Special Issue "Intrinsically Disordered Proteins and Chronic Diseases"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (1 March 2019)

Special Issue Editors

Guest Editor
Dr. Prakash Kulkarni

City of Hope National Medical Center, Duarte, CA, USA
Website | E-Mail
Interests: IDP conformational dynamics; phenotypic switching, non-genetic mechanisms in phenotypic heterogeneity; bet-hedging in evolution
Guest Editor
Dr. Vladimir N. Uversky

Molecular Medicine, University of South Florida, Tampa, USA
Website | E-Mail
Phone: 18139745816
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

Special Issue Information

Dear Colleagues,

It is now increasingly evident that a large fraction of the human proteome comprises proteins, or regions within proteins that lack a 3D structure under physiological conditions, and are referred to as intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs), respectively. Despite their lack of a stable structure, IDPs/IDPRs are involved in regulation, signaling, and control, where binding to multiple partners and high-specificity/low-affinity interactions plays a crucial role. Furthermore, intrinsic disorder is a unique structural feature that enables IDPs/IDPRs to participate in, both, one-to-many and many-to-one signaling. Since they serve as general regulators of various cellular processes, IDPs/IDPRs themselves are tightly controlled. However, when overexpressed, miss-expressed, or dysregulated, IDPs/IDPRs are prone to engage in promiscuous, often unwanted interactions and, thus, may lead to the development of various pathological states.

This Special Issue of Biomolecules is dedicated to exploring the role of IDPs in various chronic diseases. The main goal is to compile articles that describe recent progress in elucidating the mechanisms by which IDPs cause variious human diseases, such as cancer, cardiovascular disease, amyloidoses, neurodegenerative diseases, diabetes, genetic diseases, to name just a few.

Prakash Kulkarni
Vladimir N. Uversky
Guest Editors

Manuscript Submission Information

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Keywords

  • Intrinsically Disordered Protein
  • Cancer
  • Diabetes
  • Neurodegenerative diseases
  • Amyloidoses
  • Cardiovascular diseases
  • Genetic diseases
  • Protein structure
  • Protein function

Published Papers (13 papers)

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Editorial

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Open AccessEditorial
Intrinsically Disordered Proteins in Chronic Diseases
Biomolecules 2019, 9(4), 147; https://doi.org/10.3390/biom9040147
Received: 3 April 2019 / Accepted: 3 April 2019 / Published: 11 April 2019
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Abstract
It is now increasingly evident that a large fraction of the human proteome comprises proteins that, under physiological conditions, lack fixed, ordered 3D structures as a whole or have segments that are not likely to form a defined 3D structure [...] Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)

Research

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Open AccessArticle
Electrostatics of Tau Protein by Molecular Dynamics
Biomolecules 2019, 9(3), 116; https://doi.org/10.3390/biom9030116
Received: 18 February 2019 / Revised: 19 March 2019 / Accepted: 20 March 2019 / Published: 23 March 2019
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Abstract
Tau is a microtubule-associated protein that promotes microtubule assembly and stability. This protein is implicated in several neurodegenerative diseases, including Alzheimer’s. To date, the three-dimensional (3D) structure of tau has not been fully solved, experimentally. Even the most recent information is sometimes controversial [...] Read more.
Tau is a microtubule-associated protein that promotes microtubule assembly and stability. This protein is implicated in several neurodegenerative diseases, including Alzheimer’s. To date, the three-dimensional (3D) structure of tau has not been fully solved, experimentally. Even the most recent information is sometimes controversial in regard to how this protein folds, interacts, and behaves. Predicting the tau structure and its profile sheds light on the knowledge about its properties and biological function, such as the binding to microtubules (MT) and, for instance, the effect on ionic conductivity. Our findings on the tau structure suggest a disordered protein, with discrete portions of well-defined secondary structure, mostly at the microtubule binding region. In addition, the first molecular dynamics simulation of full-length tau along with an MT section was performed, unveiling tau structure when associated with MT and interaction sites. Electrostatics and conductivity were also examined to understand how tau affects the ions in the intracellular fluid environment. Our results bring a new insight into tau and tubulin MT proteins, their characteristics, and the structure–function relationship. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessArticle
Functional Segments on Intrinsically Disordered Regions in Disease-Related Proteins
Biomolecules 2019, 9(3), 88; https://doi.org/10.3390/biom9030088
Received: 22 January 2019 / Revised: 19 February 2019 / Accepted: 25 February 2019 / Published: 5 March 2019
Cited by 1 | PDF Full-text (1100 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
One of the unique characteristics of intrinsically disordered proteins (IPDs) is the existence of functional segments in intrinsically disordered regions (IDRs). A typical function of these segments is binding to partner molecules, such as proteins and DNAs. These segments play important roles in [...] Read more.
One of the unique characteristics of intrinsically disordered proteins (IPDs) is the existence of functional segments in intrinsically disordered regions (IDRs). A typical function of these segments is binding to partner molecules, such as proteins and DNAs. These segments play important roles in signaling pathways and transcriptional regulation. We conducted bioinformatics analysis to search these functional segments based on IDR predictions and database annotations. We found more than a thousand potential functional IDR segments in disease-related proteins. Large fractions of proteins related to cancers, congenital disorders, digestive system diseases, and reproductive system diseases have these functional IDRs. Some proteins in nervous system diseases have long functional segments in IDRs. The detailed analysis of some of these regions showed that the functional segments are located on experimentally verified IDRs. The proteins with functional IDR segments generally tend to come and go between the cytoplasm and the nucleus. Proteins involved in multiple diseases tend to have more protein-protein interactors, suggesting that hub proteins in the protein-protein interaction networks can have multiple impacts on human diseases. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessArticle
Conserved Glycines Control Disorder and Function in the Cold-Regulated Protein, COR15A
Biomolecules 2019, 9(3), 84; https://doi.org/10.3390/biom9030084
Received: 15 January 2019 / Revised: 15 February 2019 / Accepted: 25 February 2019 / Published: 2 March 2019
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Abstract
Cold-regulated (COR) 15A is an intrinsically disordered protein (IDP) from Arabidopsis thaliana important for freezing tolerance. During freezing-induced cellular dehydration, COR15A transitions from a disordered to mostly α-helical structure. We tested whether mutations that increase the helicity of COR15A also increase its protective [...] Read more.
Cold-regulated (COR) 15A is an intrinsically disordered protein (IDP) from Arabidopsis thaliana important for freezing tolerance. During freezing-induced cellular dehydration, COR15A transitions from a disordered to mostly α-helical structure. We tested whether mutations that increase the helicity of COR15A also increase its protective function. Conserved glycine residues were identified and mutated to alanine. Nuclear magnetic resonance (NMR) spectroscopy was used to identify residue-specific changes in helicity for wildtype (WT) COR15A and the mutants. Circular dichroism (CD) spectroscopy was used to monitor the coil–helix transition in response to increasing concentrations of trifluoroethanol (TFE) and ethylene glycol. The impact of the COR15A mutants on the stability of model membranes during a freeze–thaw cycle was investigated by fluorescence spectroscopy. The results of these experiments showed the mutants had a higher content of α-helical structure and the increased α-helicity improved membrane stabilization during freezing. Comparison of the TFE- and ethylene glycol-induced coil–helix transitions support our conclusion that increasing the transient helicity of COR15A in aqueous solution increases its ability to stabilize membranes during freezing. Altogether, our results suggest the conserved glycine residues are important for maintaining the disordered structure of COR15A but are also compatible with the formation of α-helical structure during freezing induced dehydration. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessArticle
p53 Phosphomimetics Preserve Transient Secondary Structure but Reduce Binding to Mdm2 and MdmX
Biomolecules 2019, 9(3), 83; https://doi.org/10.3390/biom9030083
Received: 23 January 2019 / Revised: 27 February 2019 / Accepted: 28 February 2019 / Published: 2 March 2019
Cited by 1 | PDF Full-text (1299 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The disordered p53 transactivation domain (p53TAD) contains specific levels of transient helical secondary structure that are necessary for its binding to the negative regulators, mouse double minute 2 (Mdm2) and MdmX. The interactions of p53 with Mdm2 and MdmX are also modulated by [...] Read more.
The disordered p53 transactivation domain (p53TAD) contains specific levels of transient helical secondary structure that are necessary for its binding to the negative regulators, mouse double minute 2 (Mdm2) and MdmX. The interactions of p53 with Mdm2 and MdmX are also modulated by posttranslational modifications (PTMs) of p53TAD including phosphorylation at S15, T18 and S20 that inhibits p53-Mdm2 binding. It is unclear whether the levels of transient secondary structure in p53TAD are changed by phosphorylation or other PTMs. We used phosphomimetic mutants to determine if adding a negative charge at positions 15 and 18 has any effect on the transient secondary structure of p53TAD and protein-protein binding. Using a combination of biophysical and structural methods, we investigated the effects of single and multisite phosphomimetics on the transient secondary structure of p53TAD and its interaction with Mdm2, MdmX, and the KIX domain. The phosphomimetics reduced Mdm2 and MdmX binding affinity by 3–5-fold, but resulted in minimal changes in transient secondary structure, suggesting that the destabilizing effect of phosphorylation on the p53TAD-Mdm2 interaction is primarily electrostatic. Phosphomimetics had no effect on the p53-KIX interaction, suggesting that increased binding of phosphorylated p53 to KIX may be influenced by decreased competition with its negative regulators. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessArticle
Structural and Dynamical Order of a Disordered Protein: Molecular Insights into Conformational Switching of PAGE4 at the Systems Level
Biomolecules 2019, 9(2), 77; https://doi.org/10.3390/biom9020077
Received: 7 January 2019 / Revised: 10 February 2019 / Accepted: 10 February 2019 / Published: 22 February 2019
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Abstract
Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less [...] Read more.
Folded proteins show a high degree of structural order and undergo (fairly constrained) collective motions related to their functions. On the other hand, intrinsically disordered proteins (IDPs), while lacking a well-defined three-dimensional structure, do exhibit some structural and dynamical ordering, but are less constrained in their motions than folded proteins. The larger structural plasticity of IDPs emphasizes the importance of entropically driven motions. Many IDPs undergo function-related disorder-to-order transitions driven by their interaction with specific binding partners. As experimental techniques become more sensitive and become better integrated with computational simulations, we are beginning to see how the modest structural ordering and large amplitude collective motions of IDPs endow them with an ability to mediate multiple interactions with different partners in the cell. To illustrate these points, here, we use Prostate-associated gene 4 (PAGE4), an IDP implicated in prostate cancer (PCa) as an example. We first review our previous efforts using molecular dynamics simulations based on atomistic AWSEM to study the conformational dynamics of PAGE4 and how its motions change in its different physiologically relevant phosphorylated forms. Our simulations quantitatively reproduced experimental observations and revealed how structural and dynamical ordering are encoded in the sequence of PAGE4 and can be modulated by different extents of phosphorylation by the kinases HIPK1 and CLK2. This ordering is reflected in changing populations of certain secondary structural elements as well as in the regularity of its collective motions. These ordered features are directly correlated with the functional interactions of WT-PAGE4, HIPK1-PAGE4 and CLK2-PAGE4 with the AP-1 signaling axis. These interactions give rise to repeated transitions between (high HIPK1-PAGE4, low CLK2-PAGE4) and (low HIPK1-PAGE4, high CLK2-PAGE4) cell phenotypes, which possess differing sensitivities to the standard PCa therapies, such as androgen deprivation therapy (ADT). We argue that, although the structural plasticity of an IDP is important in promoting promiscuous interactions, the modulation of the structural ordering is important for sculpting its interactions so as to rewire with agility biomolecular interaction networks with significant functional consequences. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessFeature PaperArticle
Molecular Crowding Tunes Material States of Ribonucleoprotein Condensates
Biomolecules 2019, 9(2), 71; https://doi.org/10.3390/biom9020071
Received: 31 December 2018 / Revised: 5 February 2019 / Accepted: 5 February 2019 / Published: 19 February 2019
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Abstract
Ribonucleoprotein (RNP) granules are membraneless liquid condensates that dynamically form, dissolve, and mature into a gel-like state in response to a changing cellular environment. RNP condensation is largely governed by promiscuous attractive inter-chain interactions mediated by low-complexity domains (LCDs). Using an archetypal disordered [...] Read more.
Ribonucleoprotein (RNP) granules are membraneless liquid condensates that dynamically form, dissolve, and mature into a gel-like state in response to a changing cellular environment. RNP condensation is largely governed by promiscuous attractive inter-chain interactions mediated by low-complexity domains (LCDs). Using an archetypal disordered RNP, fused in sarcoma (FUS), here we study how molecular crowding impacts the RNP liquid condensation. We observe that the liquid–liquid coexistence boundary of FUS is lowered by polymer crowders, consistent with an excluded volume model. With increasing bulk crowder concentration, the RNP partition increases and the diffusion rate decreases in the condensed phase. Furthermore, we show that RNP condensates undergo substantial hardening wherein protein-dense droplets transition from viscous fluid to viscoelastic gel-like states in a crowder concentration-dependent manner. Utilizing two distinct LCDs that broadly represent commonly occurring sequence motifs driving RNP phase transitions, we reveal that the impact of crowding is largely independent of LCD charge and sequence patterns. These results are consistent with a thermodynamic model of crowder-mediated depletion interaction, which suggests that inter-RNP attraction is enhanced by molecular crowding. The depletion force is likely to play a key role in tuning the physical properties of RNP condensates within the crowded cellular space. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Review

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Open AccessReview
Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins
Biomolecules 2019, 9(4), 146; https://doi.org/10.3390/biom9040146
Received: 5 March 2019 / Revised: 9 April 2019 / Accepted: 10 April 2019 / Published: 11 April 2019
Cited by 1 | PDF Full-text (2126 KB) | HTML Full-text | XML Full-text
Abstract
Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This [...] Read more.
Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This enables the IDPs to signal through multiple signaling pathways and serve as scaffolds for multi-protein complexes. The challenge in studying IDPs experimentally stems from their disordered nature. Nuclear magnetic resonance (NMR), circular dichroism, small angle X-ray scattering, and single molecule Förster resonance energy transfer (FRET) can give the local structural information and overall dimension of IDPs, but seldom provide a unified picture of the whole protein. To understand the conformational dynamics of IDPs and how their structural ensembles recognize multiple binding partners and small molecule inhibitors, knowledge-based and physics-based sampling techniques are utilized in-silico, guided by experimental structural data. However, efficient sampling of the IDP conformational ensemble requires traversing the numerous degrees of freedom in the IDP energy landscape, as well as force-fields that accurately model the protein and solvent interactions. In this review, we have provided an overview of the current state of computational methods for studying IDP structure and dynamics and discussed the major challenges faced in this field. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessReview
Spontaneous Switching among Conformational Ensembles in Intrinsically Disordered Proteins
Biomolecules 2019, 9(3), 114; https://doi.org/10.3390/biom9030114
Received: 17 January 2019 / Revised: 14 March 2019 / Accepted: 15 March 2019 / Published: 22 March 2019
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Abstract
The common conception of intrinsically disordered proteins (IDPs) is that they stochastically sample all possible configurations driven by thermal fluctuations. This is certainly true for many IDPs, which behave as swollen random coils that can be described using polymer models developed for homopolymers. [...] Read more.
The common conception of intrinsically disordered proteins (IDPs) is that they stochastically sample all possible configurations driven by thermal fluctuations. This is certainly true for many IDPs, which behave as swollen random coils that can be described using polymer models developed for homopolymers. However, the variability in interaction energy between different amino acid sequences provides the possibility that some configurations may be strongly preferred while others are forbidden. In compact globular IDPs, core hydration and packing density can vary between segments of the polypeptide chain leading to complex conformational dynamics. Here, we describe a growing number of proteins that appear intrinsically disordered by biochemical and bioinformatic characterization but switch between restricted regions of conformational space. In some cases, spontaneous switching between conformational ensembles was directly observed, but few methods can identify when an IDP is acting as a restricted chain. Such switching between disparate corners of conformational space could bias ligand binding and regulate the volume of IDPs acting as structural or entropic elements. Thus, mapping the accessible energy landscape and capturing dynamics across a wide range of timescales are essential to recognize when an IDP is acting as such a switch. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessReview
Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences
Biomolecules 2019, 9(3), 105; https://doi.org/10.3390/biom9030105
Received: 30 January 2019 / Revised: 9 March 2019 / Accepted: 13 March 2019 / Published: 16 March 2019
Cited by 1 | PDF Full-text (827 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic [...] Read more.
The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic resonance and cryo-electron microscopy recently revealed propensities of MAPs to form transient local structures and long-range contacts in the free state, and conformations adopted in complexes with microtubules and filamentous actin, as well as in pathological aggregates. In this paper, we compare the longest, 441-residue brain isoform of tau (tau40), and a 467-residue isoform of MAP2, known as MAP2c. For both molecules, we present transient structural motifs revealed by conformational analysis of experimental data obtained for free soluble forms of the proteins. We show that many of the short sequence motifs that exhibit transient structural features are linked to functional properties, manifested by specific interactions. The transient structural motifs can be therefore classified as molecular recognition elements of tau40 and MAP2c. Their interactions are further regulated by post-translational modifications, in particular phosphorylation. The structure-function analysis also explains differences between biological activities of tau40 and MAP2c. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessReview
Role of Phosphorylation in the Modulation of the Glucocorticoid Receptor’s Intrinsically Disordered Domain
Biomolecules 2019, 9(3), 95; https://doi.org/10.3390/biom9030095
Received: 22 December 2018 / Revised: 18 February 2019 / Accepted: 21 February 2019 / Published: 11 March 2019
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Abstract
Protein phosphorylation often switches cellular activity from one state to another, and this post-translational modification plays an important role in gene regulation by the nuclear hormone receptor superfamily, including the glucocorticoid receptor (GR). Cell signaling pathways that regulate phosphorylation of the GR are [...] Read more.
Protein phosphorylation often switches cellular activity from one state to another, and this post-translational modification plays an important role in gene regulation by the nuclear hormone receptor superfamily, including the glucocorticoid receptor (GR). Cell signaling pathways that regulate phosphorylation of the GR are important determinants of GR actions, including lymphoid cell apoptosis, DNA binding, and interaction with coregulatory proteins. All major functionally important phosphorylation sites in the human GR are located in its N-terminal domain (NTD), which possesses a powerful transactivation domain, AF1. The GR NTD exists as an intrinsically disordered protein (IDP) and undergoes disorder-order transition for AF1’s efficient interaction with several coregulatory proteins and subsequent AF1-mediated GR activity. It has been reported that GR’s NTD/AF1 undergoes such disorder-order transition following site-specific phosphorylation. This review provides currently available information regarding the role of GR phosphorylation in its action and highlights the possible underlying mechanisms of action. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessReview
Extreme Fuzziness: Direct Interactions between Two IDPs
Biomolecules 2019, 9(3), 81; https://doi.org/10.3390/biom9030081
Received: 15 December 2018 / Revised: 10 February 2019 / Accepted: 18 February 2019 / Published: 26 February 2019
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Abstract
Protein interactions involving intrinsically disordered proteins (IDPs) greatly extend the range of binding mechanisms available to proteins. In interactions employing coupled folding and binding, IDPs undergo disorder-to-order transitions to form a complex with a well-defined structure. In many other cases, IDPs retain structural [...] Read more.
Protein interactions involving intrinsically disordered proteins (IDPs) greatly extend the range of binding mechanisms available to proteins. In interactions employing coupled folding and binding, IDPs undergo disorder-to-order transitions to form a complex with a well-defined structure. In many other cases, IDPs retain structural plasticity in the final complexes, which have been defined as the fuzzy complexes. While a large number of fuzzy complexes have been characterized with variety of fuzzy patterns, many of the interactions are between an IDP and a structured protein. Thus, whether two IDPs can interact directly to form a fuzzy complex without disorder-to-order transition remains an open question. Recently, two studies of interactions between IDPs (4.1G-CTD/NuMA and H1/ProTα) have found a definite answer to this question. Detailed characterizations combined with nuclear magnetic resonance (NMR), single-molecule Förster resonance energy transfer (smFRET) and molecular dynamics (MD) simulation demonstrate that direct interactions between these two pairs of IDPs do form fuzzy complexes while retaining the conformational dynamics of the isolated proteins, which we name as the extremely fuzzy complexes. Extreme fuzziness completes the full spectrum of protein-protein interaction modes, suggesting that a more generalized model beyond existing binding mechanisms is required. Previous models of protein interaction could be applicable to some aspects of the extremely fuzzy interactions, but in more general sense, the distinction between native and nonnative contacts, which was used to understand protein folding and binding, becomes obscure. Exploring the phenomenon of extreme fuzziness may shed new light on molecular recognition and drug design. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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Open AccessReview
Modulation of Measles Virus NTAIL Interactions through Fuzziness and Sequence Features of Disordered Binding Sites
Biomolecules 2019, 9(1), 8; https://doi.org/10.3390/biom9010008
Received: 22 November 2018 / Revised: 10 December 2018 / Accepted: 18 December 2018 / Published: 27 December 2018
Cited by 1 | PDF Full-text (1427 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In this paper we review our recent findings on the different interaction mechanisms of the C-terminal domain of the nucleoprotein (N) of measles virus (MeV) NTAIL, a model viral intrinsically disordered protein (IDP), with two of its known binding partners, i.e., [...] Read more.
In this paper we review our recent findings on the different interaction mechanisms of the C-terminal domain of the nucleoprotein (N) of measles virus (MeV) NTAIL, a model viral intrinsically disordered protein (IDP), with two of its known binding partners, i.e., the C-terminal X domain of the phosphoprotein of MeV XD (a globular viral protein) and the heat-shock protein 70 hsp70 (a globular cellular protein). The NTAIL binds both XD and hsp70 via a molecular recognition element (MoRE) that is flanked by two fuzzy regions. The long (85 residues) N-terminal fuzzy region is a natural dampener of the interaction with both XD and hsp70. In the case of binding to XD, the N-terminal fuzzy appendage of NTAIL reduces the rate of α-helical folding of the MoRE. The dampening effect of the fuzzy appendage on XD and hsp70 binding depends on the length and fuzziness of the N-terminal region. Despite this similarity, NTAIL binding to XD and hsp70 appears to rely on completely different requirements. Almost any mutation within the MoRE decreases XD binding, whereas many of them increase the binding to hsp70. In addition, XD binding is very sensitive to the α-helical state of the MoRE, whereas hsp70 is not. Thus, contrary to hsp70, XD binding appears to be strictly dependent on the wild-type primary and secondary structure of the MoRE. Full article
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
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