Uncontrolled protein aggregation is a constant challenge in all compartments of living organisms. The failure of a peptide or protein to remain soluble often results in pathology. So far, more than 40 human diseases have been associated with the formation of extracellular fibrillar aggregates-known as amyloid fibrilsor structurally related intracellular deposits. It is well known that molecular chaperones and elaborate quality control mechanisms exist in the cell to counteract aggregation. However, an increasing number of reports during the past few years indicate that proteins have also evolved structural and sequence-based strategies to prevent aggregation. This review describes these strategies and the selection pressures that exist on protein sequences to combat their uncontrolled aggregation. We will describe the different types of mechanism evolved by proteins that adopt different conformational states including normally folded proteins, intrinsically disordered polypeptide chains, elastomeric systems and multimodular proteins.

Expanded polyglutamine (polyQ) stretches lead to protein aggregation and severe neurodegenerative diseases. A highly efficient suppressor of polyQ aggregation was identified, the DNAJB6, when molecular chaperones from the HSPH, HSPA, and DNAJ families were screened for huntingtin exon 1 aggregation in cells (Hageman et al. in Mol Cell 37(3):355–369, 2010). Furthermore, also aggregation of polyQ peptides expressed in cells was recently found to be efficiently suppressed by co-expression of DNAJB6 (Gillis et al. in J Biol Chem 288:17225–17237, 2013). These suppression effects can be due to an indirect effect of DNAJB6 on other cellular components or to a direct interaction between DNAJB6 and polyQ peptides that may depend on other cellular components. Here, we have purified the DNAJB6 protein to investigate the suppression mechanism. The purified DNAJB6 protein formed large heterogeneous oligomers, in contrast to the more canonical family member DNAJB1 which is dimeric. Purified DNAJB6 protein, at substoichiometric molar ratios, efficiently suppressed fibrillation of polyQ peptides with 45°Q in a thioflavin T fibrillation. No suppression was obtained with DNAJB1, but with the closest homologue to DNAJB6, DNAJB8. The suppression effect was independent of HSPA1 and ATP. These data, based on purified proteins and controlled fibrillation in vitro, strongly suggest that the fibrillation suppression is due to a direct protein–protein interaction between the polyQ peptides and DNAJB6 and that the DNAJB6 has unique fibrillation suppression properties lacking in DNAJB1. Together, the data obtained in cells and in vitro support the view that DNAJB6 is a peptide-binding chaperone that can interact with polyQ peptides that are incompletely degraded by and released from the proteasome.Electronic supplementary materialThe online version of this article (doi:10.1007/s12192-013-0448-5) contains supplementary material, which is available to authorized users.

Background: Hsc70 has an alleviating effect on the toxicity of polyglutamine (polyQ)-containing proteins in vivo. Results: Hsc70 binds specifically the N-terminal flank of huntingtin exon 1. Conclusion: Hsc70 interaction with huntingtin exon 1 N-terminal flank affects the conformation of the resulting assemblies. Significance: We identify the surface interfaces between Hsc70 and huntingtin exon 1, which allows the design of future therapeutic tools.

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.