Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors a...

Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade

http://baldwinlab.chem.ox.ac.uk/publications/2015TimBlobs.pdf

Phase Transition of a Disordered Nuage Protein Generates Environmentally Responsive Membraneless Organelles

In 1989, Manning, Patel, and Borchardt wrote a review of protein stability (Manning et al, Pharm Res 6:903-918, 1989), which has been widely referenced ever since At the time, recombinant protein therapy was still in its infancy This review summarizes the advances that have been made since then regarding protein stabilization and formulation In addition to a discussion of the current understanding of chemical and physical instability, sections are included on stabilization in aqueous solution and the dried state, the use of chemical modification and mutagenesis to improve stability, and the interrelationship between chemical and physical instability

Stability of Protein Pharmaceuticals: An Update

Optical chemical sensors have been the focus of much research attention in recent years because of their importance in industrial, environmental and biomedical applications [1]. This class of sensors combines chemical and biological recognition with advances in optoelectronic technologies. The application of solgel materials to these sensors, especially in the form of thin films, has attracted considerable interest due to the ease of fabrication and design flexibility of the process. The nature of the sol-gel process lends itself very well to the deposition of thin films using a variety of techniques such as dip-coating, spin-coating and spraying. In many sensor applications, the sol-gel film is used to provide a micro-porous support matrix in which analyte-sensitive molecules are entrapped and into which smaller analyte species may diffuse and interact [2,3]. Sol-gel films have many advantages as support matrices over polymer supports, including, for example, strong adhesion, good mechanical strength as well as excellent optical transparency. The versatility of the process facilitates tailoring of the physico-chemical film properties to optimize sensor performance. For example, films can be designed which have optimum porosity while minimizing leaching of the indicator molecules. In this chapter, the versatility of the sol-gel process with regard to the design of films for specific optical chemical sensor applications is highlighted.

Optical chemical sensors.

A growing number of diseases seem to be associated with inappropriate deposition of protein aggregates. Some of these diseases--such as Alzheimer's disease and systemic amyloidoses--have been recognized for a long time. However, it is now clear that ordered aggregation of pathogenic proteins does not only occur in the extracellular space, but in the cytoplasm and nucleus as well, indicating that many other diseases may also qualify as amyloidoses. The common structural and pathogenic features of these diverse protein aggregation diseases is only now being fully understood, and may provide novel opportunities for overarching therapeutic approaches such as depleting the monomeric precursor protein, inhibiting aggregation, enhancing aggregate clearance or blocking common aggregation-induced cellular toxicity pathways.

Protein aggregation diseases: pathogenicity and therapeutic perspectives

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 fibrils—or 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.

https://www.embopress.org/doi/pdf/10.1038/sj.embor.7401034

Prevention of amyloid‐like aggregation as a driving force of protein evolution

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.

/pdf/dnajb6-is-a-peptide-binding-chaperone-which-can-suppress-2oo6rc1jx2.pdf

DNAJB6 is a peptide-binding chaperone which can suppress amyloid fibrillation of polyglutamine peptides at substoichiometric molar ratios

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.

/pdf/aggregation-propensity-of-the-human-proteome-1w3wuk7e0r.pdf

Elodie Monsellier

Papers

Prevention of amyloid‐like aggregation as a driving force of protein evolution

DNAJB6 is a peptide-binding chaperone which can suppress amyloid fibrillation of polyglutamine peptides at substoichiometric molar ratios

Aggregation propensity of the human proteome.

Molecular Interaction between the Chaperone Hsc70 and the N-terminal Flank of Huntingtin Exon 1 Modulates Aggregation

Improving the Stability of an Antibody Variable Fragment by a Combination of Knowledge-based Approaches: Validation and Mechanisms