International Journal of Molecular Sciences

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Dear Colleagues,

Nearly all biological processes rely on the conformational states of interacting macromolecules. It is, therefore, not surprising that the study of protein folding and misfolding has played a central role in chemistry and biology. In particular, substantial experimental and theoretical efforts have been devoted to understanding the general rules of folding, as well as to deciphering the mechanisms that lead to misfolding and related diseases. Furthermore, the discovery that a large fraction of the proteome is essentially disordered, while being fully functional, has revolutionized our comprehension of the structure–function relationships, posing the description of intrinsically disordered proteins as a key problem in modern science.

Leading by Prof. Dr. Stefano Gianni and assisting by our Topical Advisory Panel Member Dr. Francesca Malagrinò (University of Naples Federico II), this Special Issue focuses on recent studies that contribute to our understanding of protein folding and misfolding, as well as on the role of intrinsic disorder in protein functions. Original research articles and reviews on these and related topics are welcome in this Special Issue.

Prof. Dr. Stefano Gianni
Guest Editor

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Keywords

protein folding
chaperones
foldases
energy landscape
molecular dynamics simulation
chemical kinetics
energy barriers
down-hill folding
protein misfolding
protein unfolding
amyloid structure
degenerative diseases
proteopathy
oligomer toxicity
intrinsic disorder
intrinsically disordered proteins
folding upon binding

Published Papers (2 papers)

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Research

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14 pages, 7494 KiB

Open AccessArticle

Secondary Modification of S100B Influences Anti Amyloid-β Aggregation Activity and Alzheimer’s Disease Pathology

by Romina Coelho, Chiara A. De Benedictis, Ann Katrin Sauer, António J. Figueira, Hélio Faustino, Andreas M. Grabrucker and Cláudio M. Gomes

Int. J. Mol. Sci. 2024, 25(3), 1787; https://doi.org/10.3390/ijms25031787 - 1 Feb 2024

Viewed by 1212

Abstract

Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer’s Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aβ aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aβ proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage. Herein, we report an investigation in which extracellular oxidative conditions are mimicked to test if the susceptibility of S100B to oxidation influences its protective activities. Resorting to mild oxidation of S100B, we observed methionine oxidation as inferred from mass spectrometry, but no cysteine-mediated crosslinking. Structural analysis showed that the folding, structure, and stability of oxidized S100B were not affected, and nor was its quaternary structure. However, studies on Aβ aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:Aβ binding cleft that favors interactions. Using a cell culture model to analyze the S100B functions in a highly oxidative milieu, as in AD, we observed that Aβ toxicity is rescued by the co-administration of oxidized S100B to a greater extent than by S100B. Additionally, results suggest a disrupted positive feedback loop involving S100B which is caused by its oxidation, leading to the downstream regulation of IL-17 and IFN-α2 expression as mediated by S100B. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding — Structure and Functions 2.0)

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Review

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38 pages, 7328 KiB

Open AccessReview

Amyloidogenesis: What Do We Know So Far?

by Zeina Alraawi, Nayan Banerjee, Srujana Mohanty and Thallapuranam Krishnaswamy Suresh Kumar

Int. J. Mol. Sci. 2022, 23(22), 13970; https://doi.org/10.3390/ijms232213970 - 12 Nov 2022

Cited by 6 | Viewed by 3122

Abstract

The study of protein aggregation, and amyloidosis in particular, has gained considerable interest in recent times. Several neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD) show a characteristic buildup of proteinaceous aggregates in several organs, especially the brain. Despite the enormous upsurge in research articles in this arena, it would not be incorrect to say that we still lack a crystal-clear idea surrounding these notorious aggregates. In this review, we attempt to present a holistic picture on protein aggregation and amyloids in particular. Using a chronological order of discoveries, we present the case of amyloids right from the onset of their discovery, various biophysical techniques, including analysis of the structure, the mechanisms and kinetics of the formation of amyloids. We have discussed important questions on whether aggregation and amyloidosis are restricted to a subset of specific proteins or more broadly influenced by the biophysiochemical and cellular environment. The therapeutic strategies and the significant failure rate of drugs in clinical trials pertaining to these neurodegenerative diseases have been also discussed at length. At a time when the COVID-19 pandemic has hit the globe hard, the review also discusses the plausibility of the far-reaching consequences posed by the virus, such as triggering early onset of amyloidosis. Finally, the application(s) of amyloids as useful biomaterials has also been discussed briefly in this review. Full article

(This article belongs to the Special Issue Protein Folding and Misfolding — Structure and Functions 2.0)

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