Natural selection against protein aggregation on self-interacting and essential proteins in yeast, fly, and worm

Abstract

Protein aggregation is the phenomenon of protein self-association potentially leading to detrimental effects on physiology, which is closely related to numerous human diseases such as Alzheimer's and Parkinson's disease. Despite progress in understanding the mechanism of protein aggregation, how natural selection against protein aggregation acts on subunits of protein complexes and on proteins with different contributions to organism fitness remains largely unknown. Here, we perform a proteome-wide analysis by using an experimentally validated algorithm TANGO and utilizing sequence, interactomic and phenotype-based functional genomic data from yeast, fly, and nematode. We find that proteins that are capable of forming homooligomeric complex have lower aggregation propensity compared with proteins that do not function as homooligomer. Further, proteins that are essential to the fitness of an organism have lower aggregation propensity compared with nonessential ones. Our finding suggests that the selection force against protein aggregation acts across different hierarchies of biological system.

FIG. 1.—

There is a competition between the formation of physiological oligomers and “aberrant” oligomers that are on the pathway of forming aggregates.

FIG. 2.—

The histograms of relative aggregation propensity of proteins that have experimental evidence of self-interactions (open) and those that lack such evidence (filled) are plotted for (a) Saccharomyces cerevisiae, (b) Drosophila melanogaster, and (c) Caenorhabditis elegans with the bin size of 0.25.

FIG. 3.—

The histograms of relative aggregation propensity of proteins that are essential to organismal fitness (open) and nonessential ones (filled) are plotted for (a) Saccharomyces cerevisiae and (b) Caenorhabditis elegans with the bin size of 0.25.