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Special Issue "The Role of Environment in Amyloid Aggregation"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 August 2021).

Special Issue Editor

Dr. Vytautas Smirnovas
E-Mail Website
Guest Editor
Institute of Biothechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
Interests: protein misfolding; protein aggregation; amyloid; prion; proteinaceous infectivity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The ability to form amyloid structures may be a generic property of polypeptides, and there are two major factors which define the probability of amyloid fibril formation—amino acid sequence of the protein/peptide and the environmental conditions. In the case of folded proteins, at least partial unfolding is necessary to trigger the amyloid formation pathway, so increased temperature, extreme pH conditions, addition of denaturants or any other changes in the environment leading to destabilization of protein structure are used in amyloid aggregation studies. Even in the case of disordered proteins, neutralization of charges or contact with hydrophobic surfaces may be necessary to induce amyloid formation. In addition to the specific conditions required for amyloid formation, changes in the environment may alter the mechanism of aggregation and lead to distinct amyloid fibril conformations. Finally, environment conditions affect the kinetics of aggregation and may alter the effect of anti-amyloid compounds.

The value of protein amyloid studies in vitro for health/pharma industry is limited, as extrapolation of the results toward amyloid formation in cells and organisms is not precise. The precision of extrapolation could increase with comprehensive knowledge of how the broad range of environmental conditions affect protein amyloid aggregation. It is my belief that to increase the value of our research, we must collect more data and periodically overview and condense them. Thus, I would like to invite you to share your knowledge and data on protein aggregation at different conditions and submit research or review articles to this issue.

Dr. Vytautas Smirnovas
Guest Editor

Manuscript Submission Information

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Keywords

  • protein misfolding
  • protein aggregation
  • amyloid
  • anti-amyloid compounds
  • amyloid polymorphism
  • prion
  • protein folding and stability
  • neurodegenerative diseases
  • aggregation kinetics
  • drug discovery

Published Papers (7 papers)

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Research

Article
Aggregation Condition–Structure Relationship of Mouse Prion Protein Fibrils
Int. J. Mol. Sci. 2021, 22(17), 9635; https://doi.org/10.3390/ijms22179635 - 06 Sep 2021
Viewed by 519
Abstract
Prion diseases are associated with conformational conversion of cellular prion protein into a misfolded pathogenic form, which resembles many properties of amyloid fibrils. The same prion protein sequence can misfold into different conformations, which are responsible for variations in prion disease phenotypes (prion [...] Read more.
Prion diseases are associated with conformational conversion of cellular prion protein into a misfolded pathogenic form, which resembles many properties of amyloid fibrils. The same prion protein sequence can misfold into different conformations, which are responsible for variations in prion disease phenotypes (prion strains). In this work, we use atomic force microscopy, FTIR spectroscopy and magic-angle spinning NMR to devise structural models of mouse prion protein fibrils prepared in three different denaturing conditions. We find that the fibril core region as well as the structure of its N- and C-terminal parts is almost identical between the three fibrils. In contrast, the central part differs in length of β-strands and the arrangement of charged residues. We propose that the denaturant ionic strength plays a major role in determining the structure of fibrils obtained in a particular condition by stabilizing fibril core interior-facing glutamic acid residues. Full article
(This article belongs to the Special Issue The Role of Environment in Amyloid Aggregation)
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Article
Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains
Int. J. Mol. Sci. 2021, 22(16), 8944; https://doi.org/10.3390/ijms22168944 - 19 Aug 2021
Viewed by 441
Abstract
Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network [...] Read more.
Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation. Full article
(This article belongs to the Special Issue The Role of Environment in Amyloid Aggregation)
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Article
Variability of Amyloid Propensity in Imperfect Repeats of CsgA Protein of Salmonella enterica and Escherichia coli
Int. J. Mol. Sci. 2021, 22(10), 5127; https://doi.org/10.3390/ijms22105127 - 12 May 2021
Viewed by 758
Abstract
CsgA is an aggregating protein from bacterial biofilms, representing a class of functional amyloids. Its amyloid propensity is defined by five fragments (R1–R5) of the sequence, representing non-perfect repeats. Gate-keeper amino acid residues, specific to each fragment, define the fragment’s propensity for self-aggregation [...] Read more.
CsgA is an aggregating protein from bacterial biofilms, representing a class of functional amyloids. Its amyloid propensity is defined by five fragments (R1–R5) of the sequence, representing non-perfect repeats. Gate-keeper amino acid residues, specific to each fragment, define the fragment’s propensity for self-aggregation and aggregating characteristics of the whole protein. We study the self-aggregation and secondary structures of the repeat fragments of Salmonella enterica and Escherichia coli and comparatively analyze their potential effects on these proteins in a bacterial biofilm. Using bioinformatics predictors, ATR-FTIR and FT-Raman spectroscopy techniques, circular dichroism, and transmission electron microscopy, we confirmed self-aggregation of R1, R3, R5 fragments, as previously reported for Escherichia coli, however, with different temporal characteristics for each species. We also observed aggregation propensities of R4 fragment of Salmonella enterica that is different than that of Escherichia coli. Our studies showed that amyloid structures of CsgA repeats are more easily formed and more durable in Salmonella enterica than those in Escherichia coli. Full article
(This article belongs to the Special Issue The Role of Environment in Amyloid Aggregation)
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Article
Temperature-Dependent Structural Variability of Prion Protein Amyloid Fibrils
Int. J. Mol. Sci. 2021, 22(10), 5075; https://doi.org/10.3390/ijms22105075 - 11 May 2021
Cited by 1 | Viewed by 838
Abstract
Prion protein aggregation into amyloid fibrils is associated with the onset and progression of prion diseases—a group of neurodegenerative amyloidoses. The process of such aggregate formation is still not fully understood, especially regarding their polymorphism, an event where the same type of protein [...] Read more.
Prion protein aggregation into amyloid fibrils is associated with the onset and progression of prion diseases—a group of neurodegenerative amyloidoses. The process of such aggregate formation is still not fully understood, especially regarding their polymorphism, an event where the same type of protein forms multiple, conformationally and morphologically distinct structures. Considering that such structural variations can greatly complicate the search for potential antiamyloid compounds, either by having specific propagation properties or stability, it is important to better understand this aggregation event. We have recently reported the ability of prion protein fibrils to obtain at least two distinct conformations under identical conditions, which raised the question if this occurrence is tied to only certain environmental conditions. In this work, we examined a large sample size of prion protein aggregation reactions under a range of temperatures and analyzed the resulting fibril dye-binding, secondary structure and morphological properties. We show that all temperature conditions lead to the formation of more than one fibril type and that this variability may depend on the state of the initial prion protein molecules. Full article
(This article belongs to the Special Issue The Role of Environment in Amyloid Aggregation)
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Article
Amyloid Structural Changes Studied by Infrared Microspectroscopy in Bigenic Cellular Models of Alzheimer’s Disease
Int. J. Mol. Sci. 2021, 22(7), 3430; https://doi.org/10.3390/ijms22073430 - 26 Mar 2021
Cited by 1 | Viewed by 869
Abstract
Alzheimer’s disease affects millions of lives worldwide. This terminal disease is characterized by the formation of amyloid aggregates, so-called amyloid oligomers. These oligomers are composed of β-sheet structures, which are believed to be neurotoxic. However, the actual secondary structure that contributes most to [...] Read more.
Alzheimer’s disease affects millions of lives worldwide. This terminal disease is characterized by the formation of amyloid aggregates, so-called amyloid oligomers. These oligomers are composed of β-sheet structures, which are believed to be neurotoxic. However, the actual secondary structure that contributes most to neurotoxicity remains unknown. This lack of knowledge is due to the challenging nature of characterizing the secondary structure of amyloids in cells. To overcome this and investigate the molecular changes in proteins directly in cells, we used synchrotron-based infrared microspectroscopy, a label-free and non-destructive technique available for in situ molecular imaging, to detect structural changes in proteins and lipids. Specifically, we evaluated the formation of β-sheet structures in different monogenic and bigenic cellular models of Alzheimer’s disease that we generated for this study. We report on the possibility to discern different amyloid signatures directly in cells using infrared microspectroscopy and demonstrate that bigenic (amyloid-β, α-synuclein) and (amyloid-β, Tau) neuron-like cells display changes in β-sheet load. Altogether, our findings support the notion that different molecular mechanisms of amyloid aggregation, as opposed to a common mechanism, are triggered by the specific cellular environment and, therefore, that various mechanisms lead to the development of Alzheimer’s disease. Full article
(This article belongs to the Special Issue The Role of Environment in Amyloid Aggregation)
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Article
Cold Atmospheric Plasma Modification of Amyloid β
Int. J. Mol. Sci. 2021, 22(6), 3116; https://doi.org/10.3390/ijms22063116 - 18 Mar 2021
Viewed by 686
Abstract
Cold atmospheric plasma (CAP) has attracted much attention in the fields of biotechnology and medicine owing to its potential utility in clinical applications. Recently accumulating evidence has demonstrated that CAP influences protein structures. However, there remain open questions regarding the molecular mechanisms behind [...] Read more.
Cold atmospheric plasma (CAP) has attracted much attention in the fields of biotechnology and medicine owing to its potential utility in clinical applications. Recently accumulating evidence has demonstrated that CAP influences protein structures. However, there remain open questions regarding the molecular mechanisms behind the CAP-induced structural perturbations of biomacromolecules. Here, we investigated the potential effects of CAP irradiation of amyloid β (Aβ), an amyloidogenic protein associated with Alzheimer’s disease. Using nuclear magnetic resonance spectroscopy, we observed gradual spectral changes in Aβ after a 10 s CAP pretreatment, which also suppressed its fibril formation, as revealed by thioflavin T assay. As per mass spectrometric analyses, these effects were attributed to selective oxidation of the methionine residue (Met) at position 35. Interestingly, this modification occurred when Aβ was dissolved into a pre-irradiated buffer, indicating that some reactive species oxidize the Met residue. Our results strongly suggest that the H2O2 generated in the solution by CAP irradiation is responsible for Met oxidation, which inhibits Aβ amyloid formation. The findings of the present study provide fundamental insights into plasma biology, giving clues for developing novel applications of CAP. Full article
(This article belongs to the Special Issue The Role of Environment in Amyloid Aggregation)
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Article
Effect of Ionic Strength on Thioflavin-T Affinity to Amyloid Fibrils and Its Fluorescence Intensity
Int. J. Mol. Sci. 2020, 21(23), 8916; https://doi.org/10.3390/ijms21238916 - 24 Nov 2020
Cited by 8 | Viewed by 1034
Abstract
The formation of amyloid fibrils is linked to multiple neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Despite years of research and countless studies on the topic of such aggregate formation, as well as their resulting structure, the current knowledge is still fairly limited. [...] Read more.
The formation of amyloid fibrils is linked to multiple neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease. Despite years of research and countless studies on the topic of such aggregate formation, as well as their resulting structure, the current knowledge is still fairly limited. One of the main aspects prohibiting effective aggregation tracking is the environment’s effect on amyloid-specific dyes, namely thioflavin-T (ThT). Currently, there are only a few studies hinting at ionic strength being one of the factors that modulate the dye’s binding affinity and fluorescence intensity. In this work we explore this effect under a range of ionic strength conditions, using insulin, lysozyme, mouse prion protein, and α-synuclein fibrils. We show that ionic strength is an extremely important factor affecting both the binding affinity, as well as the fluorescence intensity of ThT. Full article
(This article belongs to the Special Issue The Role of Environment in Amyloid Aggregation)
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