Abstract
Formation of amyloid-like fibrils is involved in numerous human protein deposition diseases, but is also an intrinsic property of polypeptide chains in general. Progress achieved recently now allows the aggregation propensity of proteins to be analyzed over large scales. In this work we used a previously developed predictive algorithm to analyze the propensity of the 34,180 protein sequences of the human proteome to form amyloid-like fibrils. We show that long proteins have, on average, less intense aggregation peaks than short ones. Human proteins involved in protein deposition diseases do not differ extensively from the rest of the proteome, further demonstrating the generality of protein aggregation. We were also able to reproduce some of the results obtained with other algorithms, demonstrating that they do not depend on the type of computational tool employed. For example, proteins with different subcellular localizations were found to have different aggregation propensities, in relation to the various efficiencies of quality control mechanisms. Membrane proteins, intrinsically disordered proteins, and folded proteins were confirmed to have very different aggregation propensities, as a consequence of their different structures and cellular microenvironments. In addition, gatekeeper residues at strategic positions of the sequences were found to protect human proteins from aggregation. The results of these comparative analyses highlight the existence of intimate links between the propensity of proteins to form aggregates with β-structure and their biology. In particular, they emphasize the existence of a negative selection pressure that finely modulates protein sequences in order to adapt their aggregation propensity to their biological context.
Highlights
The conversion of peptides and proteins into insoluble fibrillar aggregates is the hallmark of ca. 40 human diseases [1,2]
Our results show that different structural subpopulations of the human proteome have different average aggregation propensities, whereas proteins involved in protein deposition diseases do not differ extensively from the human proteome taken at a whole in terms of aggregation propensity
The analysis of the human proteome presented here has revealed that protein sequences have been constrained by evolution to finely modulate their aggregation propensity depending on their length, subcellular localization, and conformation
Summary
The conversion of peptides and proteins into insoluble fibrillar aggregates is the hallmark of ca. 40 human diseases [1,2]. 40 human diseases [1,2] It is clear, that the formation of such well-organized fibrillar aggregates, generally referred to as amyloid fibrils when deposition occurs extracellularly, is not a characteristic of the few unfortunate sequences associated with protein deposition diseases, but a generic property of polypeptide chains [3]. That the formation of such well-organized fibrillar aggregates, generally referred to as amyloid fibrils when deposition occurs extracellularly, is not a characteristic of the few unfortunate sequences associated with protein deposition diseases, but a generic property of polypeptide chains [3] This novel concept has raised the question as to how protein aggregation is prevented effectively in living organisms. Essential proteins were found to have a lower aggregation score than nonessential proteins, emphasizing the evolutionary pressure that has acted on the former to minimize their aggregation propensity [23]
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