Special Issue "Function, Regulation, and Dysfunction of Intrinsically Disordered Proteins, Volume II"

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Proteins and Proteomics".

Deadline for manuscript submissions: closed (25 June 2021) | Viewed by 4652

Special Issue Editors

Dr. Giuliana Fusco
E-Mail Website
Guest Editor
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Interests: biochemistry; structural biology; functional intrinsically disordered proteins; parkinson; alzheimer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It has become acknowledged that a significant portion of proteins encoded in eukaryotic and prokaryotic genomes feature a partial or total degree of structural disorder. Disordered regions can regulate the biological activity of protein molecules, such as the propensity to generate molecular complexity, including the regulation of phase separations. The involvement of intrinsically disordered proteins in fundamental biological processes, including cellular signaling, protein translation, and transcriptional regulation, is increasingly reported to be crucial in functional and pathological mechanisms. The remarkable ability of these molecules to establish macromolecular interactions with multiple biomolecular partners is likely promoted by their inherent flexibility and ability to adapt their shape. While the functional role of IDPs is attracting an increasing research focus, understanding the underlying structural and mechanistic principles of their biological activity remains a crucial research challenge. The role of kinetic versus thermodynamic control is the key to understand the way by which these elusive systems are regulated to solve their intriguing biological functions.

Dr. Giuliana Fusco
Prof. Dr. Stefano Gianni
Guest Editors

Manuscript Submission Information

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Keywords

  • intrinsically disordered proteins
  • post-translational modifications
  • phase separation
  • structural and functional dynamics
  • binding promiscuity and fuzzy complexes
  • molten globular states
  • kinetic vs thermodynamic control
  • conformational selection vs induced fit

Related Special Issue

Published Papers (3 papers)

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Research

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Article
Exploring the Release of Toxic Oligomers from α-Synuclein Fibrils with Antibodies and STED Microscopy
Life 2021, 11(5), 431; https://doi.org/10.3390/life11050431 - 11 May 2021
Cited by 2 | Viewed by 1154
Abstract
α-Synuclein (αS) is an intrinsically disordered and highly dynamic protein involved in dopamine release at presynaptic terminals. The abnormal aggregation of αS as mature fibrils into intraneuronal inclusion bodies is directly linked to Parkinson’s disease. Increasing experimental evidence suggests that soluble oligomers formed [...] Read more.
α-Synuclein (αS) is an intrinsically disordered and highly dynamic protein involved in dopamine release at presynaptic terminals. The abnormal aggregation of αS as mature fibrils into intraneuronal inclusion bodies is directly linked to Parkinson’s disease. Increasing experimental evidence suggests that soluble oligomers formed early during the aggregation process are the most cytotoxic forms of αS. This study investigated the uptake by neuronal cells of pathologically relevant αS oligomers and fibrils exploiting a range of conformation-sensitive antibodies, and the super-resolution stimulated emission depletion (STED) microscopy. We found that prefibrillar oligomers promptly penetrate neuronal membranes, thus resulting in cell dysfunction. By contrast, fibril docking to the phospholipid bilayer is accompanied by αS conformational changes with a progressive release of A11-reactive oligomers, which can enter into the neurons and trigger cell impairment. Our data provide important evidence on the role of αS fibrils as a source of harmful oligomers, which resemble the intermediate conformers formed de novo during aggregation, underling the dynamic and reversible nature of protein aggregates responsible for α-synucleinopathies. Full article
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Review

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Review
Dynamic Interplay between Copper Toxicity and Mitochondrial Dysfunction in Alzheimer’s Disease
Life 2021, 11(5), 386; https://doi.org/10.3390/life11050386 - 24 Apr 2021
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Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder, affecting millions of people worldwide, a number expected to exponentially increase in the future since no effective treatments are available so far. AD is characterized by severe cognitive dysfunctions associated with neuronal loss and connection disruption, [...] Read more.
Alzheimer’s disease (AD) is a neurodegenerative disorder, affecting millions of people worldwide, a number expected to exponentially increase in the future since no effective treatments are available so far. AD is characterized by severe cognitive dysfunctions associated with neuronal loss and connection disruption, mainly occurring in specific brain areas such as the hippocampus, cerebral cortex, and amygdala, compromising memory, language, reasoning, and social behavior. Proteomics and redox proteomics are powerful techniques used to identify altered proteins and pathways in AD, providing relevant insights on cellular pathways altered in the disease and defining novel targets exploitable for drug development. Here, we review the main results achieved by both -omics techniques, focusing on the changes occurring in AD mitochondria under oxidative stress and upon copper exposure. Relevant information arises by the comparative analysis of these results, evidencing alterations of common mitochondrial proteins, metabolic cycles, and cascades. Our analysis leads to three shared mitochondrial proteins, playing key roles in metabolism, ATP generation, oxidative stress, and apoptosis. Their potential as targets for development of innovative AD treatments is thus suggested. Despite the relevant efforts, no effective drugs against AD have been reported so far; nonetheless, various compounds targeting mitochondria have been proposed and investigated, reporting promising results. Full article
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Review
Tau Oligomers Neurotoxicity
Life 2021, 11(1), 28; https://doi.org/10.3390/life11010028 - 06 Jan 2021
Cited by 9 | Viewed by 1647
Abstract
Although the mechanisms of toxic activity of tau are not fully recognized, it is supposed that the tau toxicity is related rather not to insoluble tau aggregates but to its intermediate forms. It seems that neurofibrillar tangles (NFTs) themselves, despite being composed of [...] Read more.
Although the mechanisms of toxic activity of tau are not fully recognized, it is supposed that the tau toxicity is related rather not to insoluble tau aggregates but to its intermediate forms. It seems that neurofibrillar tangles (NFTs) themselves, despite being composed of toxic tau, are probably neither necessary nor sufficient for tau-induced neuronal dysfunction and toxicity. Tau oligomers (TauOs) formed during the early stages of tau aggregation are the pathological forms that play a key role in eliciting the loss of neurons and behavioral impairments in several neurodegenerative disorders called tauopathies. They can be found in tauopathic diseases, the most common of which is Alzheimer’s disease (AD). Evidence of co-occurrence of b-amyloid, α-synuclein, and tau into their most toxic forms, i.e., oligomers, suggests that these species interact and influence each other’s aggregation in several tauopathies. The mechanism responsible for oligomeric tau neurotoxicity is a subject of intensive investigation. In this review, we summarize the most recent literature on the damaging effect of TauOs on the stability of the genome and the function of the nucleus, energy production and mitochondrial function, cell signaling and synaptic plasticity, the microtubule assembly, neuronal cytoskeleton and axonal transport, and the effectiveness of the protein degradation system. Full article
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