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Functionally Relevant Macromolecular Interactions of Disordered Proteins 2019

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 2019) | Viewed by 52875

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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
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous special issue "Functionally Relevant Macromolecular Interactions of Disordered Proteins".

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

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Published Papers (13 papers)

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Editorial

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7 pages, 240 KiB  
Editorial
Macromolecular Interactions of Disordered Proteins
by István Simon
Int. J. Mol. Sci. 2020, 21(2), 504; https://doi.org/10.3390/ijms21020504 - 13 Jan 2020
Cited by 1 | Viewed by 1718
Abstract
Proteins are social beings [...] Full article

Research

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19 pages, 4332 KiB  
Article
In Silico Study of Rett Syndrome Treatment-Related Genes, MECP2, CDKL5, and FOXG1, by Evolutionary Classification and Disordered Region Assessment
by Muhamad Fahmi, Gen Yasui, Kaito Seki, Syouichi Katayama, Takako Kaneko-Kawano, Tetsuya Inazu, Yukihiko Kubota and Masahiro Ito
Int. J. Mol. Sci. 2019, 20(22), 5593; https://doi.org/10.3390/ijms20225593 - 8 Nov 2019
Cited by 11 | Viewed by 4560
Abstract
Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which has multiple functions such as binding to methylated DNA or interacting with a transcriptional co-repressor complex. It has been established that alterations in [...] Read more.
Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which has multiple functions such as binding to methylated DNA or interacting with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We investigated the evolution and molecular features of MeCP2, CDKL5, and FOXG1 and their binding partners using phylogenetic profiling to gain a better understanding of their similarities. We also predicted the structural order–disorder propensity and assessed the evolutionary rates per site of MeCP2, CDKL5, and FOXG1 to investigate the relationships between disordered structure and other related properties with RTT. Here, we provide insight to the structural characteristics, evolution and interaction landscapes of those three proteins. We also uncovered the disordered structure properties and evolution of those proteins which may provide valuable information for the development of therapeutic strategies of RTT. Full article
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21 pages, 5472 KiB  
Article
Sequence and Structure Properties Uncover the Natural Classification of Protein Complexes Formed by Intrinsically Disordered Proteins via Mutual Synergistic Folding
by Bálint Mészáros, László Dobson, Erzsébet Fichó and István Simon
Int. J. Mol. Sci. 2019, 20(21), 5460; https://doi.org/10.3390/ijms20215460 - 1 Nov 2019
Cited by 3 | Viewed by 2809
Abstract
Intrinsically disordered proteins mediate crucial biological functions through their interactions with other proteins. Mutual synergistic folding (MSF) occurs when all interacting proteins are disordered, folding into a stable structure in the course of the complex formation. In these cases, the folding and binding [...] Read more.
Intrinsically disordered proteins mediate crucial biological functions through their interactions with other proteins. Mutual synergistic folding (MSF) occurs when all interacting proteins are disordered, folding into a stable structure in the course of the complex formation. In these cases, the folding and binding processes occur in parallel, lending the resulting structures uniquely heterogeneous features. Currently there are no dedicated classification approaches that take into account the particular biological and biophysical properties of MSF complexes. Here, we present a scalable clustering-based classification scheme, built on redundancy-filtered features that describe the sequence and structure properties of the complexes and the role of the interaction, which is directly responsible for structure formation. Using this approach, we define six major types of MSF complexes, corresponding to biologically meaningful groups. Hence, the presented method also shows that differences in binding strength, subcellular localization, and regulation are encoded in the sequence and structural properties of proteins. While current protein structure classification methods can also handle complex structures, we show that the developed scheme is fundamentally different, and since it takes into account defining features of MSF complexes, it serves as a better representation of structures arising through this specific interaction mode. Full article
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13 pages, 1946 KiB  
Article
Depicting Conformational Ensembles of α-Synuclein by Single Molecule Force Spectroscopy and Native Mass Spectroscopy
by Roberta Corti, Claudia A. Marrano, Domenico Salerno, Stefania Brocca, Antonino Natalello, Carlo Santambrogio, Giuseppe Legname, Francesco Mantegazza, Rita Grandori and Valeria Cassina
Int. J. Mol. Sci. 2019, 20(20), 5181; https://doi.org/10.3390/ijms20205181 - 19 Oct 2019
Cited by 7 | Viewed by 3479
Abstract
Description of heterogeneous molecular ensembles, such as intrinsically disordered proteins, represents a challenge in structural biology and an urgent question posed by biochemistry to interpret many physiologically important, regulatory mechanisms. Single-molecule techniques can provide a unique contribution to this field. This work applies [...] Read more.
Description of heterogeneous molecular ensembles, such as intrinsically disordered proteins, represents a challenge in structural biology and an urgent question posed by biochemistry to interpret many physiologically important, regulatory mechanisms. Single-molecule techniques can provide a unique contribution to this field. This work applies single molecule force spectroscopy to probe conformational properties of α-synuclein in solution and its conformational changes induced by ligand binding. The goal is to compare data from such an approach with those obtained by native mass spectrometry. These two orthogonal, biophysical methods are found to deliver a complex picture, in which monomeric α-synuclein in solution spontaneously populates compact and partially compacted states, which are differently stabilized by binding to aggregation inhibitors, such as dopamine and epigallocatechin-3-gallate. Analyses by circular dichroism and Fourier-transform infrared spectroscopy show that these transitions do not involve formation of secondary structure. This comparative analysis provides support to structural interpretation of charge-state distributions obtained by native mass spectrometry and helps, in turn, defining the conformational components detected by single molecule force spectroscopy. Full article
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13 pages, 2659 KiB  
Article
Analysis of Heterodimeric “Mutual Synergistic Folding”-Complexes
by Anikó Mentes, Csaba Magyar, Erzsébet Fichó and István Simon
Int. J. Mol. Sci. 2019, 20(20), 5136; https://doi.org/10.3390/ijms20205136 - 16 Oct 2019
Cited by 7 | Viewed by 1845
Abstract
Several intrinsically disordered proteins (IDPs) are capable to adopt stable structures without interacting with a folded partner. When the folding of all interacting partners happens at the same time, coupled with the interaction in a synergistic manner, the process is called Mutual Synergistic [...] Read more.
Several intrinsically disordered proteins (IDPs) are capable to adopt stable structures without interacting with a folded partner. When the folding of all interacting partners happens at the same time, coupled with the interaction in a synergistic manner, the process is called Mutual Synergistic Folding (MSF). These complexes represent a discrete subset of IDPs. Recently, we collected information on their complexes and created the MFIB (Mutual Folding Induced by Binding) database. In a previous study, we compared homodimeric MSF complexes with homodimeric and monomeric globular proteins with similar amino acid sequence lengths. We concluded that MSF homodimers, compared to globular homodimeric proteins, have a greater solvent accessible main-chain surface area on the contact surface of the subunits, which becomes buried during dimerization. The main driving force of the folding is the mutual shielding of the water-accessible backbones, but the formation of further intermolecular interactions can also be relevant. In this paper, we will report analyses of heterodimeric MSF complexes. Our results indicate that the amino acid composition of the heterodimeric MSF monomer subunits slightly diverges from globular monomer proteins, while after dimerization, the amino acid composition of the overall MSF complexes becomes more similar to overall amino acid compositions of globular complexes. We found that inter-subunit interactions are strengthened, and additionally to the shielding of the solvent accessible backbone, other factors might play an important role in the stabilization of the heterodimeric structures, likewise energy gain resulting from the interaction of the two subunits with different amino acid compositions. We suggest that the shielding of the β-sheet backbones and the formation of a buried structural core along with the general strengthening of inter-subunit interactions together could be the driving forces of MSF protein structural ordering upon dimerization. Full article
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19 pages, 5645 KiB  
Article
Investigation into Early Steps of Actin Recognition by the Intrinsically Disordered N-WASP Domain V
by Maud Chan-Yao-Chong, Dominique Durand and Tâp Ha-Duong
Int. J. Mol. Sci. 2019, 20(18), 4493; https://doi.org/10.3390/ijms20184493 - 11 Sep 2019
Cited by 3 | Viewed by 2543
Abstract
Cellular regulation or signaling processes are mediated by many proteins which often have one or several intrinsically disordered regions (IDRs). These IDRs generally serve as binders to different proteins with high specificity. In many cases, IDRs undergo a disorder-to-order transition upon binding, following [...] Read more.
Cellular regulation or signaling processes are mediated by many proteins which often have one or several intrinsically disordered regions (IDRs). These IDRs generally serve as binders to different proteins with high specificity. In many cases, IDRs undergo a disorder-to-order transition upon binding, following a mechanism between two possible pathways, the induced fit or the conformational selection. Since these mechanisms contribute differently to the kinetics of IDR associations, it is important to investigate them in order to gain insight into the physical factors that determine the biomolecular recognition process. The verprolin homology domain (V) of the Neural Wiskott–Aldrich Syndrome Protein (N-WASP), involved in the regulation of actin polymerization, is a typical example of IDR. It is composed of two WH2 motifs, each being able to bind one actin molecule. In this study, we investigated the early steps of the recognition process of actin by the WH2 motifs of N-WASP domain V. Using docking calculations and molecular dynamics simulations, our study shows that actin is first recognized by the N-WASP domain V regions which have the highest propensity to form transient α -helices. The WH2 motif consensus sequences “LKKV” subsequently bind to actin through large conformational changes of the disordered domain V. Full article
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23 pages, 3624 KiB  
Article
Structural and Functional Properties of the Capsid Protein of Dengue and Related Flavivirus
by André F. Faustino, Ana S. Martins, Nina Karguth, Vanessa Artilheiro, Francisco J. Enguita, Joana C. Ricardo, Nuno C. Santos and Ivo C. Martins
Int. J. Mol. Sci. 2019, 20(16), 3870; https://doi.org/10.3390/ijms20163870 - 8 Aug 2019
Cited by 24 | Viewed by 4861
Abstract
Dengue, West Nile and Zika, closely related viruses of the Flaviviridae family, are an increasing global threat, due to the expansion of their mosquito vectors. They present a very similar viral particle with an outer lipid bilayer containing two viral proteins and, within [...] Read more.
Dengue, West Nile and Zika, closely related viruses of the Flaviviridae family, are an increasing global threat, due to the expansion of their mosquito vectors. They present a very similar viral particle with an outer lipid bilayer containing two viral proteins and, within it, the nucleocapsid core. This core is composed by the viral RNA complexed with multiple copies of the capsid protein, a crucial structural protein that mediates not only viral assembly, but also encapsidation, by interacting with host lipid systems. The capsid is a homodimeric protein that contains a disordered N-terminal region, an intermediate flexible fold section and a very stable conserved fold region. Since a better understanding of its structure can give light into its biological activity, here, first, we compared and analyzed relevant mosquito-borne Flavivirus capsid protein sequences and their predicted structures. Then, we studied the alternative conformations enabled by the N-terminal region. Finally, using dengue virus capsid protein as main model, we correlated the protein size, thermal stability and function with its structure/dynamics features. The findings suggest that the capsid protein interaction with host lipid systems leads to minor allosteric changes that may modulate the specific binding of the protein to the viral RNA. Such mechanism can be targeted in future drug development strategies, namely by using improved versions of pep14-23, a dengue virus capsid protein peptide inhibitor, previously developed by us. Such knowledge can yield promising advances against Zika, dengue and closely related Flavivirus. Full article
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14 pages, 1994 KiB  
Article
Raman Evidence of p53-DBD Disorder Decrease upon Interaction with the Anticancer Protein Azurin
by Sara Signorelli, Salvatore Cannistraro and Anna Rita Bizzarri
Int. J. Mol. Sci. 2019, 20(12), 3078; https://doi.org/10.3390/ijms20123078 - 24 Jun 2019
Cited by 13 | Viewed by 3376
Abstract
Raman spectroscopy, which is a suitable tool to elucidate the structural properties of intrinsically disordered proteins, was applied to investigate the changes in both the structure and the conformational heterogeneity of the DNA-binding domain (DBD) belonging to the intrinsically disordered protein p53 upon [...] Read more.
Raman spectroscopy, which is a suitable tool to elucidate the structural properties of intrinsically disordered proteins, was applied to investigate the changes in both the structure and the conformational heterogeneity of the DNA-binding domain (DBD) belonging to the intrinsically disordered protein p53 upon its binding to Azurin, an electron-transfer anticancer protein from Pseudomonas aeruginosa. The Raman spectra of the DBD and Azurin, isolated in solution or forming a complex, were analyzed by a combined analysis based on peak inspection, band convolution, and principal component analysis (PCA). In particular, our attention was focused on the Raman peaks of Tyrosine and Tryptophan residues, which are diagnostic markers of protein side chain environment, and on the Amide I band, of which the deconvolution allows us to extract information about α-helix, β-sheet, and random coil contents. The results show an increase of the secondary structure content of DBD concomitantly with a decrease of its conformational heterogeneity upon its binding to Azurin. These findings suggest an Azurin-induced conformational change of DBD structure with possible implications for p53 functionality. Full article
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11 pages, 1143 KiB  
Article
Repeats in S1 Proteins: Flexibility and Tendency for Intrinsic Disorder
by Andrey Machulin, Evgenia Deryusheva, Mikhail Lobanov and Oxana Galzitskaya
Int. J. Mol. Sci. 2019, 20(10), 2377; https://doi.org/10.3390/ijms20102377 - 14 May 2019
Cited by 14 | Viewed by 2403
Abstract
An important feature of ribosomal S1 proteins is multiple copies of structural domains in bacteria, the number of which changes in a strictly limited range from one to six. For S1 proteins, little is known about the contribution of flexible regions to protein [...] Read more.
An important feature of ribosomal S1 proteins is multiple copies of structural domains in bacteria, the number of which changes in a strictly limited range from one to six. For S1 proteins, little is known about the contribution of flexible regions to protein domain function. We exhaustively studied a tendency for intrinsic disorder and flexibility within and between structural domains for all available UniProt S1 sequences. Using charge–hydrophobicity plot cumulative distribution function (CH-CDF) analysis we classified 53% of S1 proteins as ordered proteins; the remaining proteins were related to molten globule state. S1 proteins are characterized by an equal ratio of regions connecting the secondary structure within and between structural domains, which indicates a similar organization of separate S1 domains and multi-domain S1 proteins. According to the FoldUnfold and IsUnstruct programs, in the multi-domain proteins, relatively short flexible or disordered regions are predominant. The lowest percentage of flexibility is in the central parts of multi-domain proteins. Our results suggest that the ratio of flexibility in the separate domains is related to their roles in the activity and functionality of S1: a more stable and compact central part in the multi-domain proteins is vital for RNA interaction, terminals domains are important for other functions. Full article
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18 pages, 3065 KiB  
Article
Intrinsically Disordered Linkers Impart Processivity on Enzymes by Spatial Confinement of Binding Domains
by Beata Szabo, Tamas Horvath, Eva Schad, Nikoletta Murvai, Agnes Tantos, Lajos Kalmar, Lucía Beatriz Chemes, Kyou-Hoon Han and Peter Tompa
Int. J. Mol. Sci. 2019, 20(9), 2119; https://doi.org/10.3390/ijms20092119 - 29 Apr 2019
Cited by 13 | Viewed by 3895
Abstract
(1) Background: Processivity is common among enzymes and mechanochemical motors that synthesize, degrade, modify or move along polymeric substrates, such as DNA, RNA, polysaccharides or proteins. Processive enzymes can make multiple rounds of modification without releasing the substrate/partner, making their operation extremely effective [...] Read more.
(1) Background: Processivity is common among enzymes and mechanochemical motors that synthesize, degrade, modify or move along polymeric substrates, such as DNA, RNA, polysaccharides or proteins. Processive enzymes can make multiple rounds of modification without releasing the substrate/partner, making their operation extremely effective and economical. The molecular mechanism of processivity is rather well understood in cases when the enzyme structurally confines the substrate, such as the DNA replication factor PCNA, and also when ATP energy is used to confine the succession of molecular events, such as with mechanochemical motors. Processivity may also result from the kinetic bias of binding imposed by spatial confinement of two binding elements connected by an intrinsically disordered (ID) linker. (2) Method: By statistical physical modeling, we show that this arrangement results in processive systems, in which the linker ensures an optimized effective concentration around novel binding site(s), favoring rebinding over full release of the polymeric partner. (3) Results: By analyzing 12 such proteins, such as cellulase, and RNAse-H, we illustrate that in these proteins linker length and flexibility, and the kinetic parameters of binding elements, are fine-tuned for optimizing processivity. We also report a conservation of structural disorder, special amino acid composition of linkers, and the correlation of their length with step size. (4) Conclusion: These observations suggest a unique type of entropic chain function of ID proteins, that may impart functional advantages on diverse enzymes in a variety of biological contexts. Full article
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Review

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14 pages, 1192 KiB  
Review
The Role of Post-Translational Modifications in the Phase Transitions of Intrinsically Disordered Proteins
by Izzy Owen and Frank Shewmaker
Int. J. Mol. Sci. 2019, 20(21), 5501; https://doi.org/10.3390/ijms20215501 - 5 Nov 2019
Cited by 129 | Viewed by 9404
Abstract
Advances in genomics and proteomics have revealed eukaryotic proteomes to be highly abundant in intrinsically disordered proteins that are susceptible to diverse post-translational modifications. Intrinsically disordered regions are critical to the liquid–liquid phase separation that facilitates specialized cellular functions. Here, we discuss how [...] Read more.
Advances in genomics and proteomics have revealed eukaryotic proteomes to be highly abundant in intrinsically disordered proteins that are susceptible to diverse post-translational modifications. Intrinsically disordered regions are critical to the liquid–liquid phase separation that facilitates specialized cellular functions. Here, we discuss how post-translational modifications of intrinsically disordered protein segments can regulate the molecular condensation of macromolecules into functional phase-separated complexes. Full article
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20 pages, 3646 KiB  
Review
The Significance of the Intrinsically Disordered Regions for the Functions of the bHLH Transcription Factors
by Aneta Tarczewska and Beata Greb-Markiewicz
Int. J. Mol. Sci. 2019, 20(21), 5306; https://doi.org/10.3390/ijms20215306 - 24 Oct 2019
Cited by 29 | Viewed by 4995
Abstract
The bHLH proteins are a family of eukaryotic transcription factors regulating expression of a wide range of genes involved in cell differentiation and development. They contain the Helix-Loop-Helix (HLH) domain, preceded by a stretch of basic residues, which are responsible for dimerization and [...] Read more.
The bHLH proteins are a family of eukaryotic transcription factors regulating expression of a wide range of genes involved in cell differentiation and development. They contain the Helix-Loop-Helix (HLH) domain, preceded by a stretch of basic residues, which are responsible for dimerization and binding to E-box sequences. In addition to the well-preserved DNA-binding bHLH domain, these proteins may contain various additional domains determining the specificity of performed transcriptional regulation. According to this, the family has been divided into distinct classes. Our aim was to emphasize the significance of existing disordered regions within the bHLH transcription factors for their functionality. Flexible, intrinsically disordered regions containing various motives and specific sequences allow for multiple interactions with transcription co-regulators. Also, based on in silico analysis and previous studies, we hypothesize that the bHLH proteins have a general ability to undergo spontaneous phase separation, forming or participating into liquid condensates which constitute functional centers involved in transcription regulation. We shortly introduce recent findings on the crucial role of the thermodynamically liquid-liquid driven phase separation in transcription regulation by disordered regions of regulatory proteins. We believe that further experimental studies should be performed in this field for better understanding of the mechanism of gene expression regulation (among others regarding oncogenes) by important and linked to many diseases the bHLH transcription factors. Full article
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16 pages, 2608 KiB  
Review
bHLH–PAS Proteins: Their Structure and Intrinsic Disorder
by Marta Kolonko and Beata Greb-Markiewicz
Int. J. Mol. Sci. 2019, 20(15), 3653; https://doi.org/10.3390/ijms20153653 - 26 Jul 2019
Cited by 26 | Viewed by 6364
Abstract
The basic helix–loop–helix/Per-ARNT-SIM (bHLH–PAS) proteins are a class of transcriptional regulators, commonly occurring in living organisms and highly conserved among vertebrates and invertebrates. These proteins exhibit a relatively well-conserved domain structure: the bHLH domain located at the N-terminus, followed by PAS-A and PAS-B [...] Read more.
The basic helix–loop–helix/Per-ARNT-SIM (bHLH–PAS) proteins are a class of transcriptional regulators, commonly occurring in living organisms and highly conserved among vertebrates and invertebrates. These proteins exhibit a relatively well-conserved domain structure: the bHLH domain located at the N-terminus, followed by PAS-A and PAS-B domains. In contrast, their C-terminal fragments present significant variability in their primary structure and are unique for individual proteins. C-termini were shown to be responsible for the specific modulation of protein action. In this review, we present the current state of knowledge, based on NMR and X-ray analysis, concerning the structural properties of bHLH–PAS proteins. It is worth noting that all determined structures comprise only selected domains (bHLH and/or PAS). At the same time, substantial parts of proteins, comprising their long C-termini, have not been structurally characterized to date. Interestingly, these regions appear to be intrinsically disordered (IDRs) and are still a challenge to research. We aim to emphasize the significance of IDRs for the flexibility and function of bHLH–PAS proteins. Finally, we propose modern NMR methods for the structural characterization of the IDRs of bHLH–PAS proteins. Full article
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