Special Issue "The Amazing World of IDPs in Human Diseases"

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (15 October 2020).

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A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Simona Maria Monti
E-Mail Website
Guest Editor
Biostructures and Bioimaging Institute-CNR, Via Mezzocannone 16, 80134 Naples, Italy
Interests: chemical biology; structural and functional characterization of proteins and bioactive peptides; intrinsically disordered proteins; carbonic anhydrases; protein biophysics; cancer biology; protein-protein, protein-DNA interaction studies; cancer-related proteins; non enzymatic glycation and AGEs; oxidative stress
Special Issues and Collections in MDPI journals
Dr. Giuseppina De Simone
E-Mail Website
Guest Editor
Biostructures 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
Special Issues and Collections in MDPI journals
Dr. Emma Langella
E-Mail Website
Guest Editor
Biostructures 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 and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

It is now clearly established that some proteins or protein regions are devoid of any stable secondary and/or tertiary structure under physiological conditions, but still possess fundamental biological functions. These intrinsically disordered proteins (IDPs) or regions (IDRs) have peculiar features due to their plasticity as the capacity of binding their biological targets with high specificity and low affinity, and the possibility of interaction with numerous partners. IDPs and IDRs are especially prevalent in eukaryotes suggesting the necessity of disorder, associated signaling and regulation in nucleated cells where they are involved in many key functions. However, also a correlation between intrinsic disorder and various human diseases such as cancer, diabetes, amyloidoses and neurodegenerative diseases is now evident, highlighting the great importance of the topic.

In this Special Issue, we invite researchers to contribute with original research articles as well as reviews, on the amazing world of the IDPs or IDRs involved with human diseases. In particular, contributions focusing on the prediction, identification and characterization of these, with emphasis to their role in cell-signaling and regulation will be welcomed.

Dr. Simona Maria Monti
Dr. Giuseppina De Simone
Dr. Emma Langella
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2000 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.

Keywords

  • intrinsically disordered proteins
  • intrinsically disordered regions
  • protein misfolding
  • functions of intrinsic disorder
  • molecular recognition features
  • protein-protein interactions
  • protein-nucleic acids interactions
  • protein disorder and pathology

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Published Papers (10 papers)

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Editorial

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Editorial
The Amazing World of IDPs in Human Diseases
Biomolecules 2021, 11(2), 333; https://doi.org/10.3390/biom11020333 - 23 Feb 2021
Viewed by 472
Abstract
It has been clearly established that some proteins or protein regions are devoid of any stable secondary and/or tertiary structure under physiological conditions, but still possess fundamental biological functions [...] Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)

Research

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Article
Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome
Biomolecules 2020, 10(12), 1642; https://doi.org/10.3390/biom10121642 - 07 Dec 2020
Cited by 1 | Viewed by 773
Abstract
The 26S proteasome is the endpoint of the ubiquitin- and ATP-dependent degradation pathway. Over the years, ATP was regarded as completely essential for 26S proteasome function due to its role in ubiquitin-signaling, substrate unfolding and ensuring its structural integrity. We have previously reported [...] Read more.
The 26S proteasome is the endpoint of the ubiquitin- and ATP-dependent degradation pathway. Over the years, ATP was regarded as completely essential for 26S proteasome function due to its role in ubiquitin-signaling, substrate unfolding and ensuring its structural integrity. We have previously reported that physiological concentrations of NADH are efficient in replacing ATP to maintain the integrity of an enzymatically functional 26S PC. However, the substrate specificity of the NADH-stabilized 26S proteasome complex (26S PC) was never assessed. Here, we show that the binding of NADH to the 26S PC inhibits the ATP-dependent and ubiquitin-independent degradation of the structured ODC enzyme. Moreover, the NADH-stabilized 26S PC is efficient in degrading intrinsically disordered protein (IDP) substrates that might not require ATP-dependent unfolding, such as p27, Tau, c-Fos and more. In some cases, NADH-26S proteasomes were more efficient in processing IDPs than the ATP-26S PC. These results indicate that in vitro, physiological concentrations of NADH can alter the processivity of ATP-dependent 26S PC substrates such as ODC and, more importantly, the NADH-stabilized 26S PCs promote the efficient degradation of many IDPs. Thus, ATP-independent, NADH-dependent 26S proteasome activity exemplifies a new principle of how mitochondria might directly regulate 26S proteasome substrate specificity. Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)
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Article
Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2
Biomolecules 2020, 10(11), 1533; https://doi.org/10.3390/biom10111533 - 10 Nov 2020
Cited by 2 | Viewed by 709
Abstract
Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-binding protein involved in neuronal development and maturation. Loss-of-function mutations in MeCP2 result in Rett syndrome (RTT), a neurodevelopmental disorder that is the main cause of mental retardation in females. MeCP2 is [...] Read more.
Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-binding protein involved in neuronal development and maturation. Loss-of-function mutations in MeCP2 result in Rett syndrome (RTT), a neurodevelopmental disorder that is the main cause of mental retardation in females. MeCP2 is an intrinsically disordered protein (IDP) constituted by six domains. Two domains are the main responsible elements for DNA binding (methyl-CpG binding domain, MBD) and recruitment of gene transcription/silencing machinery (transcription repressor domain, TRD). These two domains concentrate most of the RTT-associated mutations. R106W and R133C are associated with severe and mild RTT phenotype, respectively. We have performed a comprehensive characterization of the structural and functional impact of these substitutions at molecular level. Because we have previously shown that the MBD-flanking disordered domains (N-terminal domain, NTD, and intervening domain, ID) exert a considerable influence on the structural and functional features of the MBD (Claveria-Gimeno, R. et al. Sci Rep. 2017, 7, 41635), here we report the biophysical study of the influence of the protein scaffold on the structural and functional effect induced by these two RTT-associated mutations. These results represent an example of how a given mutation may show different effects (sometimes opposing effects) depending on the molecular context. Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)
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Article
A Phosphorylation-Induced Switch in the Nuclear Localization Sequence of the Intrinsically Disordered NUPR1 Hampers Binding to Importin
Biomolecules 2020, 10(9), 1313; https://doi.org/10.3390/biom10091313 - 11 Sep 2020
Cited by 4 | Viewed by 823
Abstract
Several carrier proteins are involved in protein transport from the cytoplasm to the nucleus in eukaryotic cells. One of those is importin α, of which there are several human isoforms; among them, importin α3 (Impα3) has a high flexibility. The protein NUPR1, a [...] Read more.
Several carrier proteins are involved in protein transport from the cytoplasm to the nucleus in eukaryotic cells. One of those is importin α, of which there are several human isoforms; among them, importin α3 (Impα3) has a high flexibility. The protein NUPR1, a nuclear protein involved in the cell-stress response and cell cycle regulation, is an intrinsically disordered protein (IDP) that has a nuclear localization sequence (NLS) to allow for nuclear translocation. NUPR1 does localize through the whole cell. In this work, we studied the affinity of the isolated wild-type NLS region (residues 54–74) of NUPR1 towards Impα3 and several mutants of the NLS region by using several biophysical techniques and molecular docking approaches. The NLS region of NUPR1 interacted with Impα3, opening the way to model the nuclear translocation of disordered proteins. All the isolated NLS peptides were disordered. They bound to Impα3 with low micromolar affinity (1.7–27 μM). Binding was hampered by removal of either Lys65 or Lys69 residues, indicating that positive charges were important; furthermore, binding decreased when Thr68 was phosphorylated. The peptide phosphorylated at Thr68, as well as four phospho-mimetic peptides (all containing the Thr68Glu mutation), showed the presence of a sequential NN(i,i + 1) nuclear Overhauser effect (NOE) in the 2D-1H-NMR (two-dimensional–proton NMR) spectra, indicating the presence of turn-like conformations. Thus, the phosphorylation of Thr68 modulates the binding of NUPR1 to Impα3 by a conformational, entropy-driven switch from a random-coil conformation to a turn-like structure. Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)
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Article
Ancient Evolutionary Origin of Intrinsically Disordered Cancer Risk Regions
Biomolecules 2020, 10(8), 1115; https://doi.org/10.3390/biom10081115 - 28 Jul 2020
Cited by 4 | Viewed by 536
Abstract
Cancer is a heterogeneous genetic disease that alters the proper functioning of proteins involved in key regulatory processes such as cell cycle, DNA repair, survival, or apoptosis. Mutations often accumulate in hot-spots regions, highlighting critical functional modules within these proteins that need to [...] Read more.
Cancer is a heterogeneous genetic disease that alters the proper functioning of proteins involved in key regulatory processes such as cell cycle, DNA repair, survival, or apoptosis. Mutations often accumulate in hot-spots regions, highlighting critical functional modules within these proteins that need to be altered, amplified, or abolished for tumor formation. Recent evidence suggests that these mutational hotspots can correspond not only to globular domains, but also to intrinsically disordered regions (IDRs), which play a significant role in a subset of cancer types. IDRs have distinct functional properties that originate from their inherent flexibility. Generally, they correspond to more recent evolutionary inventions and show larger sequence variations across species. In this work, we analyzed the evolutionary origin of disordered regions that are specifically targeted in cancer. Surprisingly, the majority of these disordered cancer risk regions showed remarkable conservation with ancient evolutionary origin, stemming from the earliest multicellular animals or even beyond. Nevertheless, we encountered several examples where the mutated region emerged at a later stage compared with the origin of the gene family. We also showed the cancer risk regions become quickly fixated after their emergence, but evolution continues to tinker with their genes with novel regulatory elements introduced even at the level of humans. Our concise analysis provides a much clearer picture of the emergence of key regulatory elements in proteins and highlights the importance of taking into account the modular organisation of proteins for the analyses of evolutionary origin. Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)
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Article
Protein–Protein Interactions Mediated by Intrinsically Disordered Protein Regions Are Enriched in Missense Mutations
Biomolecules 2020, 10(8), 1097; https://doi.org/10.3390/biom10081097 - 24 Jul 2020
Cited by 3 | Viewed by 1250
Abstract
Because proteins are fundamental to most biological processes, many genetic diseases can be traced back to single nucleotide variants (SNVs) that cause changes in protein sequences. However, not all SNVs that result in amino acid substitutions cause disease as each residue is under [...] Read more.
Because proteins are fundamental to most biological processes, many genetic diseases can be traced back to single nucleotide variants (SNVs) that cause changes in protein sequences. However, not all SNVs that result in amino acid substitutions cause disease as each residue is under different structural and functional constraints. Influential studies have shown that protein–protein interaction interfaces are enriched in disease-associated SNVs and depleted in SNVs that are common in the general population. These studies focus primarily on folded (globular) protein domains and overlook the prevalent class of protein interactions mediated by intrinsically disordered regions (IDRs). Therefore, we investigated the enrichment patterns of missense mutation-causing SNVs that are associated with disease and cancer, as well as those present in the healthy population, in structures of IDR-mediated interactions with comparisons to classical globular interactions. When comparing the different categories of interaction interfaces, division of the interface regions into solvent-exposed rim residues and buried core residues reveal distinctive enrichment patterns for the various types of missense mutations. Most notably, we demonstrate a strong enrichment at the interface core of interacting IDRs in disease mutations and its depletion in neutral ones, which supports the view that the disruption of IDR interactions is a mechanism underlying many diseases. Intriguingly, we also found an asymmetry across the IDR interaction interface in the enrichment of certain missense mutation types, which may hint at an increased variant tolerance and urges further investigations of IDR interactions. Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)
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Article
Nickel and GTP Modulate Helicobacter pylori UreG Structural Flexibility
Biomolecules 2020, 10(7), 1062; https://doi.org/10.3390/biom10071062 - 16 Jul 2020
Cited by 3 | Viewed by 853
Abstract
UreG is a P-loop GTP hydrolase involved in the maturation of nickel-containing urease, an essential enzyme found in plants, fungi, bacteria, and archaea. This protein couples the hydrolysis of GTP to the delivery of Ni(II) into the active site of apo-urease, interacting with [...] Read more.
UreG is a P-loop GTP hydrolase involved in the maturation of nickel-containing urease, an essential enzyme found in plants, fungi, bacteria, and archaea. This protein couples the hydrolysis of GTP to the delivery of Ni(II) into the active site of apo-urease, interacting with other urease chaperones in a multi-protein complex necessary for enzyme activation. Whereas the conformation of Helicobacter pylori (Hp) UreG was solved by crystallography when it is in complex with two other chaperones, in solution the protein was found in a disordered and flexible form, defining it as an intrinsically disordered enzyme and indicating that the well-folded structure found in the crystal state does not fully reflect the behavior of the protein in solution. Here, isothermal titration calorimetry and site-directed spin labeling coupled to electron paramagnetic spectroscopy were successfully combined to investigate HpUreG structural dynamics in solution and the effect of Ni(II) and GTP on protein mobility. The results demonstrate that, although the protein maintains a flexible behavior in the metal and nucleotide bound forms, concomitant addition of Ni(II) and GTP exerts a structural change through the crosstalk of different protein regions. Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)
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Article
Unstructured Biology of Proteins from Ubiquitin-Proteasome System: Roles in Cancer and Neurodegenerative Diseases
Biomolecules 2020, 10(5), 796; https://doi.org/10.3390/biom10050796 - 21 May 2020
Cited by 3 | Viewed by 1718
Abstract
The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of [...] Read more.
The 26S proteasome is a large (~2.5 MDa) protein complex consisting of at least 33 different subunits and many other components, which form the ubiquitin proteasomal system (UPS), an ATP-dependent protein degradation system in the cell. UPS serves as an essential component of the cellular protein surveillance machinery, and its dysfunction leads to cancer, neurodegenerative and immunological disorders. Importantly, the functions and regulations of proteins are governed by the combination of ordered regions, intrinsically disordered protein regions (IDPRs) and molecular recognition features (MoRFs). The structure–function relationships of UPS components have not been identified completely; therefore, in this study, we have carried out the functional intrinsic disorder and MoRF analysis for potential neurodegenerative disease and anti-cancer targets of this pathway. Our report represents the presence of significant intrinsic disorder and disorder-based binding regions in several UPS proteins, such as extraproteasomal polyubiquitin receptors (UBQLN1 and UBQLN2), proteasome-associated polyubiquitin receptors (ADRM1 and PSMD4), deubiquitinating enzymes (DUBs) (ATXN3 and USP14), and ubiquitinating enzymes (E2 (UBE2R2) and E3 (STUB1) enzyme). We believe this study will have implications for the conformation-specific roles of different regions of these proteins. This will lead to a better understanding of the molecular basis of UPS-associated diseases. Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)
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Review

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Review
The Disordered Cellular Multi-Tasker WIP and Its Protein–Protein Interactions: A Structural View
Biomolecules 2020, 10(7), 1084; https://doi.org/10.3390/biom10071084 - 21 Jul 2020
Cited by 3 | Viewed by 800
Abstract
WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein–protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function [...] Read more.
WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein–protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function from cell biology studies, summarized in several reviews, with a structural description of WIP interactions, highlighting works that present a molecular view of WIP’s protein–protein interactions. This provides a deeper understanding of the mechanisms by which WIP mediates its biological functions. The fully disordered WIP also serves as an intriguing example of how intrinsically disordered proteins (IDPs) exert their function. WIP consists of consecutive small functional domains and motifs that interact with a host of cellular partners, with a striking preponderance of proline-rich motif capable of interactions with several well-recognized binding partners; indeed, over 30% of the WIP primary structure are proline residues. We focus on the binding motifs and binding interfaces of three important WIP segments, the actin-binding N-terminal domain, the central domain that binds SH3 domains of various interaction partners, and the WASp-binding C-terminal domain. Beyond the obvious importance of a more fundamental understanding of the biology of this central cellular player, this approach carries an immediate and highly beneficial effect on drug-design efforts targeting WIP and its binding partners. These factors make the value of such structural studies, challenging as they are, readily apparent. Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)
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Review
Salient Features of Monomeric Alpha-Synuclein Revealed by NMR Spectroscopy
Biomolecules 2020, 10(3), 428; https://doi.org/10.3390/biom10030428 - 10 Mar 2020
Cited by 3 | Viewed by 1344
Abstract
Elucidating the structural details of proteins is highly valuable and important for the proper understanding of protein function. In the case of intrinsically disordered proteins (IDPs), however, obtaining the structural details is quite challenging, as the traditional structural biology tools have only limited [...] Read more.
Elucidating the structural details of proteins is highly valuable and important for the proper understanding of protein function. In the case of intrinsically disordered proteins (IDPs), however, obtaining the structural details is quite challenging, as the traditional structural biology tools have only limited use. Nuclear magnetic resonance (NMR) is a unique experimental tool that provides ensemble conformations of IDPs at atomic resolution, and when studying IDPs, a slightly different experimental strategy needs to be employed than the one used for globular proteins. We address this point by reviewing many NMR investigations carried out on the α-synuclein protein, the aggregation of which is strongly correlated with Parkinson’s disease. Full article
(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases)
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