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Functionally Relevant Macromolecular Interactions of Disordered Proteins
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Functionally Relevant Macromolecular Interactions of Disordered Proteins

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 2018) | Viewed by 84104

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Istvan Simon

E-Mail Website
Guest Editor
1. Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, 1117 Budapest, Hungary
2. Center of Excellence of the Hungarian Academy of Sciences, 1117 Budapest, Hungary
Interests: protein structures; protein dynamics; protein conformation; protein folding; protein bioinformatics; protein interactions; membrane proteins; protein stability; intrinsically disordered proteins; protein biophysics; protein binding; molecular biophysics; protein refolding; membrane transport proteins; computational structural biology; structural bioinformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is common that most proteins function in folded form. Another significant portion of proteins or protein segments spend a part- or sometimes most- of their time in an unstructured/disordered form. They generally fold only temporarily-typically on the surface of another protein or other macromolecule during their biochemical activity. This phenomenon has been widely studied in the past decade. However, we are expecting a great deal of new information about the functional relevance of this coupled folding and binding for this issue of IJMS. Up-to-date databases like IDEAL and DisProt are listing unstructured proteins, while ELM and DisBind are listing binding segments of this protein. A new database, Schad E et al. "DIBS: a repository of disordered binding sites mediated interactions with ordered proteins" has recently been made available in Bioinformatics: https://doi.org/10.1093/bioinformatics/btx640. A smaller but not negligible portion of disordered proteins fold via interaction with one or more disordered protein molecules. During this joint folding process, there is no template to use- the two or more polypeptide chains have to fold jointly by themselves. Since few attempts have been reported in the literature on these kinds of complexes, I kindly call your attention that the first such database Ficho E et al. "MFIB: a repository of protein complexes with mutual folding induced by binding" recently became available in Bioinformatics: https://doi.org/10.1093/bioinformatics/btx486

Prof. Dr. Istvan Simon
Guest Editor

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Keywords

  • disordered protein
  • unstructured protein
  • coupled folding and binding
  • mutual folding
  • protein complex

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Published Papers (19 papers)

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12 pages, 951 KiB  
Article
Hydrodynamic Behavior of the Intrinsically Disordered Potyvirus Protein VPg, of the Translation Initiation Factor eIF4E and of their Binary Complex
by Jocelyne Walter, Amandine Barra, Bénédicte Doublet, Nicolas Céré, Justine Charon and Thierry Michon
Int. J. Mol. Sci. 2019, 20(7), 1794; https://doi.org/10.3390/ijms20071794 - 11 Apr 2019
Cited by 6 | Viewed by 3347
Abstract
Protein intrinsic disorder is involved in many biological processes and good experimental models are valuable to investigate its functions. The potyvirus genome-linked protein, VPg, displays many features of an intrinsically disordered protein. The virus cycle requires the formation of a complex between VPg [...] Read more.
Protein intrinsic disorder is involved in many biological processes and good experimental models are valuable to investigate its functions. The potyvirus genome-linked protein, VPg, displays many features of an intrinsically disordered protein. The virus cycle requires the formation of a complex between VPg and eIF4E, one of the host translation initiation factors. An in-depth characterization of the hydrodynamic properties of VPg, eIF4E, and of their binary complex VPg-eIF4E was carried out. Two complementary experimental approaches, size-exclusion chromatography and fluorescence anisotropy, which is more resolving and revealed especially suitable when protein concentration is the limiting factor, allowed to estimate monomers compaction upon complex formation. VPg possesses a high degree of hydration which is in agreement with its classification as a partially folded protein in between a molten and pre-molten globule. The natively disordered first 46 amino acids of eIF4E contribute to modulate the protein hydrodynamic properties. The addition of an N-ter His tag decreased the conformational entropy of this intrinsically disordered region. A comparative study between the two tagged and untagged proteins revealed the His tag contribution to proteins hydrodynamic behavior. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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18 pages, 9331 KiB  
Article
The Effect of FG-Nup Phosphorylation on NPC Selectivity: A One-Bead-Per-Amino-Acid Molecular Dynamics Study
by Ankur Mishra, Wouter Sipma, Liesbeth M. Veenhoff, Erik Van der Giessen and Patrick R. Onck
Int. J. Mol. Sci. 2019, 20(3), 596; https://doi.org/10.3390/ijms20030596 - 30 Jan 2019
Cited by 11 | Viewed by 7535
Abstract
Nuclear pore complexes (NPCs) are large protein complexes embedded in the nuclear envelope separating the cytoplasm from the nucleoplasm in eukaryotic cells. They function as selective gates for the transport of molecules in and out of the nucleus. The inner wall of the [...] Read more.
Nuclear pore complexes (NPCs) are large protein complexes embedded in the nuclear envelope separating the cytoplasm from the nucleoplasm in eukaryotic cells. They function as selective gates for the transport of molecules in and out of the nucleus. The inner wall of the NPC is coated with intrinsically disordered proteins rich in phenylalanine-glycine repeats (FG-repeats), which are responsible for the intriguing selectivity of NPCs. The phosphorylation state of the FG-Nups is controlled by kinases and phosphatases. In the current study, we extended our one-bead-per-amino-acid (1BPA) model for intrinsically disordered proteins to account for phosphorylation. With this, we performed molecular dynamics simulations to probe the effect of phosphorylation on the Stokes radius of isolated FG-Nups, and on the structure and transport properties of the NPC. Our results indicate that phosphorylation causes a reduced attraction between the residues, leading to an extension of the FG-Nups and the formation of a significantly less dense FG-network inside the NPC. Furthermore, our simulations show that upon phosphorylation, the transport rate of inert molecules increases, while that of nuclear transport receptors decreases, which can be rationalized in terms of modified hydrophobic, electrostatic, and steric interactions. Altogether, our models provide a molecular framework to explain how extensive phosphorylation of FG-Nups decreases the selectivity of the NPC. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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16 pages, 2223 KiB  
Article
The C Terminus of the Ribosomal-Associated Protein LrtA Is an Intrinsically Disordered Oligomer
by José L. Neira, A. Marcela Giudici, Felipe Hornos, Arantxa Arbe and Bruno Rizzuti
Int. J. Mol. Sci. 2018, 19(12), 3902; https://doi.org/10.3390/ijms19123902 - 05 Dec 2018
Cited by 2 | Viewed by 2543
Abstract
The 191-residue-long LrtA protein of Synechocystis sp. PCC 6803 is involved in post-stress survival and in stabilizing 70S ribosomal particles. It belongs to the hibernating promoting factor (HPF) family, intervening in protein synthesis. The protein consists of two domains: The N-terminal region (N-LrtA, [...] Read more.
The 191-residue-long LrtA protein of Synechocystis sp. PCC 6803 is involved in post-stress survival and in stabilizing 70S ribosomal particles. It belongs to the hibernating promoting factor (HPF) family, intervening in protein synthesis. The protein consists of two domains: The N-terminal region (N-LrtA, residues 1–101), which is common to all the members of the HPF, and seems to be well-folded; and the C-terminal region (C-LrtA, residues 102–191), which is hypothesized to be disordered. In this work, we studied the conformational preferences of isolated C-LrtA in solution. The protein was disordered, as shown by computational modelling, 1D-1H NMR, steady-state far-UV circular dichroism (CD) and chemical and thermal denaturations followed by fluorescence and far-UV CD. Moreover, at physiological conditions, as indicated by several biochemical and hydrodynamic techniques, isolated C-LrtA intervened in a self-association equilibrium, involving several oligomerization reactions. Thus, C-LrtA was an oligomeric disordered protein. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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9 pages, 1497 KiB  
Communication
Direct Single-Molecule Observation of Sequential DNA Bending Transitions by the Sox2 HMG Box
by Mahdi Muhammad Moosa, Phoebe S. Tsoi, Kyoung-Jae Choi, Allan Chris M. Ferreon and Josephine C. Ferreon
Int. J. Mol. Sci. 2018, 19(12), 3865; https://doi.org/10.3390/ijms19123865 - 04 Dec 2018
Cited by 7 | Viewed by 3300
Abstract
Sox2 is a pioneer transcription factor that initiates cell fate reprogramming through locus-specific differential regulation. Mechanistically, it was assumed that Sox2 achieves its regulatory diversity via heterodimerization with partner transcription factors. Here, utilizing single-molecule fluorescence spectroscopy, we show that Sox2 alone can modulate [...] Read more.
Sox2 is a pioneer transcription factor that initiates cell fate reprogramming through locus-specific differential regulation. Mechanistically, it was assumed that Sox2 achieves its regulatory diversity via heterodimerization with partner transcription factors. Here, utilizing single-molecule fluorescence spectroscopy, we show that Sox2 alone can modulate DNA structural landscape in a dosage-dependent manner. We propose that such stoichiometric tuning of regulatory DNAs is crucial to the diverse biological functions of Sox2, and represents a generic mechanism of conferring functional plasticity and multiplicity to transcription factors. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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12 pages, 2688 KiB  
Article
Both Intrinsically Disordered Regions and Structural Domains Evolve Rapidly in Immune-Related Mammalian Proteins
by Keiichi Homma, Hiroto Anbo, Tamotsu Noguchi and Satoshi Fukuchi
Int. J. Mol. Sci. 2018, 19(12), 3860; https://doi.org/10.3390/ijms19123860 - 04 Dec 2018
Cited by 4 | Viewed by 2648
Abstract
Eukaryotic proteins consist of structural domains (SDs) and intrinsically disordered regions (IDRs), i.e., regions that by themselves do not assume unique three-dimensional structures. IDRs are generally subject to less constraint and evolve more rapidly than SDs. Proteins with a lower number of protein-to-protein [...] Read more.
Eukaryotic proteins consist of structural domains (SDs) and intrinsically disordered regions (IDRs), i.e., regions that by themselves do not assume unique three-dimensional structures. IDRs are generally subject to less constraint and evolve more rapidly than SDs. Proteins with a lower number of protein-to-protein interactions (PPIs) are also less constrained and tend to evolve fast. Extracellular proteins of mammals, especially immune-related extracellular proteins, on average have relatively high evolution rates. This article aims to examine if a high evolution rate in IDRs or that in SDs accounts for the rapid evolution of extracellular proteins. To this end, we classified eukaryotic proteins based on their cellular localizations and analyzed them. Moreover, we divided proteins into SDs and IDRs and calculated the respective evolution rate. Fractional IDR content is positively correlated with evolution rate. For their fractional IDR content, immune-related extracellular proteins show an aberrantly high evolution rate. IDRs evolve more rapidly than SDs in most subcellular localizations. In extracellular proteins, however, the difference is diminished. For immune-related proteins in mammals in particular, the evolution rates in SDs come close to those in IDRs. Thus high evolution rates in both IDRs and SDs account for the rapid evolution of immune-related proteins. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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12 pages, 1353 KiB  
Article
The Melting Diagram of Protein Solutions and Its Thermodynamic Interpretation
by Kálmán Tompa, Mónika Bokor and Péter Tompa
Int. J. Mol. Sci. 2018, 19(11), 3571; https://doi.org/10.3390/ijms19113571 - 12 Nov 2018
Cited by 4 | Viewed by 2799
Abstract
Here we present a novel method for the characterization of the hydration of protein solutions based on measuring and evaluating two-component wide-line 1H NMR signals. We also provide a description of key elements of the procedure conceived for the thermodynamic interpretation of [...] Read more.
Here we present a novel method for the characterization of the hydration of protein solutions based on measuring and evaluating two-component wide-line 1H NMR signals. We also provide a description of key elements of the procedure conceived for the thermodynamic interpretation of such results. These interdependent experimental and theoretical treatments provide direct experimental insight into the potential energy surface of proteins. The utility of our approach is demonstrated through the examples of two proteins of distinct structural classes: the globular, structured ubiquitin; and the intrinsically disordered ERD10 (early response to dehydration 10). We provide a detailed analysis and interpretation of data recorded earlier by cooling and slowly warming the protein solutions through thermal equilibrium states. We introduce and use order parameters that can be thus derived to characterize the distribution of potential energy barriers inhibiting the movement of water molecules bound to the surface of the protein. Our results enable a quantitative description of the ratio of ordered and disordered parts of proteins, and of the energy relations of protein–water bonds in aqueous solutions of the proteins. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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14 pages, 1661 KiB  
Article
Disordered Regions of Mixed Lineage Leukemia 4 (MLL4) Protein Are Capable of RNA Binding
by Beáta Szabó, Nikoletta Murvai, Rawan Abukhairan, Éva Schád, József Kardos, Bálint Szeder, László Buday and Ágnes Tantos
Int. J. Mol. Sci. 2018, 19(11), 3478; https://doi.org/10.3390/ijms19113478 - 05 Nov 2018
Cited by 10 | Viewed by 3802
Abstract
Long non-coding RNAs (lncRNAs) are emerging as important regulators of cellular processes and are extensively involved in the development of different cancers; including leukemias. As one of the accepted methods of lncRNA function is affecting chromatin structure; lncRNA binding has been shown for [...] Read more.
Long non-coding RNAs (lncRNAs) are emerging as important regulators of cellular processes and are extensively involved in the development of different cancers; including leukemias. As one of the accepted methods of lncRNA function is affecting chromatin structure; lncRNA binding has been shown for different chromatin modifiers. Histone lysine methyltransferases (HKMTs) are also subject of lncRNA regulation as demonstrated for example in the case of Polycomb Repressive Complex 2 (PRC2). Mixed Lineage Leukemia (MLL) proteins that catalyze the methylation of H3K4 have been implicated in several different cancers; yet many details of their regulation and targeting remain elusive. In this work we explored the RNA binding capability of two; so far uncharacterized regions of MLL4; with the aim of shedding light to the existence of possible regulatory lncRNA interactions of the protein. We demonstrated that both regions; one that contains a predicted RNA binding sequence and one that does not; are capable of binding to different RNA constructs in vitro. To our knowledge, these findings are the first to indicate that an MLL protein itself is capable of lncRNA binding. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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12 pages, 2098 KiB  
Article
Physical Background of the Disordered Nature of “Mutual Synergetic Folding” Proteins
by Csaba Magyar, Anikó Mentes, Erzsébet Fichó, Miklós Cserző and István Simon
Int. J. Mol. Sci. 2018, 19(11), 3340; https://doi.org/10.3390/ijms19113340 - 26 Oct 2018
Cited by 6 | Viewed by 3042
Abstract
Intrinsically disordered proteins (IDPs) lack a well-defined 3D structure. Their disordered nature enables them to interact with several other proteins and to fulfil their vital biological roles, in most cases after coupled folding and binding. In this paper, we analyze IDPs involved in [...] Read more.
Intrinsically disordered proteins (IDPs) lack a well-defined 3D structure. Their disordered nature enables them to interact with several other proteins and to fulfil their vital biological roles, in most cases after coupled folding and binding. In this paper, we analyze IDPs involved in a new mechanism, mutual synergistic folding (MSF). These proteins define a new subset of IDPs. Recently we collected information on these complexes and created the Mutual Folding Induced by Binding (MFIB) database. These protein complexes exhibit considerable structural variation, and almost half of them are homodimers, but there is a significant amount of heterodimers and various kinds of oligomers. In order to understand the basic background of the disordered character of the monomers found in MSF complexes, the simplest part of the MFIB database, the homodimers are analyzed here. We conclude that MFIB homodimeric proteins have a larger solvent-accessible main-chain surface area on the contact surface of the subunits, when compared to globular homodimeric proteins. The main driving force of the dimerization is the mutual shielding of the water-accessible backbones and the formation of extra intermolecular interactions. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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16 pages, 1634 KiB  
Article
Co-Evolution of Intrinsically Disordered Proteins with Folded Partners Witnessed by Evolutionary Couplings
by Rita Pancsa, Fruzsina Zsolyomi and Peter Tompa
Int. J. Mol. Sci. 2018, 19(11), 3315; https://doi.org/10.3390/ijms19113315 - 25 Oct 2018
Cited by 19 | Viewed by 5098
Abstract
Although improved strategies for the detection and analysis of evolutionary couplings (ECs) between protein residues already enable the prediction of protein structures and interactions, they are mostly restricted to conserved and well-folded proteins. Whereas intrinsically disordered proteins (IDPs) are central to cellular interaction [...] Read more.
Although improved strategies for the detection and analysis of evolutionary couplings (ECs) between protein residues already enable the prediction of protein structures and interactions, they are mostly restricted to conserved and well-folded proteins. Whereas intrinsically disordered proteins (IDPs) are central to cellular interaction networks, due to the lack of strict structural constraints, they undergo faster evolutionary changes than folded domains. This makes the reliable identification and alignment of IDP homologs difficult, which led to IDPs being omitted in most large-scale residue co-variation analyses. By preforming a dedicated analysis of phylogenetically widespread bacterial IDP–partner interactions, here we demonstrate that partner binding imposes constraints on IDP sequences that manifest in detectable interprotein ECs. These ECs were not detected for interactions mediated by short motifs, rather for those with larger IDP–partner interfaces. Most identified coupled residue pairs reside close (<10 Å) to each other on the interface, with a third of them forming multiple direct atomic contacts. EC-carrying interfaces of IDPs are enriched in negatively charged residues, and the EC residues of both IDPs and partners preferentially reside in helices. Our analysis brings hope that IDP–partner interactions difficult to study could soon be successfully dissected through residue co-variation analysis. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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13 pages, 1992 KiB  
Article
A Protein Intrinsic Disorder Approach for Characterising Differentially Expressed Genes in Transcriptome Data: Analysis of Cell-Adhesion Regulated Gene Expression in Lymphoma Cells
by Gustav Arvidsson and Anthony P. H. Wright
Int. J. Mol. Sci. 2018, 19(10), 3101; https://doi.org/10.3390/ijms19103101 - 10 Oct 2018
Cited by 3 | Viewed by 2676
Abstract
Conformational protein properties are coupled to protein functionality and could provide a useful parameter for functional annotation of differentially expressed genes in transcriptome studies. The aim was to determine whether predicted intrinsic protein disorder was differentially associated with proteins encoded by genes that [...] Read more.
Conformational protein properties are coupled to protein functionality and could provide a useful parameter for functional annotation of differentially expressed genes in transcriptome studies. The aim was to determine whether predicted intrinsic protein disorder was differentially associated with proteins encoded by genes that are differentially regulated in lymphoma cells upon interaction with stromal cells, an interaction that occurs in microenvironments, such as lymph nodes that are protective for lymphoma cells during chemotherapy. Intrinsic disorder protein properties were extracted from the Database of Disordered Protein Prediction (D2P2), which contains data from nine intrinsic disorder predictors. Proteins encoded by differentially regulated cell-adhesion regulated genes were enriched in intrinsically disordered regions (IDRs) compared to other genes both with regard to IDR number and length. The enrichment was further ascribed to down-regulated genes. Consistently, a higher proportion of proteins encoded by down-regulated genes contained at least one IDR or were completely disordered. We conclude that down-regulated genes in stromal cell-adherent lymphoma cells encode proteins that are characterized by elevated levels of intrinsically disordered conformation, indicating the importance of down-regulating functional mechanisms associated with intrinsically disordered proteins in these cells. Further, the approach provides a generally applicable and complementary alternative to classification of differentially regulated genes using gene ontology or pathway enrichment analysis. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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14 pages, 2674 KiB  
Article
Decision-Tree Based Meta-Strategy Improved Accuracy of Disorder Prediction and Identified Novel Disordered Residues Inside Binding Motifs
by Bi Zhao and Bin Xue
Int. J. Mol. Sci. 2018, 19(10), 3052; https://doi.org/10.3390/ijms19103052 - 07 Oct 2018
Cited by 12 | Viewed by 2585
Abstract
Using computational techniques to identify intrinsically disordered residues is practical and effective in biological studies. Therefore, designing novel high-accuracy strategies is always preferable when existing strategies have a lot of room for improvement. Among many possibilities, a meta-strategy that integrates the results of [...] Read more.
Using computational techniques to identify intrinsically disordered residues is practical and effective in biological studies. Therefore, designing novel high-accuracy strategies is always preferable when existing strategies have a lot of room for improvement. Among many possibilities, a meta-strategy that integrates the results of multiple individual predictors has been broadly used to improve the overall performance of predictors. Nonetheless, a simple and direct integration of individual predictors may not effectively improve the performance. In this project, dual-threshold two-step significance voting and neural networks were used to integrate the predictive results of four individual predictors, including: DisEMBL, IUPred, VSL2, and ESpritz. The new meta-strategy has improved the prediction performance of intrinsically disordered residues significantly, compared to all four individual predictors and another four recently-designed predictors. The improvement was validated using five-fold cross-validation and in independent test datasets. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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15 pages, 1883 KiB  
Article
Arabidopsis Heat Stress-Induced Proteins Are Enriched in Electrostatically Charged Amino Acids and Intrinsically Disordered Regions
by David Alvarez-Ponce, Mario X. Ruiz-González, Francisco Vera-Sirera, Felix Feyertag, Miguel A. Perez-Amador and Mario A. Fares
Int. J. Mol. Sci. 2018, 19(8), 2276; https://doi.org/10.3390/ijms19082276 - 03 Aug 2018
Cited by 9 | Viewed by 3856
Abstract
Comparison of the proteins of thermophilic, mesophilic, and psychrophilic prokaryotes has revealed several features characteristic to proteins adapted to high temperatures, which increase their thermostability. These characteristics include a profusion of disulfide bonds, salt bridges, hydrogen bonds, and hydrophobic interactions, and a depletion [...] Read more.
Comparison of the proteins of thermophilic, mesophilic, and psychrophilic prokaryotes has revealed several features characteristic to proteins adapted to high temperatures, which increase their thermostability. These characteristics include a profusion of disulfide bonds, salt bridges, hydrogen bonds, and hydrophobic interactions, and a depletion in intrinsically disordered regions. It is unclear, however, whether such differences can also be observed in eukaryotic proteins or when comparing proteins that are adapted to temperatures that are more subtly different. When an organism is exposed to high temperatures, a subset of its proteins is overexpressed (heat-induced proteins), whereas others are either repressed (heat-repressed proteins) or remain unaffected. Here, we determine the expression levels of all genes in the eukaryotic model system Arabidopsis thaliana at 22 and 37 °C, and compare both the amino acid compositions and levels of intrinsic disorder of heat-induced and heat-repressed proteins. We show that, compared to heat-repressed proteins, heat-induced proteins are enriched in electrostatically charged amino acids and depleted in polar amino acids, mirroring thermophile proteins. However, in contrast with thermophile proteins, heat-induced proteins are enriched in intrinsically disordered regions, and depleted in hydrophobic amino acids. Our results indicate that temperature adaptation at the level of amino acid composition and intrinsic disorder can be observed not only in proteins of thermophilic organisms, but also in eukaryotic heat-induced proteins; the underlying adaptation pathways, however, are similar but not the same. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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21 pages, 2942 KiB  
Article
The Cyanobacterial Ribosomal-Associated Protein LrtA from Synechocystis sp. PCC 6803 Is an Oligomeric Protein in Solution with Chameleonic Sequence Properties
by Lellys M. Contreras, Paz Sevilla, Ana Cámara-Artigas, José G. Hernández-Cifre, Bruno Rizzuti, Francisco J. Florencio, María Isabel Muro-Pastor, José García de la Torre and José L. Neira
Int. J. Mol. Sci. 2018, 19(7), 1857; https://doi.org/10.3390/ijms19071857 - 24 Jun 2018
Cited by 5 | Viewed by 3365
Abstract
The LrtA protein of Synechocystis sp. PCC 6803 intervenes in cyanobacterial post-stress survival and in stabilizing 70S ribosomal particles. It belongs to the hibernating promoting factor (HPF) family of proteins, involved in protein synthesis. In this work, we studied the conformational preferences and [...] Read more.
The LrtA protein of Synechocystis sp. PCC 6803 intervenes in cyanobacterial post-stress survival and in stabilizing 70S ribosomal particles. It belongs to the hibernating promoting factor (HPF) family of proteins, involved in protein synthesis. In this work, we studied the conformational preferences and stability of isolated LrtA in solution. At physiological conditions, as shown by hydrodynamic techniques, LrtA was involved in a self-association equilibrium. As indicated by Nuclear Magnetic Resonance (NMR), circular dichroism (CD) and fluorescence, the protein acquired a folded, native-like conformation between pH 6.0 and 9.0. However, that conformation was not very stable, as suggested by thermal and chemical denaturations followed by CD and fluorescence. Theoretical studies of its highly-charged sequence suggest that LrtA had a Janus sequence, with a context-dependent fold. Our modelling and molecular dynamics (MD) simulations indicate that the protein adopted the same fold observed in other members of the HPF family (β-α-β-β-β-α) at its N-terminal region (residues 1–100), whereas the C terminus (residues 100–197) appeared disordered and collapsed, supporting the overall percentage of overall secondary structure obtained by CD deconvolution. Then, LrtA has a chameleonic sequence and it is the first member of the HPF family involved in a self-association equilibrium, when isolated in solution. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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16 pages, 3012 KiB  
Article
Deciphering RNA-Recognition Patterns of Intrinsically Disordered Proteins
by Ambuj Srivastava, Shandar Ahmad and M. Michael Gromiha
Int. J. Mol. Sci. 2018, 19(6), 1595; https://doi.org/10.3390/ijms19061595 - 29 May 2018
Cited by 16 | Viewed by 4120
Abstract
Intrinsically disordered regions (IDRs) and protein (IDPs) are highly flexible owing to their lack of well-defined structures. A subset of such proteins interacts with various substrates; including RNA; frequently adopting regular structures in the final complex. In this work; we have analysed a [...] Read more.
Intrinsically disordered regions (IDRs) and protein (IDPs) are highly flexible owing to their lack of well-defined structures. A subset of such proteins interacts with various substrates; including RNA; frequently adopting regular structures in the final complex. In this work; we have analysed a dataset of protein–RNA complexes undergoing disorder-to-order transition (DOT) upon binding. We found that DOT regions are generally small in size (less than 3 residues) for RNA binding proteins. Like structured proteins; positively charged residues are found to interact with RNA molecules; indicating the dominance of electrostatic and cation-π interactions. However, a comparison of binding frequency shows that interface hydrophobic and aromatic residues have more interactions in only DOT regions than in a protein. Further; DOT regions have significantly higher exposure to water than their structured counterparts. Interactions of DOT regions with RNA increase the sheet formation with minor changes in helix forming residues. We have computed the interaction energy for amino acids–nucleotide pairs; which showed the preference of His–G; Asn–U and Ser–U at for the interface of DOT regions. This study provides insights to understand protein–RNA interactions and the results could also be used for developing a tool for identifying DOT regions in RNA binding proteins. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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12 pages, 2051 KiB  
Article
Acetylation Disfavors Tau Phase Separation
by Josephine C. Ferreon, Antrix Jain, Kyoung-Jae Choi, Phoebe S. Tsoi, Kevin R. MacKenzie, Sung Yun Jung and Allan Chris Ferreon
Int. J. Mol. Sci. 2018, 19(5), 1360; https://doi.org/10.3390/ijms19051360 - 04 May 2018
Cited by 122 | Viewed by 9375
Abstract
Neuropathological aggregates of the intrinsically disordered microtubule-associated protein Tau are hallmarks of Alzheimer’s disease, with decades of research devoted to studying the protein’s aggregation properties both in vitro and in vivo. Recent demonstrations that Tau is capable of undergoing liquid-liquid phase separation (LLPS) [...] Read more.
Neuropathological aggregates of the intrinsically disordered microtubule-associated protein Tau are hallmarks of Alzheimer’s disease, with decades of research devoted to studying the protein’s aggregation properties both in vitro and in vivo. Recent demonstrations that Tau is capable of undergoing liquid-liquid phase separation (LLPS) reveal the possibility that protein-enriched phase separated compartments could serve as initiation sites for Tau aggregation, as shown for other amyloidogenic proteins, such as the Fused in Sarcoma protein (FUS) and TAR DNA-binding protein-43 (TDP-43). Although truncation, mutation, and hyperphosphorylation have been shown to enhance Tau LLPS and aggregation, the effect of hyperacetylation on Tau aggregation remains unclear. Here, we investigate how the acetylation of Tau affects its potential to undergo phase separation and aggregation. Our data show that the hyperacetylation of Tau by p300 histone acetyltransferase (HAT) disfavors LLPS, inhibits heparin-induced aggregation, and impedes access to LLPS-initiated microtubule assembly. We propose that Tau acetylation prevents the toxic effects of LLPS-dependent aggregation but, nevertheless, contributes to Tau loss-of-function pathology by inhibiting Tau LLPS-mediated microtubule assembly. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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Review

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34 pages, 3107 KiB  
Review
Modulation of Disordered Proteins with a Focus on Neurodegenerative Diseases and Other Pathologies
by Anne H. S. Martinelli, Fernanda C. Lopes, Elisa B. O. John, Célia R. Carlini and Rodrigo Ligabue-Braun
Int. J. Mol. Sci. 2019, 20(6), 1322; https://doi.org/10.3390/ijms20061322 - 15 Mar 2019
Cited by 40 | Viewed by 6826
Abstract
Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when [...] Read more.
Intrinsically disordered proteins (IDPs) do not have rigid 3D structures, showing changes in their folding depending on the environment or ligands. Intrinsically disordered proteins are widely spread in eukaryotic genomes, and these proteins participate in many cell regulatory metabolism processes. Some IDPs, when aberrantly folded, can be the cause of some diseases such as Alzheimer′s, Parkinson′s, and prionic, among others. In these diseases, there are modifications in parts of the protein or in its entirety. A common conformational variation of these IDPs is misfolding and aggregation, forming, for instance, neurotoxic amyloid plaques. In this review, we discuss some IDPs that are involved in neurodegenerative diseases (such as beta amyloid, alpha synuclein, tau, and the “IDP-like” PrP), cancer (p53, c-Myc), and diabetes (amylin), focusing on the structural changes of these IDPs that are linked to such pathologies. We also present the IDP modulation mechanisms that can be explored in new strategies for drug design. Lastly, we show some candidate drugs that can be used in the future for the treatment of diseases caused by misfolded IDPs, considering that cancer therapy has more advanced research in comparison to other diseases, while also discussing recent and future developments in this area of research. Therefore, we aim to provide support to the study of IDPs and their modulation mechanisms as promising approaches to combat such severe diseases. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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15 pages, 2912 KiB  
Review
Modeling of Disordered Protein Structures Using Monte Carlo Simulations and Knowledge-Based Statistical Force Fields
by Maciej Pawel Ciemny, Aleksandra Elzbieta Badaczewska-Dawid, Monika Pikuzinska, Andrzej Kolinski and Sebastian Kmiecik
Int. J. Mol. Sci. 2019, 20(3), 606; https://doi.org/10.3390/ijms20030606 - 31 Jan 2019
Cited by 35 | Viewed by 5671
Abstract
The description of protein disordered states is important for understanding protein folding mechanisms and their functions. In this short review, we briefly describe a simulation approach to modeling protein interactions, which involve disordered peptide partners or intrinsically disordered protein regions, and unfolded states [...] Read more.
The description of protein disordered states is important for understanding protein folding mechanisms and their functions. In this short review, we briefly describe a simulation approach to modeling protein interactions, which involve disordered peptide partners or intrinsically disordered protein regions, and unfolded states of globular proteins. It is based on the CABS coarse-grained protein model that uses a Monte Carlo (MC) sampling scheme and a knowledge-based statistical force field. We review several case studies showing that description of protein disordered states resulting from CABS simulations is consistent with experimental data. The case studies comprise investigations of protein–peptide binding and protein folding processes. The CABS model has been recently made available as the simulation engine of multiscale modeling tools enabling studies of protein–peptide docking and protein flexibility. Those tools offer customization of the modeling process, driving the conformational search using distance restraints, reconstruction of selected models to all-atom resolution, and simulation of large protein systems in a reasonable computational time. Therefore, CABS can be combined in integrative modeling pipelines incorporating experimental data and other modeling tools of various resolution. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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15 pages, 2106 KiB  
Review
Structural Determinants of the Prion Protein N-Terminus and Its Adducts with Copper Ions
by Carolina Sánchez-López, Giulia Rossetti, Liliana Quintanar and Paolo Carloni
Int. J. Mol. Sci. 2019, 20(1), 18; https://doi.org/10.3390/ijms20010018 - 20 Dec 2018
Cited by 16 | Viewed by 7345
Abstract
The N-terminus of the prion protein is a large intrinsically disordered region encompassing approximately 125 amino acids. In this paper, we review its structural and functional properties, with a particular emphasis on its binding to copper ions. The latter is exploited by the [...] Read more.
The N-terminus of the prion protein is a large intrinsically disordered region encompassing approximately 125 amino acids. In this paper, we review its structural and functional properties, with a particular emphasis on its binding to copper ions. The latter is exploited by the region’s conformational flexibility to yield a variety of biological functions. Disease-linked mutations and proteolytic processing of the protein can impact its copper-binding properties, with important structural and functional implications, both in health and disease progression. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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Other

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9 pages, 684 KiB  
Concept Paper
Pathogens and Disease Play Havoc on the Host Epiproteome—The “First Line of Response” Role for Proteomic Changes Influenced by Disorder
by Erik H. A. Rikkerink
Int. J. Mol. Sci. 2018, 19(3), 772; https://doi.org/10.3390/ijms19030772 - 08 Mar 2018
Cited by 8 | Viewed by 3297
Abstract
Organisms face stress from multiple sources simultaneously and require mechanisms to respond to these scenarios if they are to survive in the long term. This overview focuses on a series of key points that illustrate how disorder and post-translational changes can combine to [...] Read more.
Organisms face stress from multiple sources simultaneously and require mechanisms to respond to these scenarios if they are to survive in the long term. This overview focuses on a series of key points that illustrate how disorder and post-translational changes can combine to play a critical role in orchestrating the response of organisms to the stress of a changing environment. Increasingly, protein complexes are thought of as dynamic multi-component molecular machines able to adapt through compositional, conformational and/or post-translational modifications to control their largely metabolic outputs. These metabolites then feed into cellular physiological homeostasis or the production of secondary metabolites with novel anti-microbial properties. The control of adaptations to stress operates at multiple levels including the proteome and the dynamic nature of proteomic changes suggests a parallel with the equally dynamic epigenetic changes at the level of nucleic acids. Given their properties, I propose that some disordered protein platforms specifically enable organisms to sense and react rapidly as the first line of response to change. Using examples from the highly dynamic host-pathogen and host-stress response, I illustrate by example how disordered proteins are key to fulfilling the need for multiple levels of integration of response at different time scales to create robust control points. Full article
(This article belongs to the Special Issue Functionally Relevant Macromolecular Interactions of Disordered Proteins)
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