![]() 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. 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 order to carry out their biological function, proteins need to fold into well-defined three-dimensional structures. 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. We also find that short-living proteins are more often associated to deposition diseases. 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. 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 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.
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