Intrinsically Disordered Proteins (Closed)

A topical collection in Biomolecules (ISSN 2218-273X). This collection belongs to the section "Cellular Biochemistry".

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Editors


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Collection Editor
Department of Molecular Medicine, USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC07, Tampa, FL 33612, USA
Interests: intrinsically disordered proteins; protein folding; protein misfolding; partially folded proteins; protein aggregation; protein structure; protein function; protein stability; protein biophysics; protein bioinformatics; conformational diseases; protein–ligand interactions; protein–protein interactions; liquid-liquid phase transitions
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Collection Editor
Institute of Biostructures and Bioimaging (IBB)-CNR, Via Pietro Castellino, 111, 80131 Napoli, Italia
Interests: tumor associated proteins; carbonic anhydrase; intrinsically disordered proteins; CAF-1 chemical biology; protein–protein interaction
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Collection Editor
Biostructure and Bioimaging Institute-CNR, Via Mezzocannone 16, 80134 Naples, Italy
Interests: structural characterization of proteins; structural characterization of protein–ligand complexes; X ray crystallography; rational drug design; protein bioinformatics; carbonic anhydrase; cancer-related proteins
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Collection Editor
Biostructure and Bioimaging Institute-CNR, Via Mezzocannone 16, 80134 Naples, Italy
Interests: computational chemistry; molecular dynamics simulations; modeling; protein-ligand docking; protein-protein docking; computer-aided drug design; binding free energy calculations; intrinsically disordered proteins; carbonic anhydrases; oligonucleotides; Alzheimer-related proteins; cancer-related proteins
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

As follows from the title, this Topical Collection “Intrinsically Disordered Proteins” aims to collect high-quality research articles, communications, and review articles in all the aspects related to the protein intrinsic disorder phenomenon. This Collection covers a wide range of topics, including structural manifestations of intrinsic disorder; functionality of intrinsically disordered proteins/regions; abundance of intrinsically disordered proteins; structure–function relationships for these proteins/regions; roles of intrinsic disorder in various biological processes; the intrinsic disorder-based mechanisms of regulation, recognition, and signaling; correlation between intrinsically disordered proteins and diseases; expression analysis of genes encoding intrinsically disordered proteins; description of experimental and computational techniques applicable for the analysis of structure and function of intrinsically disordered proteins.

The Topical Collection “Intrinsically Disordered Proteins” has several goals:

  • To provide a platform devoted to protein intrinsic disorder that assembles top-quality papers on all aspects of this topic and promotes the field.
  • To raise awareness about biological importance and abundance of intrinsically disordered proteins.
  • To define and build a worldwide community of scientists interested in intrinsically disordered proteins, and to facilitate communication among them.
  • To provide resources to enhance the effort of laboratories working on intrinsically disordered proteins.

I encourage you to share your data and thoughts in this broad field that clearly demonstrates the physiological and pathological importance of intrinsically disordered proteins.

Dr. Vladimir N. Uversky
Dr. Simona Maria Monti
Dr. Giuseppina De Simone
Dr. Emma Langella
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 collection 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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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.

Published Papers (10 papers)

2023

Jump to: 2020, 2019, 2018, 2016, 2013, 2012

15 pages, 3338 KiB  
Article
The Origin of Discrepancies between Predictions and Annotations in Intrinsically Disordered Proteins
by Mátyás Pajkos, Gábor Erdős and Zsuzsanna Dosztányi
Biomolecules 2023, 13(10), 1442; https://doi.org/10.3390/biom13101442 - 25 Sep 2023
Cited by 1 | Viewed by 1524
Abstract
Disorder prediction methods that can discriminate between ordered and disordered regions have contributed fundamentally to our understanding of the properties and prevalence of intrinsically disordered proteins (IDPs) in proteomes as well as their functional roles. However, a recent large-scale assessment of the performance [...] Read more.
Disorder prediction methods that can discriminate between ordered and disordered regions have contributed fundamentally to our understanding of the properties and prevalence of intrinsically disordered proteins (IDPs) in proteomes as well as their functional roles. However, a recent large-scale assessment of the performance of these methods indicated that there is still room for further improvements, necessitating novel approaches to understand the strengths and weaknesses of individual methods. In this study, we compared two methods, IUPred and disorder prediction, based on the pLDDT scores derived from AlphaFold2 (AF2) models. We evaluated these methods using a dataset from the DisProt database, consisting of experimentally characterized disordered regions and subsets associated with diverse experimental methods and functions. IUPred and AF2 provided consistent predictions in 79% of cases for long disordered regions; however, for 15% of these cases, they both suggested order in disagreement with annotations. These discrepancies arose primarily due to weak experimental support, the presence of intermediate states, or context-dependent behavior, such as binding-induced transitions. Furthermore, AF2 tended to predict helical regions with high pLDDT scores within disordered segments, while IUPred had limitations in identifying linker regions. These results provide valuable insights into the inherent limitations and potential biases of disorder prediction methods. Full article
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2020

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24 pages, 4508 KiB  
Article
The Anti-Inflammatory Protein TNIP1 Is Intrinsically Disordered with Structural Flexibility Contributed by Its AHD1-UBAN Domain
by Rambon Shamilov, Olga Vinogradova and Brian J. Aneskievich
Biomolecules 2020, 10(11), 1531; https://doi.org/10.3390/biom10111531 - 10 Nov 2020
Cited by 3 | Viewed by 2772
Abstract
TNFAIP3 interacting protein 1 (TNIP1) interacts with numerous non-related cellular, viral, and bacterial proteins. TNIP1 is also linked with multiple chronic inflammatory disorders on the gene and protein levels, through numerous single-nucleotide polymorphisms and reduced protein amounts. Despite the importance of TNIP1 function, [...] Read more.
TNFAIP3 interacting protein 1 (TNIP1) interacts with numerous non-related cellular, viral, and bacterial proteins. TNIP1 is also linked with multiple chronic inflammatory disorders on the gene and protein levels, through numerous single-nucleotide polymorphisms and reduced protein amounts. Despite the importance of TNIP1 function, there is limited investigation as to how its conformation may impact its apparent multiple roles. Hub proteins like TNIP1 are often intrinsically disordered proteins. Our initial in silico assessments suggested TNIP1 is natively unstructured, featuring numerous potentials intrinsically disordered regions, including the ABIN homology domain 1-ubiquitin binding domain in ABIN proteins and NEMO (AHD1-UBAN) domain associated with its anti-inflammatory function. Using multiple biophysical approaches, we demonstrate the structural flexibility of full-length TNIP1 and the AHD1-UBAN domain. We present evidence the AHD1-UBAN domain exists primarily as a pre-molten globule with limited secondary structure in solution. Data presented here suggest the previously described coiled-coil conformation of the crystallized UBAN-only region may represent just one of possibly multiple states for the AHD1-UBAN domain in solution. These data also characterize the AHD1-UBAN domain in solution as mostly monomeric with potential to undergo oligomerization under specific environmental conditions (e.g., binding partner availability, pH-dependence). This proposed intrinsic disorder across TNIP1 and within the AHD1-UBAN region is likely to impact TNIP1 function and interaction with its multiple partners. Full article
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23 pages, 2729 KiB  
Editorial
Intrinsically Disordered Proteins: Insights from Poincaré, Waddington, and Lamarck
by Prakash Kulkarni
Biomolecules 2020, 10(11), 1490; https://doi.org/10.3390/biom10111490 - 28 Oct 2020
Cited by 8 | Viewed by 3190
Abstract
The past quarter-century may justly be referred to as a period analogous to the “Cambrian explosion” in the history of proteins. This period is marked by the appearance of the intrinsically disordered proteins (IDPs) on the scene since their discovery in the mid-1990s. [...] Read more.
The past quarter-century may justly be referred to as a period analogous to the “Cambrian explosion” in the history of proteins. This period is marked by the appearance of the intrinsically disordered proteins (IDPs) on the scene since their discovery in the mid-1990s. Here, I first reflect on how we accidentally stumbled on these fascinating molecules. Next, I describe our research on the IDPs over the past decade and identify six areas as important for future research in this field. In addition, I draw on discoveries others in the field have made to present a more comprehensive essay. More specifically, I discuss the role of IDPs in two fundamental aspects of life: in phenotypic switching, and in multicellularity that marks one of the major evolutionary transitions. I highlight how serendipity, imagination, and an interdisciplinary approach embodying empirical evidence and theoretical insights from the works of Poincaré, Waddington, and Lamarck, shaped our thinking, and how this led us to propose the MRK hypothesis, a conceptual framework addressing phenotypic switching, the emergence of new traits, and adaptive evolution via nongenetic and IDP conformation-based mechanisms. Finally, I present a perspective on the evolutionary link between phenotypic switching and the origin of multicellularity. Full article
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2019

Jump to: 2023, 2020, 2018, 2016, 2013, 2012

15 pages, 2171 KiB  
Article
Recruitment of DNA Repair MRN Complex by Intrinsically Disordered Protein Domain Fused to Cas9 Improves Efficiency of CRISPR-Mediated Genome Editing
by Nina Reuven, Julia Adler, Karin Broennimann, Nadav Myers and Yosef Shaul
Biomolecules 2019, 9(10), 584; https://doi.org/10.3390/biom9100584 - 8 Oct 2019
Cited by 21 | Viewed by 5572
Abstract
CRISPR/Cas9 is a powerful tool for genome editing in cells and organisms. Nevertheless, introducing directed templated changes by homology-directed repair (HDR) requires the cellular DNA repair machinery, such as the MRN complex (Mre11/Rad50/Nbs1). To improve the process, we tailored chimeric constructs of Cas9, [...] Read more.
CRISPR/Cas9 is a powerful tool for genome editing in cells and organisms. Nevertheless, introducing directed templated changes by homology-directed repair (HDR) requires the cellular DNA repair machinery, such as the MRN complex (Mre11/Rad50/Nbs1). To improve the process, we tailored chimeric constructs of Cas9, in which SpCas9 was fused at its N- or C-terminus to a 126aa intrinsically disordered domain from HSV-1 alkaline nuclease (UL12) that recruits the MRN complex. The chimeric Cas9 constructs were two times more efficient in homology-directed editing of endogenous loci in tissue culture cells. This effect was dependent upon the MRN-recruiting activity of the domain and required lower amounts of the chimeric Cas9 in comparison with unmodified Cas9. The new constructs improved the yield of edited cells when making endogenous point mutations or inserting small tags encoded by oligonucleotide donor DNA (ssODN), and also with larger insertions encoded by plasmid DNA donor templates. Improved editing was achieved with both transfected plasmid-encoded Cas9 constructs as well as recombinant Cas9 protein transfected as ribonucleoprotein complexes. Our strategy was highly efficient in restoring a genetic defect in a cell line, exemplifying the possible implementation of our strategy in gene therapy. These constructs provide a simple approach to improve directed editing. Full article
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Graphical abstract

2018

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5 pages, 207 KiB  
Editorial
Intrinsically Disordered Proteins and the Janus Challenge
by Prakash Kulkarni and Vladimir N. Uversky
Biomolecules 2018, 8(4), 179; https://doi.org/10.3390/biom8040179 - 18 Dec 2018
Cited by 6 | Viewed by 4513
Abstract
To gain a new insight into the role of proteins in the origin of life on Earth, we present the Janus Challenge: identify an intrinsically disordered protein (IDP), naturally occurring or synthetic, that has catalytic activity. For example, such a catalytic IDP may [...] Read more.
To gain a new insight into the role of proteins in the origin of life on Earth, we present the Janus Challenge: identify an intrinsically disordered protein (IDP), naturally occurring or synthetic, that has catalytic activity. For example, such a catalytic IDP may perform condensation reactions to catalyze a peptide bond or a phosphodiester bond formation utilizing natural/un-natural amino acids or nucleotides, respectively. The IDP may also have autocatalytic, de novo synthesis, or self-replicative activity. Meeting this challenge may not only shed new light and provide an alternative to the RNA world hypothesis, but it may also serve as an impetus for technological advances with important biomedical applications. Full article
17 pages, 1552 KiB  
Article
pH-Induced Folding of the Caspase-Cleaved Par-4 Tumor Suppressor: Evidence of Structure Outside of the Coiled Coil Domain
by Andrea M. Clark, Komala Ponniah, Meghan S. Warden, Emily M. Raitt, Andrea C. Yawn and Steven M. Pascal
Biomolecules 2018, 8(4), 162; https://doi.org/10.3390/biom8040162 - 4 Dec 2018
Cited by 9 | Viewed by 4408
Abstract
Prostate apoptosis response-4 (Par-4) is a 38 kDa largely intrinsically disordered tumor suppressor protein that functions in cancer cell apoptosis. Par-4 down-regulation is often observed in cancer while up-regulation is characteristic of neurodegenerative conditions such as Alzheimer’s disease. Cleavage of Par-4 by caspase-3 [...] Read more.
Prostate apoptosis response-4 (Par-4) is a 38 kDa largely intrinsically disordered tumor suppressor protein that functions in cancer cell apoptosis. Par-4 down-regulation is often observed in cancer while up-regulation is characteristic of neurodegenerative conditions such as Alzheimer’s disease. Cleavage of Par-4 by caspase-3 activates tumor suppression via formation of an approximately 25 kDa fragment (cl-Par-4) that enters the nucleus and inhibits Bcl-2 and NF-ƙB, which function in pro-survival pathways. Here, we have investigated the structure of cl-Par-4 using biophysical techniques including circular dichroism (CD) spectroscopy, dynamic light scattering (DLS), and intrinsic tyrosine fluorescence. The results demonstrate pH-dependent folding of cl-Par-4, with high disorder and aggregation at neutral pH, but a largely folded, non-aggregated conformation at acidic pH. Full article
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15 pages, 1340 KiB  
Review
Single Molecule FRET: A Powerful Tool to Study Intrinsically Disordered Proteins
by Sharonda J. LeBlanc, Prakash Kulkarni and Keith R. Weninger
Biomolecules 2018, 8(4), 140; https://doi.org/10.3390/biom8040140 - 8 Nov 2018
Cited by 46 | Viewed by 7312
Abstract
Intrinsically disordered proteins (IDPs) are often modeled using ideas from polymer physics that suggest they smoothly explore all corners of configuration space. Experimental verification of this random, dynamic behavior is difficult as random fluctuations of IDPs cannot be synchronized across an ensemble. Single [...] Read more.
Intrinsically disordered proteins (IDPs) are often modeled using ideas from polymer physics that suggest they smoothly explore all corners of configuration space. Experimental verification of this random, dynamic behavior is difficult as random fluctuations of IDPs cannot be synchronized across an ensemble. Single molecule fluorescence (or Förster) resonance energy transfer (smFRET) is one of the few approaches that are sensitive to transient populations of sub-states within molecular ensembles. In some implementations, smFRET has sufficient time resolution to resolve transitions in IDP behaviors. Here we present experimental issues to consider when applying smFRET to study IDP configuration. We illustrate the power of applying smFRET to IDPs by discussing two cases in the literature of protein systems for which smFRET has successfully reported phosphorylation-induced modification (but not elimination) of the disordered properties that have been connected to impacts on the related biological function. The examples we discuss, PAGE4 and a disordered segment of the GluN2B subunit of the NMDA receptor, illustrate the great potential of smFRET to inform how IDP function can be regulated by controlling the detailed ensemble of disordered states within biological networks. Full article
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2016

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2249 KiB  
Review
NMR Meets Tau: Insights into Its Function and Pathology
by Guy Lippens, Isabelle Landrieu, Caroline Smet, Isabelle Huvent, Neha S. Gandhi, Benoît Gigant, Clément Despres, Haoling Qi and Juan Lopez
Biomolecules 2016, 6(2), 28; https://doi.org/10.3390/biom6020028 - 7 Jun 2016
Cited by 23 | Viewed by 8069
Abstract
In this review, we focus on what we have learned from Nuclear Magnetic Resonance (NMR) studies on the neuronal microtubule-associated protein Tau. We consider both the mechanistic details of Tau: the tubulin relationship and its aggregation process. Phosphorylation of Tau is intimately linked [...] Read more.
In this review, we focus on what we have learned from Nuclear Magnetic Resonance (NMR) studies on the neuronal microtubule-associated protein Tau. We consider both the mechanistic details of Tau: the tubulin relationship and its aggregation process. Phosphorylation of Tau is intimately linked to both aspects. NMR spectroscopy has depicted accurate phosphorylation patterns by different kinases, and its non-destructive character has allowed functional assays with the same samples. Finally, we will discuss other post-translational modifications of Tau and its interaction with other cellular factors in relationship to its (dys)function. Full article
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2013

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1349 KiB  
Article
Biophysical Characterization of α-Synuclein and Rotenone Interaction
by Blanca A. Silva, Ólöf Einarsdóttir, Anthony L. Fink and Vladimir N. Uversky
Biomolecules 2013, 3(3), 703-732; https://doi.org/10.3390/biom3030703 - 24 Sep 2013
Cited by 27 | Viewed by 9630
Abstract
Previous studies revealed that pesticides interact with α-synuclein and accelerate the rate of fibrillation. These results are consistent with the prevailing hypothesis that the direct interaction of α-synuclein with pesticides is one of many suspected factors leading to α-synuclein fibrillation and ultimately to [...] Read more.
Previous studies revealed that pesticides interact with α-synuclein and accelerate the rate of fibrillation. These results are consistent with the prevailing hypothesis that the direct interaction of α-synuclein with pesticides is one of many suspected factors leading to α-synuclein fibrillation and ultimately to Parkinson’s disease. In this study, the biophysical properties and fibrillation kinetics of α-synuclein in the presence of rotenone were investigated and, more specifically, the effects of rotenone on the early-stage misfolded forms of α-synuclein were considered. The thioflavine T (ThT) fluorescence assay studies provide evidence that early-phase misfolded α-synuclein forms are affected by rotenone and that the fibrillation process is accelerated. Further characterization by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) shows that rotenone increases the amount of ordered secondary structure in this intrinsically disordered protein. Morphological characterization by transmission electron microscopy (TEM) and atomic force microscopy (AFM) provide visualization of the differences in the aggregated α-synuclein species developing during the early kinetics of the fibrillation process in the absence and presence of rotenone. We believe that these data provide useful information for a better understanding of the molecular basis of rotenone-induced misfolding and aggregation of α-synuclein. Full article
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2012

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2526 KiB  
Article
Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics
by Koji Umezawa, Jinzen Ikebe, Mitsunori Takano, Haruki Nakamura and Junichi Higo
Biomolecules 2012, 2(1), 104-121; https://doi.org/10.3390/biom2010104 - 22 Feb 2012
Cited by 16 | Viewed by 8887
Abstract
The phosphorylated kinase-inducible activation domain (pKID) adopts a helix–loop–helix structure upon binding to its partner KIX, although it is unstructured in the unbound state. The N-terminal and C-terminal regions of pKID, which adopt helices in the complex, are called, respectively, αA and [...] Read more.
The phosphorylated kinase-inducible activation domain (pKID) adopts a helix–loop–helix structure upon binding to its partner KIX, although it is unstructured in the unbound state. The N-terminal and C-terminal regions of pKID, which adopt helices in the complex, are called, respectively, αA and αB. We performed all-atom multicanonical molecular dynamics simulations of pKID with and without KIX in explicit solvents to generate conformational ensembles. Although the unbound pKID was disordered overall, αA and αB exhibited a nascent helix propensity; the propensity of αA was stronger than that of αB, which agrees with experimental results. In the bound state, the free-energy landscape of αB involved two low free-energy fractions: native-like and non-native fractions. This result suggests that αB folds according to the induced-fit mechanism. The αB-helix direction was well aligned as in the NMR complex structure, although the αA helix exhibited high flexibility. These results also agree quantitatively with experimental observations. We have detected that the αB helix can bind to another site of KIX, to which another protein MLL also binds with the adopting helix. Consequently, MLL can facilitate pKID binding to the pKID-binding site by blocking the MLL-binding site. This also supports experimentally obtained results. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: To be determined
Authors: Michael A. Menze; et al.
Affiliation: Department of Biology, University of Louisville, Louisville, KY 40292, USA

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