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Special Issue "Protein Structural Dynamics 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 (31 December 2019).

Special Issue Editor

Prof. Dr. Shin-ichi Tate
E-Mail Website
Guest Editor
Department of Mathematical and Life Sciences, School of Science; Research Center for the Mathematics on Chromatin Live Dynamics (RcMcD), Hiroshima University, 1-3-1, Kagamiyama, Higashi-Hiroshima 739-8526, Japan
Interests: protein structure; protein structural dynamics; intrinsically disordered protein; protein aggregation; nuclear magnetic resonance spectroscopy
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Special Issue Information

Dear colleagues,

Protein structural dynamics is intimately related to protein functions. Structure biology demands high-resolution structures primarily coming from X-ray crystallography. However, the crystal structure does not always give a comprehensive understanding of the functional mechanism. This inability is often ascribed to a lack of insight into the time-dependent spatial rearrangement of the regulatory residues, domains, and subunits in proteins, which emphasizes the importance in exploring how structural dynamics engages in functional regulation in proteins. Progress in the experimental and theoretical approaches has improved our understanding of protein structural dynamics and has updated the protein structure and function relationships by adding the roles of structural dynamics. The technical advances have also expanded the research targets from folded proteins to intrinsically disordered proteins that travel much wider conformational spaces over the folded proteins. Intrinsically disordered proteins with liquid–liquid phase separation properties have become focused, which unveils the other remarkable roles of structural dynamics in regulating the phase transition of the protein solution.

The Special Issue “Protein Structural Dynamics 2019” is a continuation of the successful 2018 issue “Protein Structural Dynamics”. This issue also aims to present the contemporary research on protein structural dynamics, which may include original articles covering technical development, experimental reports on some particular proteins, and theoretical research, as well as review papers relating to the subjects.

Prof. Dr. Shin-ichi Tate
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Protein strutural dynamics
  • Enzyme functions
  • Intrinsically disordered proteins
  • NMR
  • Single molecular FRET (fluorecense resonance energy transfer)
  • Molecular dynamics simulation
  • Coarse grained molecular dynamics simulation

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Published Papers (6 papers)

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Research

Open AccessArticle
Dynamic Behavior of p53 Driven by Delay and a Microrna-34a-Mediated Feedback Loop
Int. J. Mol. Sci. 2020, 21(4), 1271; https://doi.org/10.3390/ijms21041271 - 13 Feb 2020
Abstract
The tumor suppressor protein p53 is a critical hub in the comprehensive transcriptional network that inhibits the growth of cells after acute stress stimulation. In this paper, an integrated model of the p53 signaling pathway in response to DNA damage is proposed and [...] Read more.
The tumor suppressor protein p53 is a critical hub in the comprehensive transcriptional network that inhibits the growth of cells after acute stress stimulation. In this paper, an integrated model of the p53 signaling pathway in response to DNA damage is proposed and the p53 stability and oscillatory dynamics are analyzed. Through theoretical analysis and numerical simulation, we find that the delay as a bifurcation parameter can drive the p53-Mdm2 module to undergo a supercritical Hopf bifurcation, thereby producing oscillation behavior. Moreover, we demonstrate how the positive feedback loop formed by p53* and microRNA-34a (miR-34a) with the feature of double-negative regulation produces limit-cycle oscillations. Further, we find that miR-34a can affect the critical value of Hopf bifurcation in delay-induced p53 networks. In addition, we show that ATM, once activated by DNA damage, makes p53* undergo two Hopf bifurcations. These results revealed that both time delay and miR-34a can have tumor suppressing roles by promoting p53 oscillation or high level expression, which will provide a perspective for promoting the development of anti-cancer drugs by targeting miR-34a and time delay. Full article
(This article belongs to the Special Issue Protein Structural Dynamics 2019)
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Open AccessArticle
PEA-15 C-Terminal Tail Allosterically Modulates Death-Effector Domain Conformation and Facilitates Protein–Protein Interactions
Int. J. Mol. Sci. 2019, 20(13), 3335; https://doi.org/10.3390/ijms20133335 - 07 Jul 2019
Abstract
Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) exerts its regulatory roles on several critical cellular pathways through protein–protein interactions depending on its phosphorylation states. It can either inhibit the extracellular signal-regulated kinase (ERK) activities when it is dephosphorylated or block the assembly of [...] Read more.
Phosphoprotein enriched in astrocytes, 15 kDa (PEA-15) exerts its regulatory roles on several critical cellular pathways through protein–protein interactions depending on its phosphorylation states. It can either inhibit the extracellular signal-regulated kinase (ERK) activities when it is dephosphorylated or block the assembly of death-inducing signaling complex (DISC) and the subsequent activation of apoptotic initiator, caspase-8, when it is phosphorylated. Due to the important roles of PEA-15 in regulating these pathways that lead to opposite cellular outcomes (cell proliferation vs. cell death), we proposed a phosphostasis (phosphorylation homeostasis) model, in which the phosphorylation states of the protein are vigorously controlled and regulated to maintain a delicate balance. The phosphostasis gives rise to the protective cellular functions of PEA-15 to preserve optimum cellular conditions. In this article, using advanced multidimensional nuclear magnetic resonance (NMR) techniques combined with a novel chemical shift (CS)-Rosetta algorithm for de novo protein structural determination, we report a novel conformation of PEA-15 death-effector domain (DED) upon interacting with ERK2. This new conformation is modulated by the irregularly structured C-terminal tail when it first recognizes and binds to ERK2 at the d-peptide recruitment site (DRS) in an allosteric manner, and is facilitated by the rearrangement of the surface electrostatic and hydrogen-bonding interactions on the DED. In this ERK2-bound conformation, three of the six helices (α2, α3, and α4) comprising the DED reorient substantially in comparison to the free-form structure, exposing key residues on the other three helices that directly interact with ERK2 at the DEF-docking site (docking site for ERK, FxF) and the activation loop. Additionally, we provide evidence that the phosphorylation of the C-terminal tail leads to a distinct conformation of DED, allowing efficient interactions with Fas-associated death domain (FADD) protein at the DISC. Our results substantiate the allosteric regulatory roles of the C-terminal tail in modulating DED conformation and facilitating protein–protein interactions of PEA-15. Full article
(This article belongs to the Special Issue Protein Structural Dynamics 2019)
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Open AccessArticle
Insight of the Interaction between 2,4-thiazolidinedione and Human Serum Albumin: A Spectroscopic, Thermodynamic and Molecular Docking Study
Int. J. Mol. Sci. 2019, 20(11), 2727; https://doi.org/10.3390/ijms20112727 - 03 Jun 2019
Cited by 1
Abstract
Thiazolidinedione derivatives (TZDs) have attracted attention because of their pharmacological effects. For example, certain TZDs have been reported to ameliorate type II diabetes by binding and activating PPARs (peroxisome proliferator-activated receptors). Nonetheless, no information is available on the interaction between the heterocyclic 2, [...] Read more.
Thiazolidinedione derivatives (TZDs) have attracted attention because of their pharmacological effects. For example, certain TZDs have been reported to ameliorate type II diabetes by binding and activating PPARs (peroxisome proliferator-activated receptors). Nonetheless, no information is available on the interaction between the heterocyclic 2, 4-thiazolidinedione (2,4-TZD) moiety and serum albumin, which could affect the pharmacokinetics and pharmacodynamics of TZDs. In this study, we investigated the binding of 2,4-TZD to human serum albumin (HSA). Intrinsic fluorescence spectroscopy revealed a 1:1 binding stoichiometry between 2,4-TZD and HSA with a binding constant (Kb) of 1.69 ± 0.15 × 103 M−1 at 298 K. Isothermal titration calorimetry studies showed that 2,4-TZD/HSA binding was an exothermic and spontaneous reaction. Molecular docking analysis revealed that 2,4-TZD binds to HSA subdomain IB and that the complex formed is stabilized by van der Waal’s interactions and hydrogen bonds. Molecular dynamics simulation confirmed the stability of the HSA-TZD complex. Further, circular dichroism and 3D fluorescence studies showed that the global conformation of HSA was slightly altered by 2,4-TZD binding, enhancing its stability. The results obtained herein further help in understanding the pharmacokinetic properties of thiazolidinedione. Full article
(This article belongs to the Special Issue Protein Structural Dynamics 2019)
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Open AccessArticle
Oligomeric Architecture of Mouse Activating Nkrp1 Receptors on Living Cells
Int. J. Mol. Sci. 2019, 20(8), 1884; https://doi.org/10.3390/ijms20081884 - 16 Apr 2019
Abstract
Mouse activating Nkrp1 proteins are commonly described as type II transmembrane receptors with disulfide-linked homodimeric structure. Their function and the manner in which Nkrp1 proteins of mouse strain (C57BL/6) oligomerize are still poorly understood. To assess the oligomerization state of Nkrp1 proteins, mouse [...] Read more.
Mouse activating Nkrp1 proteins are commonly described as type II transmembrane receptors with disulfide-linked homodimeric structure. Their function and the manner in which Nkrp1 proteins of mouse strain (C57BL/6) oligomerize are still poorly understood. To assess the oligomerization state of Nkrp1 proteins, mouse activating EGFP-Nkrp1s were expressed in mammalian lymphoid cells and their oligomerization evaluated by Förster resonance energy transfer (FRET). Alternatively, Nkrp1s oligomers were detected by Western blotting to specify the ratio between monomeric and dimeric forms. We also performed structural characterization of recombinant ectodomains of activating Nkrp1 receptors. Nkrp1 isoforms c1, c2 and f were expressed prevalently as homodimers, whereas the Nkrp1a displays larger proportion of monomers on the cell surface. Cysteine-to-serine mutants revealed the importance of all stalk cysteines for protein dimerization in living cells with a major influence of cysteine at position 74 in two Nkrp1 protein isoforms. Our results represent a new insight into the oligomerization of Nkrp1 receptors on lymphoid cells, which will help to determine their function. Full article
(This article belongs to the Special Issue Protein Structural Dynamics 2019)
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Open AccessArticle
A Molecular Dynamics Approach to Explore the Intramolecular Signal Transduction of PPAR-α
Int. J. Mol. Sci. 2019, 20(7), 1666; https://doi.org/10.3390/ijms20071666 - 03 Apr 2019
Abstract
Dynamics and functions of the peroxisome proliferator-activated receptor (PPAR)-α are modulated by the types of ligands that bind to the orthosteric sites. While several X-ray crystal structures of PPAR-α have been determined in their agonist-bound forms, detailed structural information in their apo and [...] Read more.
Dynamics and functions of the peroxisome proliferator-activated receptor (PPAR)-α are modulated by the types of ligands that bind to the orthosteric sites. While several X-ray crystal structures of PPAR-α have been determined in their agonist-bound forms, detailed structural information in their apo and antagonist-bound states are still lacking. To address these limitations, we apply unbiased molecular dynamics simulations to three different PPAR-α systems to determine their modulatory mechanisms. Herein, we performed hydrogen bond and essential dynamics analyses to identify the important residues involved in polar interactions and conformational structural variations, respectively. Furthermore, betweenness centrality network analysis was carried out to identify key residues for intramolecular signaling. The differences observed in the intramolecular signal flow between apo, agonist- and antagonist-bound forms of PPAR-α will be useful for calculating maps of information flow and identifying key residues crucial for signal transductions. The predictions derived from our analysis will be of great help to medicinal chemists in the design of effective PPAR-α modulators and additionally in understanding their regulation and signal transductions. Full article
(This article belongs to the Special Issue Protein Structural Dynamics 2019)
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Open AccessArticle
Single-Molecule Imaging and Computational Microscopy Approaches Clarify the Mechanism of the Dimerization and Membrane Interactions of Green Fluorescent Protein
Int. J. Mol. Sci. 2019, 20(6), 1410; https://doi.org/10.3390/ijms20061410 - 20 Mar 2019
Abstract
Green fluorescent protein (GFP) is widely used as a biomarker in living systems; however, GFP and its variants are prone to forming low-affinity dimers under physiological conditions. This undesirable tendency is exacerbated when fluorescent proteins (FP) are confined to membranes, fused to naturally-oligomeric [...] Read more.
Green fluorescent protein (GFP) is widely used as a biomarker in living systems; however, GFP and its variants are prone to forming low-affinity dimers under physiological conditions. This undesirable tendency is exacerbated when fluorescent proteins (FP) are confined to membranes, fused to naturally-oligomeric proteins, or expressed at high levels in cells. Oligomerization of FPs introduces artifacts into the measurement of subunit stoichiometry, as well as interactions between proteins fused to FPs. Introduction of a single mutation, A206K, has been shown to disrupt hydrophobic interactions in the region responsible for GFP dimerization, thereby contributing to its monomerization. Nevertheless, a detailed understanding of how this single amino acid-dependent inhibition of dimerization in GFP occurs at the atomic level is still lacking. Single-molecule experiments combined with computational microscopy (atomistic molecular dynamics) revealed that the amino group of A206 contributes to GFP dimer formation via a multivalent electrostatic interaction. We further showed that myristoyl modification is an efficient mechanism to promote membrane attachment of GFP. Molecular dynamics-based site-directed mutagenesis has been used to identify the key functional residues in FPs. The data presented here have been utilized as a monomeric control in downstream single-molecule studies, facilitating more accurate stoichiometry quantification of functional protein complexes in living cells. Full article
(This article belongs to the Special Issue Protein Structural Dynamics 2019)
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