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

• DOI: 10.1371/journal.pcbi.1002090
• Publication Date: 2011-06-23T20:49:34Z
• Authors: Greet De Baets; Joke Reumers; Javier Delgado Bl...; Joaquin Dopazo; Joost Schymkowitz; Frederic Rousseau
• Keywords: 0303 health sciences; Time Factors; QH301-705.5; Protein Stability; Gene Expression Profiling; Protein Array Analysis; Computational Biology; Membrane Proteins; Proteins; Statistics, Nonparametric; Evolution, Molecular; 03 medical and health sciences; Humans; Thermodynamics; Disease Susceptibility; Biology (General); Databases, Protein; Research Article

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.