions reduces propensity to selfassembly (Pechmann et al, 2009) This means that regions under the evolutionary pressure of protein function may be the same that lead to aberrant aggregation (Lee et al, 2010; Masino et al, 2011; Temussi et al, 2021). The library of beta-lactamase mutants targeted instead the whole stably structured enzyme (Fantini et al, 2020) With these two systems, we investigated whether and how aggregation acts as a constraint of the evolutionary process by finely tuning the selection of proteins to fit in a specific environment (Tartaglia et al, 2007). While aggregation leads always to protein depletion, we aimed to determine if the detrimental or beneficial effects sensitively depend on the context and nature of the selection sieve
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