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Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms

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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 (30 September 2020) | Viewed by 53067

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Special Issue Editors

Dr. Stefania Brocca

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Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy
Interests: intrinsically disordered proteins; phase separations; charge-induced conformational transitions; structural and functional properties of hydrolytic enzymes
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Rita Grandori

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Department of Biotechnology and Biosciences, University of Milano‐Bicocca, Piazza della Scienza 2, 20126 Milan, Italy
Interests: eyes by LC-MS for neurodegeneration

Dr. Sonia Longhi

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Laboratoire Architecture et Fonction des Macromolécules Biologiques (AFMB), Aix-Marseille University and CNRS, UMR 7257, 13288 Marseille, France
Interests: intrinsically disordered proteins; folding copuled to binding; protein-protein interactions; structural transitions; paramyxoviruses
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Intrinsically disordered proteins (IDPs) represent ~50% of the human proteome and are implicated in major human diseases, such as cancer, neurodegeneration, and viral infections, emerging as potential targets for therapeutic approaches. In spite of the increasing interest attracted by IDPs in the last decades, the mechanistic relationships between structural disorder and biological function remain a major challenge. Moreover, IDP structural characterization requires description of dynamic and heterogeneous molecular ensembles and their rearrangements in response to environmental conditions. This Special Issue will highlight the link between the peculiar physicochemical properties of these polymers, their interactions, and their role under physiological and pathological conditions. Advanced biophysical methods for IDP structural investigation will also be discussed. Most of the papers derive from contributions to the International Summer School on “Intrinsically disordered proteins (IDPs)—From Physical Chemistry to Pathogenic Mechanisms” held in Como, Italy, in September 2019.

Topics include, without being limited to:: IDP identification, classification and characterization, liquid–liquid phase transitions, membrane-less organelles, conformational ensembles, molecular recognition, fuzzy complexes, protein networks, cancer, neurodegeneration, virus regulation, enzymatic IDPs, biophysical and mass spectrometry techniques, -omics approaches, disorder and aggregation prediction, computational modeling.

Prof. Stefania Brocca
Dr. Rita Grandori
Prof. Dr. Sonia Longhi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Related Special Issue

Intrinsically Disordered Proteins (IDPs) 2.0 in International Journal of Molecular Sciences (5 articles)

Published Papers (14 papers)

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Research

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40 pages, 18405 KiB

Open AccessArticle

Experimental Evidence of Intrinsic Disorder and Amyloid Formation by the Henipavirus W Proteins

by Giulia Pesce, Frank Gondelaud, Denis Ptchelkine, Juliet F. Nilsson, Christophe Bignon, Jérémy Cartalas, Patrick Fourquet and Sonia Longhi

Int. J. Mol. Sci. 2022, 23(2), 923; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020923 - 15 Jan 2022

Cited by 5 | Viewed by 2605

Abstract

Henipaviruses are severe human pathogens within the Paramyxoviridae family. Beyond the P protein, the Henipavirus P gene also encodes the V and W proteins which share with P their N-terminal, intrinsically disordered domain (NTD) and possess a unique C-terminal domain. Henipavirus W proteins antagonize interferon (IFN) signaling through NTD-mediated binding to STAT1 and STAT4, and prevent type I IFN expression and production of chemokines. Structural and molecular information on Henipavirus W proteins is lacking. By combining various bioinformatic approaches, we herein show that the Henipaviruses W proteins are predicted to be prevalently disordered and yet to contain short order-prone segments. Using limited proteolysis, differential scanning fluorimetry, analytical size exclusion chromatography, far-UV circular dichroism and small-angle X-ray scattering, we experimentally confirmed their overall disordered nature. In addition, using Congo red and Thioflavin T binding assays and negative-staining transmission electron microscopy, we show that the W proteins phase separate to form amyloid-like fibrils. The present study provides an additional example, among the few reported so far, of a viral protein forming amyloid-like fibrils, therefore significantly contributing to enlarge our currently limited knowledge of viral amyloids. In light of the critical role of the Henipavirus W proteins in evading the host innate immune response and of the functional role of phase separation in biology, these studies provide a conceptual asset to further investigate the functional impact of the phase separation abilities of the W proteins. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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17 pages, 2026 KiB

Open AccessArticle

Short Disordered Epitope of CRTAM Ig-Like V Domain as a Potential Target for Blocking Antibodies

by Julio Angel Vázquez-Martínez, Miguel Angel Gómez-Lim, Edgar Morales-Ríos, Jorge Alberto Gonzalez-y-Merchand and Vianney Ortiz-Navarrete

Int. J. Mol. Sci. 2020, 21(22), 8798; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228798 - 20 Nov 2020

Viewed by 2353

Abstract

Class-I Restricted T Cell-Associated Molecule (CRTAM) is a protein that is expressed after T cell activation. The interaction of CRTAM with its ligand, nectin-like 2 (Necl2), is required for the efficient production of IL-17, IL-22, and IFNγ by murine CD4 T cells, and it plays a role in optimal CD8 T and NK cell cytotoxicity. CRTAM promotes the pro-inflammatory cytokine profile; therefore, it may take part in the immunopathology of autoimmune diseases such as diabetes type 1 or colitis. Thus, antibodies that block the interaction between CRTAM and Necl2 would be useful for controlling the production of these inflammatory cytokines. In this work, using bioinformatics predictions, we identified three short disordered epitopes (sDE1-3) that are located in the Ig-like domains of murine CRTAM and are conserved in mammalian species. We performed a structural analysis by molecular dynamics simulations of sDE1 (QHPALKSSKY, Ig-like V), sDE2 (QRNGEKSVVK, Ig-like C1), and sDE3 (CSTERSKKPPPQI, Ig-like C1). sDE1, which is located within a loop of the contact interface of the heterotypic interaction with Nectl2, undergoes an order–disorder transition. On the contrary, even though sDE2 and sDE3 are flexible and also located within loops, they do not undergo order–disorder transitions. We evaluated the immunogenicity of sDE1 and sDE3 through the expression of these epitopes in chimeric L1 virus-like particles. We confirmed that sDE1 induces polyclonal antibodies that recognize the native folding of CRTAM expressed in activated murine CD4 T cells. In contrast, sDE3 induces polyclonal antibodies that recognize the recombinant protein hCRTAM-Fc, but not the native CRTAM. Thus, in this study, an exposed disordered epitope in the Ig-like V domain of CRTAM was identified as a potential site for therapeutic antibodies. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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23 pages, 6989 KiB

Open AccessArticle

Effects of Detergent on α-Synuclein Structure: A Native MS-Ion Mobility Study

by Rani Moons, Renate van der Wekken-de Bruijne, Stuart Maudsley, Filip Lemière, Anne-Marie Lambeir and Frank Sobott

Int. J. Mol. Sci. 2020, 21(21), 7884; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217884 - 23 Oct 2020

Cited by 8 | Viewed by 2578

Abstract

The intrinsically disordered protein α-synuclein plays a major role in Parkinson’s disease. The protein can oligomerize resulting in the formation of various aggregated species in neuronal cells, leading to neurodegeneration. The interaction of α-synuclein with biological cell membranes plays an important role for specific functions of α-synuclein monomers, e.g., in neurotransmitter release. Using different types of detergents to mimic lipid molecules present in biological membranes, including the presence of Ca²⁺ ions as an important structural factor, we aimed to gain an understanding of how α-synuclein interacts with membrane models and how this affects the protein conformation and potential oligomerization. We investigated detergent binding stoichiometry, affinity and conformational changes of α-synuclein taking detergent concentration, different detergent structures and charges into account. With native nano-electrospray ionization ion mobility-mass spectrometry, we were able to detect unique conformational patterns resulting from binding of specific detergents to α-synuclein. Our data demonstrate that α-synuclein monomers can interact with detergent molecules irrespective of their charge, that protein-micelle interactions occur and that micelle properties are an important factor. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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18 pages, 1909 KiB

Open AccessArticle

The Paralogue of the Intrinsically Disordered Nuclear Protein 1 Has a Nuclear Localization Sequence that Binds to Human Importin α3

by José L. Neira, Bruno Rizzuti, Ana Jiménez-Alesanco, Olga Abián, Adrián Velázquez-Campoy and Juan L. Iovanna

Int. J. Mol. Sci. 2020, 21(19), 7428; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197428 - 08 Oct 2020

Cited by 7 | Viewed by 2176

Abstract

Numerous carrier proteins intervene in protein transport from the cytoplasm to the nucleus in eukaryotic cells. One of those is importin α, with several human isoforms; among them, importin α3 (Impα3) features a particularly high flexibility. The protein NUPR1L is an intrinsically disordered protein (IDP), evolved as a paralogue of nuclear protein 1 (NUPR1), which is involved in chromatin remodeling and DNA repair. It is predicted that NUPR1L has a nuclear localization sequence (NLS) from residues Arg51 to Gln74, in order to allow for nuclear translocation. We studied in this work the ability of intact NUPR1L to bind Impα3 and its depleted species, ∆Impα3, without the importin binding domain (IBB), using fluorescence, isothermal titration calorimetry (ITC), circular dichroism (CD), nuclear magnetic resonance (NMR), and molecular docking techniques. Furthermore, the binding of the peptide matching the isolated NLS region of NUPR1L (NLS-NUPR1L) was also studied using the same methods. Our results show that NUPR1L was bound to Imp α3 with a low micromolar affinity (~5 μM). Furthermore, a similar affinity value was observed for the binding of NLS-NUPR1L. These findings indicate that the NLS region, which was unfolded in isolation in solution, was essentially responsible for the binding of NUPR1L to both importin species. This result was also confirmed by our in silico modeling. The binding reaction of NLS-NUPR1L to ∆Impα3 showed a larger affinity (i.e., lower dissociation constant) compared with that of Impα3, confirming that the IBB could act as an auto-inhibition region of Impα3. Taken together, our findings pinpoint the theoretical predictions of the NLS region in NUPR1L and, more importantly, suggest that this IDP relies on an importin for its nuclear translocation. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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12 pages, 1441 KiB

Open AccessArticle

DispHred: A Server to Predict pH-Dependent Order–Disorder Transitions in Intrinsically Disordered Proteins

by Jaime Santos, Valentín Iglesias, Carlos Pintado, Juan Santos-Suárez and Salvador Ventura

Int. J. Mol. Sci. 2020, 21(16), 5814; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165814 - 13 Aug 2020

Cited by 15 | Viewed by 3926

Abstract

The natively unfolded nature of intrinsically disordered proteins (IDPs) relies on several physicochemical principles, of which the balance between a low sequence hydrophobicity and a high net charge appears to be critical. Under this premise, it is well-known that disordered proteins populate a defined region of the charge–hydropathy (C–H) space and that a linear boundary condition is sufficient to distinguish between folded and disordered proteins, an approach widely applied for the prediction of protein disorder. Nevertheless, it is evident that the C–H relation of a protein is not unalterable but can be modulated by factors extrinsic to its sequence. Here, we applied a C–H-based analysis to develop a computational approach that evaluates sequence disorder as a function of pH, assuming that both protein net charge and hydrophobicity are dependent on pH solution. On that basis, we developed DispHred, the first pH-dependent predictor of protein disorder. Despite its simplicity, DispHred displays very high accuracy in identifying pH-induced order/disorder protein transitions. DispHred might be useful for diverse applications, from the analysis of conditionally disordered segments to the synthetic design of disorder tags for biotechnological applications. Importantly, since many disorder predictors use hydrophobicity as an input, the here developed framework can be implemented in other state-of-the-art algorithms. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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15 pages, 1934 KiB

Open AccessArticle

Spectroscopic Investigation of the Kinetic Mechanism Involved in the Association of Potyviral VPg with the Host Plant Translation Initiation Factor eIF4E

by Jocelyne Walter, Amandine Barra, Justine Charon, Geneviève Tavert-Roudet and Thierry Michon

Int. J. Mol. Sci. 2020, 21(16), 5618; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165618 - 05 Aug 2020

Cited by 7 | Viewed by 2283

Abstract

The infectious cycle of potyviruses requires the formation of a complex between the viral genome-linked protein VPg and the host eukaryotic translation initiation factor 4E, eIF4E. Mutations associated with plant resistance to potyviruses were previously mapped at the eIF4E surface, while on the virus side, mutations leading to plant resistance breaking were identified within the VPg. In the present study, fluorescence spectroscopy was used to probe the contribution of the VPg intrinsically disordered region bearing amino acids determinant of the resistance breaking, to the VPg–eIF4E binding mechanism. Synthetic peptides encompassing the VPg_88–120 central region were found to tightly bind to eIF4E. Fluorescence energy transfer experiments show that, upon binding to eIF4E, the N and C termini of the VPg_88–111 fragment move closer to one another, at a distance compatible with a α-helix folding. When the VPg_112–120 region, which contains amino acids associated with resistance breakdown, is appended to VPg_88–111, the complex formation with eIF4E switches from a single-step to a two-step kinetic model. This study revisits a recent investigation of the VPg–eIF4E complex by specifying the contribution of the VPg central helix and its appended disordered region to VPg association with eIF4E. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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16 pages, 2944 KiB

Open AccessArticle

Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid Assembly

by Oscar Palomino-Hernandez, Fiamma A. Buratti, Pamela S. Sacco, Giulia Rossetti, Paolo Carloni and Claudio O. Fernandez

Int. J. Mol. Sci. 2020, 21(14), 5061; https://doi.org/10.3390/ijms21145061 - 17 Jul 2020

Cited by 3 | Viewed by 2769

Abstract

Recent studies suggest that Tyr-39 might play a critical role for both the normal function and the pathological dysfunction of α-synuclein (αS), an intrinsically disordered protein involved in Parkinson’s disease. We perform here a comparative analysis between the structural features of human αS and its Y39A, Y39F, and Y39L variants. By the combined application of site-directed mutagenesis, biophysical techniques, and enhanced sampling molecular simulations, we show that removing aromatic functionality at position 39 of monomeric αS leads to protein variants populating more compact conformations, conserving its disordered nature and secondary structure propensities. Contrasting with the subtle changes induced by mutations on the protein structure, removing aromaticity at position 39 impacts strongly on the interaction of αS with the potent amyloid inhibitor phthalocyanine tetrasulfonate (PcTS). Our findings further support the role of Tyr-39 in forming essential inter and intramolecular contacts that might have important repercussions for the function and the dysfunction of αS. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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13 pages, 2516 KiB

Open AccessCommunication

Experimentally Determined Long Intrinsically Disordered Protein Regions Are Now Abundant in the Protein Data Bank

by Alexander Miguel Monzon, Marco Necci, Federica Quaglia, Ian Walsh, Giuseppe Zanotti, Damiano Piovesan and Silvio C. E. Tosatto

Int. J. Mol. Sci. 2020, 21(12), 4496; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124496 - 24 Jun 2020

Cited by 22 | Viewed by 3662

Abstract

Intrinsically disordered protein regions are commonly defined from missing electron density in X-ray structures. Experimental evidence for long disorder regions (LDRs) of at least 30 residues was so far limited to manually curated proteins. Here, we describe a comprehensive and large-scale analysis of experimental LDRs for 3133 unique proteins, demonstrating an increasing coverage of intrinsic disorder in the Protein Data Bank (PDB) in the last decade. The results suggest that long missing residue regions are a good quality source to annotate intrinsically disordered regions and perform functional analysis in large data sets. The consensus approach used to define LDRs allows to evaluate context dependent disorder and provide a common definition at the protein level. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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Review

Jump to: Research

15 pages, 2217 KiB

Open AccessReview

Phase Separation of Intrinsically Disordered Nucleolar Proteins Relate to Localization and Function

by Francisco Guillen-Chable, Andrea Bayona, Luis Carlos Rodríguez-Zapata and Enrique Castano

Int. J. Mol. Sci. 2021, 22(23), 13095; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313095 - 03 Dec 2021

Cited by 7 | Viewed by 2889

Abstract

The process of phase separation allows for the establishment and formation of subcompartmentalized structures, thus enabling cells to perform simultaneous processes with precise organization and low energy requirements. Chemical modifications of proteins, RNA, and lipids alter the molecular environment facilitating enzymatic reactions at higher concentrations in particular regions of the cell. In this review, we discuss the nucleolus as an example of the establishment, dynamics, and maintenance of a membraneless organelle with a high level of organization. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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31 pages, 2051 KiB

Open AccessReview

Liquid–Liquid Phase Separation by Intrinsically Disordered Protein Regions of Viruses: Roles in Viral Life Cycle and Control of Virus–Host Interactions

by Stefania Brocca, Rita Grandori, Sonia Longhi and Vladimir Uversky

Int. J. Mol. Sci. 2020, 21(23), 9045; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239045 - 28 Nov 2020

Cited by 91 | Viewed by 9139

Abstract

Intrinsically disordered proteins (IDPs) are unable to adopt a unique 3D structure under physiological conditions and thus exist as highly dynamic conformational ensembles. IDPs are ubiquitous and widely spread in the protein realm. In the last decade, compelling experimental evidence has been gathered, pointing to the ability of IDPs and intrinsically disordered regions (IDRs) to undergo liquid–liquid phase separation (LLPS), a phenomenon driving the formation of membrane-less organelles (MLOs). These biological condensates play a critical role in the spatio-temporal organization of the cell, where they exert a multitude of key biological functions, ranging from transcriptional regulation and silencing to control of signal transduction networks. After introducing IDPs and LLPS, we herein survey available data on LLPS by IDPs/IDRs of viral origin and discuss their functional implications. We distinguish LLPS associated with viral replication and trafficking of viral components, from the LLPS-mediated interference of viruses with host cell functions. We discuss emerging evidence on the ability of plant virus proteins to interfere with the regulation of MLOs of the host and propose that bacteriophages can interfere with bacterial LLPS, as well. We conclude by discussing how LLPS could be targeted to treat phase separation-associated diseases, including viral infections. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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9 pages, 1042 KiB

Open AccessReview

Classifying the Binding Modes of Disordered Proteins

by Monika Fuxreiter

Int. J. Mol. Sci. 2020, 21(22), 8615; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228615 - 16 Nov 2020

Cited by 43 | Viewed by 2806

Abstract

Disordered proteins often act as interaction hubs in cellular pathways, via the specific recognition of a distinguished set of partners. While disordered regions can adopt a well-defined conformation upon binding, the coupled folding to binding model does not explain how interaction versatility is achieved. Here, I present a classification scheme for the binding modes of disordered protein regions, based on their conformational heterogeneity in the bound state. Binding modes are defined as (i) disorder-to-order transitions leading to a well-defined bound state, (ii) disordered binding leading to a disordered bound state and (iii) fuzzy binding when the degree of disorder in the bound state may vary with the partner or cellular conditions. Fuzzy binding includes polymorphic bound structures, conditional folding and dynamic binding. This classification scheme describes the structural continuum of complexes involving disordered regions as well as their context-dependent interaction behaviors. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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30 pages, 2615 KiB

Open AccessReview

Relevance of Electrostatic Charges in Compactness, Aggregation, and Phase Separation of Intrinsically Disordered Proteins

by Greta Bianchi, Sonia Longhi, Rita Grandori and Stefania Brocca

Int. J. Mol. Sci. 2020, 21(17), 6208; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176208 - 27 Aug 2020

Cited by 45 | Viewed by 5542

Abstract

The abundance of intrinsic disorder in the protein realm and its role in a variety of physiological and pathological cellular events have strengthened the interest of the scientific community in understanding the structural and dynamical properties of intrinsically disordered proteins (IDPs) and regions (IDRs). Attempts at rationalizing the general principles underlying both conformational properties and transitions of IDPs/IDRs must consider the abundance of charged residues (Asp, Glu, Lys, and Arg) that typifies these proteins, rendering them assimilable to polyampholytes or polyelectrolytes. Their conformation strongly depends on both the charge density and distribution along the sequence (i.e., charge decoration) as highlighted by recent experimental and theoretical studies that have introduced novel descriptors. Published experimental data are revisited herein in the frame of this formalism, in a new and possibly unitary perspective. The physicochemical properties most directly affected by charge density and distribution are compaction and solubility, which can be described in a relatively simplified way by tools of polymer physics. Dissecting factors controlling such properties could contribute to better understanding complex biological phenomena, such as fibrillation and phase separation. Furthermore, this knowledge is expected to have enormous practical implications for the design, synthesis, and exploitation of bio-derived materials and the control of natural biological processes. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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32 pages, 3573 KiB

Open AccessReview

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

by Elena Vacchi, Alain Kaelin-Lang and Giorgia Melli

Int. J. Mol. Sci. 2020, 21(14), 5030; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145030 - 16 Jul 2020

Cited by 17 | Viewed by 5836

Abstract

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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13 pages, 1568 KiB

Open AccessReview

Understanding the Binding Induced Folding of Intrinsically Disordered Proteins by Protein Engineering: Caveats and Pitfalls

by Francesca Malagrinò, Lorenzo Visconti, Livia Pagano, Angelo Toto, Francesca Troilo and Stefano Gianni

Int. J. Mol. Sci. 2020, 21(10), 3484; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103484 - 15 May 2020

Cited by 10 | Viewed by 3282

Abstract

Many proteins lack a well-defined three-dimensional structure in isolation. These proteins, typically denoted as intrinsically disordered proteins (IDPs), may display a characteristic disorder-to-order transition when binding their physiological partner(s). From an experimental perspective, it is of great importance to establish the general grounds to understand how such folding processes may be explored. Here we discuss the caveats and the pitfalls arising when applying to IDPs one of the key techniques to characterize the folding of globular proteins, the Φ value analysis. This method is based on measurements of the free energy changes of transition and native states upon conservative, non-disrupting, mutations. On the basis of available data, we reinforce the validity of Φ value analysis in the study of IDPs and suggest future experiments to further validate this powerful experimental method. Full article

(This article belongs to the Special Issue Intrinsically Disordered Proteins (IDPs): From Physical Chemistry to Pathogenic Mechanisms)

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