Preventing peptide and protein misbehavior

Arosio, Paolo; Meisl, Georg; Andreasen, Maria; Knowles, Tuomas P. J.

doi:10.1073/pnas.1505170112

Cited by 7 publications

(4 citation statements)

References 22 publications

(22 reference statements)

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“…In summary, understanding how cells regulate and harness protein aggregation will not only open new insights into exciting cell biology, but, quite unexpectedly, might also help to better understand disease mechanisms and allow devising novel treatments. Pathologic protein assemblies are associated with more than 30 diseases, and amyloidrelated pathologies are currently estimated to affect 45 million people worldwide, a number predicted to triple by 2050 mainly due to ageing of the population [84]. Thus, as there is an urgent need to understand and ultimately cure or prevent these irreversible processes, the study of protein aggregation has become a central area of research.…”

Section: Discussionmentioning

confidence: 99%

Reversible, functional amyloids: towards an understanding of their regulation in yeast and humans

et al. 2018

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Protein aggregates, and in particular amyloids, are generally considered to be inherently irreversible aberrant clumps, and are often associated with pathologies, such as Alzheimer's disease, Parkinson's disease, or systemic amyloidosis. However, recent evidence demonstrates that some aggregates are not only fully reversible, but also perform essential physiological functions. Despite these new findings, very little is known about how these functional protein aggregates are regulated in a physiological context. Here, we take the yeast pyruvate kinase Cdc19 as an example of a protein forming functional, reversible, solid, amyloid-like aggregates in response to stress conditions. Cdc19 aggregation is regulated via an aggregation-prone low complexity region (LCR). In favorable growth conditions, this LCR is prevented from aggregating by phosphorylation or oligomerization, while upon glucose starvation it becomes exposed and allows aggregation. We suggest that LCR phosphorylation, oligomerization or partner-binding may be general and widespread mechanisms regulating LCR-mediated reversible protein aggregation. Moreover, we show that, as predicted by computational tools, Cdc19 forms amyloid-like aggregates in vitro. Interestingly, we also observe striking similarities between Cdc19 and its mammalian counterpart, PKM2. Indeed, also PKM2 harbors a LCR and contains several peptides with high amyloidogenic propensity, which coincide with known phosphorylation sites. Thus, we speculate that the formation of reversible, amyloid-like aggregates may be a general physiological mechanism for cells to adapt to stress conditions, and that the underlying regulatory mechanisms may be conserved from yeast to humans.

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Section: Discussionmentioning

confidence: 99%

Reversible, functional amyloids: towards an understanding of their regulation in yeast and humans

et al. 2018

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“…At the molecular level, a given inhibitor may interact particularly favorably with one of the species present during the aggregation reaction (34). Some inhibitors suppress a single microscopic step, whereas others act on more than one step, depending on whether the inhibitor interacts with monomers, oligomers, or fibrils (23,24,34).…”

Section: Discussionmentioning

confidence: 99%

“…Secondary nucleation is a positive feedback mechanism that can lead to the rapid amplification of the number of aggregates once an initial population has been formed (20,22) and also be very effective in the production of toxic oligomers (20,21). Inhibition of secondary nucleation, therefore, appears likely to be an important approach to reduce the pathogenicity associated with protein aggregation (34). Indeed, the discovery that specific molecular chaperones can act in a highly selective manner to suppress secondary nucleation suggests that this approach is exploited by living systems to reduce the risks of protein aggregation in vivo.…”

Section: Discussionmentioning

confidence: 99%

Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication

Munke

Persson

Weiffert

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The aggregation of the amyloid β peptide (Aβ) into amyloid fibrils is a defining characteristic of Alzheimer's disease. Because of the complexity of this aggregation process, effective therapeutic inhibitors will need to target the specific microscopic steps that lead to the production of neurotoxic species. We introduce a strategy for generating fibril-specific antibodies that selectively suppress fibril-dependent secondary nucleation of the 42-residue form of Aβ (Aβ42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of Aβ42. Starting from large phage display libraries of single-chain antibody fragments (scFvs), the three-stage approach that we describe includes (i) selection of scFvs with high affinity for Aβ42 fibrils after removal of scFvs that bind Aβ42 in its monomeric form; (ii) ranking, by surface plasmon resonance affinity measurements, of the resulting candidate scFvs that bind to the Aβ42 fibrils; and (iii) kinetic screening and analysis to find the scFvs that inhibit selectively the fibril-catalyzed secondary nucleation process in Aβ42 aggregation. By applying this approach, we have identified four scFvs that inhibit specifically the fibril-dependent secondary nucleation process. Our method also makes it possible to discard antibodies that inhibit elongation, an important factor because the suppression of elongation does not target directly the production of toxic oligomers and may even lead to its increase. On the basis of our results, we suggest that the method described here could form the basis for rationally designed immunotherapy strategies to combat Alzheimer's and related neurodegenerative diseases.Alzheimer | antibody | inhibitor | drug development | self-assembly

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“…Abelein and colleagues used NMR relaxation dispersion and fluorescence kinetic methods to show that Zn 2+ transiently binds to residues in the N terminus of the Aβ1–40 monomeric peptide and efficiently retards fibril formation, primarily by inhibiting fibril end elongation . Accordingly, Zn 2+ has a protective role against the formation of fibres from the Aβ peptide, which is closely associated with AD . Metal ions affect the kinetics of Aβ aggregation, and these findings provide a basis for determining the mechanism of Aβ aggregation and the role of the Aβ N‐terminus.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the behaviour of β‐amyloid peptide variants during oligomerization and fibrillation

Shi

Zhang

Liu

2017

Journal of Peptide Science

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The oligomerization and fibrillation of β-amyloid (Aβ) peptides are important events in the pathogenesis of Alzheimer's disease. However, the motifs within the Aβ sequence that contribute to oligomerization and fibrillation and the complex interplay among these short motifs are unclear. In this study, the oligomerization and fibrillation abilities of the Aβ variants Aβ1-28, Aβ1-36, Aβ11-42, Aβ17-42, Aβ1-40 and Aβ1-42 were examined by thioflavin T fluorescence, western blotting and transmission electron microscopy. Compared with two C-terminal-truncated peptides (i.e. Aβ1-28 and Aβ1-36), Aβ11-42, Aβ17-42 and Aβ1-42 had stronger abilities to form oligomers. This indicated that amino acids 37-42 strengthen the β-hairpin structure of Aβ. Both Aβ1-42 and Aβ1-40 could form fibres, but Aβ17-42 formed irregular fibres, suggesting that amino acids 1-17 were essential for Aβ fibre formation. Aβ1-28 and Aβ1-36 exhibited weak oligomerization and fibrillation, implying that they formed an unstable β-hairpin structure owing to the incomplete C-terminal region. Intermediate peptides were likely to form a stable structure, consistent with previous results. This work explains the roles and interplay among motifs within Aβ during oligomerization and fibrillation. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

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Preventing peptide and protein misbehavior

Cited by 7 publications

References 22 publications

Reversible, functional amyloids: towards an understanding of their regulation in yeast and humans

Reversible, functional amyloids: towards an understanding of their regulation in yeast and humans

Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication

Dissecting the behaviour of β‐amyloid peptide variants during oligomerization and fibrillation

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