Aggregation is a Context-Dependent Constraint on Protein Evolution

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.

Interplay between disordered regions in RNAs and proteins modulates interactions within stress granules and processing bodies

“…At the same time, proteins enriched in SGs and PBs are more disordered and form a larger number of contacts with proteins and RNAs. Taken together, our data suggest that structural disorder is a property that distinguishes dynamic fuzzy-like assemblies such as PBs and SGs from other solid-like aggregates [31,32].…”

A Computational Approach Reveals the Ability of Amyloids to Sequester RNA: the Alpha Synuclein Case

“…2A ) and performed a mutational analysis with 10 000 random single mutations (Fig. 2C) 61 . The two approaches show consistent results.…”

ALS/FTD: Evolution, Aging, and Cellular Metabolic Exhaustion

“…Indeed, it has been proposed that the protein deposits may in some cases be beneficial as they contribute to reducing the pool of intracellular pathogenic oligomers, regardless of the mechanism of their pathogenicity (molecular toxicity or turnover costs), and outside the cells, these deposits will be less likely to interfere with cellular functions, and also less costly as they would be less targeted (and less accessible) to the intracellular proteases ( 73 ). In studies of TAR DNA binding protein 43 (TDP-43), beneficial effects of protein aggregation has also been observed ( 66 , 68 ), suggesting that the toxicity occurs via a non-aggregated state, which we propose below is a state that is more easily subject to costly turnover.…”

“…Proteins reach a native state but can change their folded structure if the environment changes (protein misfolding) leading to aggregates ( 66 , 67 ). Mutations can also induce conformational changes and aggregation ( 68 ).…”

“…It has been widely assumed that protein misfolding is pathogenic via some specific molecular toxicity as larger aggregates (i.e., protein deposits) or as more recently accepted, in the intracellular oligomeric state, with suggestions including interaction with other proteins and cell membranes ( 68 ). However, so far, the direct pathogenic species and mode of action remains obscure and therapeutic approaches that have been developed toward targeting the misfolded proteins directly, have so far met with the little clinical success ( 72 ).…”