Aggregation Propensity of the Human Proteome

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.

Position‐Dependent Electrostatic Protection against Protein Aggregation

“…Such gatekeeper residues are electrostatically charged and prevent the ordered association of aggregation-prone regions of different molecules. [10,12,16,[18][19][20] Gatekeeper residues have been observed in various systems, but the magnitude and specificity of their effects have remained elusive. Herein we therefore focus on a quantitative characterisation of the gatekeeping effect through a combination of biosensor measurements, atomic force microscopy, and quantitative sequence-based design approaches.…”

Disulfide Bonds Reduce the Toxicity of the Amyloid Fibrils Formed by an Extracellular Protein

“…This can be concomitant with significant decreases in the toxicity of the resulting fibrils, which suggests that disulfide bonds have coevolved with protein sequences to reduce toxic aggregation. [21] Experimental Section…”

Protein folding and aggregation in bacteria

“…Regions promoting the deposition process have been designated hot spots (HS), and substitutions in these regions almost invariably result in changes in protein solubility, whereas mutations outside of these regions have a more moderate or even neutral effect [151,[154][155][156][157]. HS regions are enriched in aliphatic and aromatic residues (Val, Leu, Ile, Phe, Tyr, Trp) [152,158]. The presence of charges of the same sign is avoided but not the existence of opposing charges, which favors specific interactions between polypeptide chains [152].…”

“…These residues act as gatekeepers and prevent the selfassembly of HS even if they are exposed after synthesis or by local fluctuations. The Pro-constrained conformation is incompatible with b-structures, whereas the positively charged residues promote repulsion between adjacent chains and, being long and flexible, make the self-assembly process unfavorable from an entropic point of view [152,158]. In addition, when associated to hydrophobic stretches, these residues act as reporters for the cellular quality control machinery to facilitate HS identification and blockage by the molecular chaperones [152].…”