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Special Issue "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: 30 September 2019.

Special Issue Editor

Guest Editor
Prof. Dr. Istvan Simon Website E-Mail
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
Phone: +36-1-382-6710
Interests: protein bioinformatics; protein interactions; membrane proteins; protein stability; intrinsically disordered proteins; protein structure; protein folding; protein biophysics; protein binding; protein dynamics; protein conformation; molecular biophysics; protein refolding; membrane transport proteins; computational structural biology; structural bioinformatics

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

Manuscript Submission Information

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Keywords

  • Disordered protein
  • Unstructured protein
  • Coupled folding and binding
  • Mutual folding

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Published Papers (6 papers)

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Research

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Open AccessArticle
Investigation into Early Steps of Actin Recognition by the Intrinsically Disordered N-WASP Domain V
Int. J. Mol. Sci. 2019, 20(18), 4493; https://doi.org/10.3390/ijms20184493 - 11 Sep 2019
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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Open AccessArticle
Structural and Functional Properties of the Capsid Protein of Dengue and Related Flavivirus
Int. J. Mol. Sci. 2019, 20(16), 3870; https://doi.org/10.3390/ijms20163870 - 08 Aug 2019
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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Open AccessArticle
Raman Evidence of p53-DBD Disorder Decrease upon Interaction with the Anticancer Protein Azurin
Int. J. Mol. Sci. 2019, 20(12), 3078; https://doi.org/10.3390/ijms20123078 - 24 Jun 2019
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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Open AccessArticle
Repeats in S1 Proteins: Flexibility and Tendency for Intrinsic Disorder
Int. J. Mol. Sci. 2019, 20(10), 2377; https://doi.org/10.3390/ijms20102377 - 14 May 2019
Cited by 1
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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Open AccessArticle
Intrinsically Disordered Linkers Impart Processivity on Enzymes by Spatial Confinement of Binding Domains
Int. J. Mol. Sci. 2019, 20(9), 2119; https://doi.org/10.3390/ijms20092119 - 29 Apr 2019
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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Open AccessReview
bHLH–PAS Proteins: Their Structure and Intrinsic Disorder
Int. J. Mol. Sci. 2019, 20(15), 3653; https://doi.org/10.3390/ijms20153653 - 26 Jul 2019
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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