Abstract
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.
Highlights
Biological networks are fine-tuned to respond to narrow changes in protein concentration
Sensitivity to protein aggregation is determined by intrinsic protein parameters such as the efficiency of the folding process [5], thermodynamic stability [6,7], the aggregation propensity of the protein sequence [8,9] and its ability to be recognized by the protein quality control system [10]
In earlier work it has been shown that 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
Summary
Biological networks are fine-tuned to respond to narrow changes in protein concentration. We previously showed that evolutionary forces shape protein sequences in order to minimize their aggregation propensity, by strategically placing aggregationopposing gatekeeper residues along the sequence [11,12] This insight has been confirmed by independent studies [13,14,15,16], the extent to which selective pressures mould protein sequences is most likely not uniform, but determined by the biological context in which the protein functions [17]. We reasoned that proteins with high turnover rate and short lifetime will have, on average, lower risk of misfolding than long-living proteins Their respective sequences should experience different selective pressures against protein aggregation. Such evolutionary pressure might have resulted in different affinities towards molecular chaperones and different implications towards aggregation-related diseases
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