An Evolutionary Trade-Off between Protein Turnover Rate and Protein Aggregation Favors a Higher Aggregation Propensity in Fast Degrading Proteins

We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing ‘gatekeeper’ residues at strategic places along the sequence of proteins. Here we analyzed the relationship between protein lifetime and protein aggregation by combining experimentally determined turnover rates, expression data, structural data and chaperone interaction data on a set of more than 500 proteins. We find that selective pressure on protein sequences against aggregation is not homogeneous but that short-living proteins on average have a higher aggregation propensity and fewer chaperone interactions than long-living proteins. We also find that short-living proteins are more often associated to deposition diseases. These findings suggest that the efficient degradation of high-turnover proteins is sufficient to preclude aggregation, but also that factors that inhibit proteasomal activity, such as physiological ageing, will primarily affect the aggregation of short-living proteins.
Author Summary In order to carry out their biological function, proteins need to fold into well-defined three-dimensional structures. Protein aggregation is a process whereby proteins misfold into inactive and often toxic higher order structures, which is implied in about 30 human diseases such as Alzheimer's disease, Parkinson's disease and systemic amyloidosis. In earlier work it has been shown that although protein aggregation is an intrinsic property of polypeptide chains that cannot be entirely avoided, evolution has optimized protein sequences to minimize the risk of aggregation in a proteome. Here we show that this pressure is not uniform, but that proteins with a short lifetime have on average a higher aggregation propensity than long-living proteins. In addition, we show that high turnover proteins also make fewer interactions with chaperones. Taken together, these observations suggest that under normal physiological conditions the aggregation propensity of short-lived proteins does not represent a significant treat for the biochemistry of the cell. Presumably the strong dependence of these proteins on proteasomal degradation is sufficient to preclude the accumulation of aggregates. As proteasomal activity declines with age this would also explain why we observe a higher association of high turnover proteins with age-dependent aggregation-related diseases.