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Structure, Function and Dynamics in Proteins: 2nd Edition
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Structure, Function and Dynamics in Proteins: 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 December 2024 | Viewed by 4739

Special Issue Editor

Dr. Luigi Russo

E-Mail Website
Guest Editor
Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania Luigi Vanvitelli, Via Antonio Vivaldi 43, 81100 Caserta, Italy
Interests: nuclear magnetic resonance spectroscopy; protein structure and dynamics; protein folding and misfolding; metal-binding protein; conformational equilibria; neurodegenerative diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue continues on from the previous edition, “Structure, Function and Dynamics in Proteins”.

The structure–dynamics–function relationship plays crucial roles in the biological function of proteins. High-resolution protein structures can currently be obtained from X-ray crystallography (X-ray), nuclear magnetic resonance (NMR) and cryo-electron microscopy (Cryo-EM) techniques, as well as, under certain conditions, computer molecular modeling. Sometimes, three-dimensional protein structures fail to give a complete understanding of the concerned functional mechanisms. Protein dynamics and conformational transitions, in most biological functions, are the essential link that connects high-resolution structural details with cellular processes ranging from protein folding, enzymatic catalysis to signaling, solute transport and synaptic transmission. Over the last decades, experimental techniques such as NMR relaxation, fluorescence spectroscopy, time-resolved X-ray and molecular dynamics have made substantial progress in providing an accurate description, at an atomic level, of protein dynamics on timescales of nano- and microseconds. Moreover, recent progress in the experimental and theoretical methodologies has expanded the scope of research into understanding the interplay between protein structural dynamics and functions for folded and intrinsically disordered proteins. This Special Issue of IJMS aims to make a substantial contribution to the understanding of protein structural dynamics and functional relationships by publishing innovative studies in the fields of protein structural dynamics and protein functions. We encourage researchers to submit original papers covering technical development, experimental studies on some specific proteins, clinical studies with biomolecules and theoretical research, as well as review articles relating to the topic.

Dr. Luigi Russo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protein structure and dynamics
  • protein–protein and protein–DNA interactions
  • protein folding and misfolding
  • protein aggregation processes
  • intermediate/misfolded states
  • conformational equilibria
  • DNA and ligand recognition mechanisms
  • membrane receptors
  • enzyme dynamics
  • metal-binding proteins
  • intrinsically disordered proteins
  • cell signaling
  • phase separation mechanims
  • solution- and solid-state nmr
  • molecular dynamics simulations
  • time-resolved X-ray
  • NMR relaxation
  • in-/on-cell NMR
  • Cryo-EM
  • fluorescence polarization
  • surface plasmon resonance
  • static and dynamic light scattering
  • isothermal titration calorimetry
  • microscale thermophoresis
  • protein–fragment complementation assay
  • cross-linking
  • protein microarray

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Published Papers (6 papers)

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Research

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27 pages, 3971 KiB  
Article
The Delayed Turnover of Proteasome Processing of Myocilin upon Dexamethasone Stimulation Introduces the Profiling of Trabecular Meshwork Cells’ Ubiquitylome
by Grazia Raffaella Tundo, Dario Cavaterra, Irene Pandino, Gabriele Antonio Zingale, Sara Giammaria, Alessandra Boccaccini, Manuele Michelessi, Gloria Roberti, Lucia Tanga, Carmela Carnevale, Michele Figus, Giuseppe Grasso, Massimo Coletta, Alessio Bocedi, Francesco Oddone and Diego Sbardella
Int. J. Mol. Sci. 2024, 25(18), 10017; https://doi.org/10.3390/ijms251810017 - 17 Sep 2024
Viewed by 336
Abstract
Glaucoma is chronic optic neuropathy whose pathogenesis has been associated with the altered metabolism of Trabecular Meshwork Cells, which is a cell type involved in the synthesis and remodeling of the trabecular meshwork, the main drainage pathway of the aqueous humor. Starting from [...] Read more.
Glaucoma is chronic optic neuropathy whose pathogenesis has been associated with the altered metabolism of Trabecular Meshwork Cells, which is a cell type involved in the synthesis and remodeling of the trabecular meshwork, the main drainage pathway of the aqueous humor. Starting from previous findings supporting altered ubiquitin signaling, in this study, we investigated the ubiquitin-mediated turnover of myocilin (MYOC/TIGR gene), which is a glycoprotein with a recognized role in glaucoma pathogenesis, in a human Trabecular Meshwork strain cultivated in vitro in the presence of dexamethasone. This is a validated experimental model of steroid-induced glaucoma, and myocilin upregulation by glucocorticoids is a phenotypic marker of Trabecular Meshwork strains. Western blotting and native-gel electrophoresis first uncovered that, in the presence of dexamethasone, myocilin turnover by proteasome particles was slower than in the absence of the drug. Thereafter, co-immunoprecipitation, RT-PCR and gene-silencing studies identified STUB1/CHIP as a candidate E3-ligase of myocilin. In this regard, dexamethasone treatment was found to downregulate STUB1/CHIP levels by likely promoting its proteasome-mediated turnover. Hence, to strengthen the working hypothesis about global alterations of ubiquitin-signaling, the first profiling of TMCs ubiquitylome, in the presence and absence of dexamethasone, was here undertaken by diGLY proteomics. Application of this workflow effectively highlighted a robust dysregulation of key pathways (e.g., phospholipid signaling, β-catenin, cell cycle regulation) in dexamethasone-treated Trabecular Meshwork Cells, providing an ubiquitin-centered perspective around the effect of glucocorticoids on metabolism and glaucoma pathogenesis. Full article
(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins: 2nd Edition)
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17 pages, 4451 KiB  
Article
Unfolding Mechanism and Fibril Formation Propensity of Human Prion Protein in the Presence of Molecular Crowding Agents
by Manoj Madheswaran, Nataliia Ventserova, Gianluca D’Abrosca, Giulia Salzano, Luigi Celauro, Federico Angelo Cazzaniga, Carla Isernia, Gaetano Malgieri, Fabio Moda, Luigi Russo, Giuseppe Legname and Roberto Fattorusso
Int. J. Mol. Sci. 2024, 25(18), 9916; https://doi.org/10.3390/ijms25189916 - 13 Sep 2024
Viewed by 326
Abstract
The pathological process of prion diseases implicates that the normal physiological cellular prion protein (PrPC) converts into misfolded abnormal scrapie prion (PrPSc) through post-translational modifications that increase β-sheet conformation. We recently demonstrated that HuPrP(90–231) thermal unfolding is partially irreversible [...] Read more.
The pathological process of prion diseases implicates that the normal physiological cellular prion protein (PrPC) converts into misfolded abnormal scrapie prion (PrPSc) through post-translational modifications that increase β-sheet conformation. We recently demonstrated that HuPrP(90–231) thermal unfolding is partially irreversible and characterized by an intermediate state (β-PrPI), which has been revealed to be involved in the initial stages of PrPC fibrillation, with a seeding activity comparable to that of human infectious prions. In this study, we report the thermal unfolding characterization, in cell-mimicking conditions, of the truncated (HuPrP(90–231)) and full-length (HuPrP(23–231)) human prion protein by means of CD and NMR spectroscopy, revealing that HuPrP(90–231) thermal unfolding is characterized by two successive transitions, as in buffer solution. The amyloidogenic propensity of HuPrP(90–231) under crowded conditions has also been investigated. Our findings show that although the prion intermediate, structurally very similar to β-PrPI, forms at a lower temperature compared to when it is dissolved in buffer solution, in cell-mimicking conditions, the formation of prion fibrils requires a longer incubation time, outlining how molecular crowding influences both the equilibrium states of PrP and its kinetic pathways of folding and aggregation. Full article
(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins: 2nd Edition)
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19 pages, 8891 KiB  
Article
NMR Dynamic View of the Stabilization of the WW4 Domain by Neutral NaCl and Kosmotropic Na2SO4 and NaH2PO4
by Liang-Zhong Lim and Jianxing Song
Int. J. Mol. Sci. 2024, 25(16), 9091; https://doi.org/10.3390/ijms25169091 - 22 Aug 2024
Viewed by 386
Abstract
The Hofmeister series categorizes ions based on their effects on protein stability, yet the microscopic mechanism remains a mystery. In this series, NaCl is neutral, Na2SO4 and Na2HPO4 are kosmotropic, while GdmCl and NaSCN are chaotropic. This [...] Read more.
The Hofmeister series categorizes ions based on their effects on protein stability, yet the microscopic mechanism remains a mystery. In this series, NaCl is neutral, Na2SO4 and Na2HPO4 are kosmotropic, while GdmCl and NaSCN are chaotropic. This study employs CD and NMR to investigate the effects of NaCl, Na2SO4, and Na2HPO4 on the conformation, stability, binding, and backbone dynamics (ps-ns and µs-ms time scales) of the WW4 domain with a high stability and accessible side chains at concentrations ≤ 200 mM. The results indicated that none of the three salts altered the conformation of WW4 or showed significant binding to the four aliphatic hydrophobic side chains. NaCl had no effect on its thermal stability, while Na2SO4 and Na2HPO4 enhanced the stability by ~5 °C. Interestingly, NaCl only weakly interacted with the Arg27 amide proton, whereas Na2SO4 bound to Arg27 and Phe31 amide protons with Kd of 32.7 and 41.6 mM, respectively. Na2HPO4, however, bound in a non-saturable manner to Trp9, His24, and Asn36 amide protons. While the three salts had negligible effects on ps-ns backbone dynamics, NaCl and Na2SO4 displayed no effect while Na2HPO4 significantly increased the µs-ms backbone dynamics. These findings, combined with our recent results with GdmCl and NaSCN, suggest a microscopic mechanism for the Hofmeister series. Additionally, the data revealed a lack of simple correlation between thermodynamic stability and backbone dynamics, most likely due to enthalpy–entropy compensation. Our study rationalizes the selection of chloride and phosphate as the primary anions in extracellular and intracellular spaces, as well as polyphosphate as a primitive chaperone in certain single-cell organisms. Full article
(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins: 2nd Edition)
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19 pages, 6270 KiB  
Article
A Comparative Analysis of SARS-CoV-2 Variants of Concern (VOC) Spike Proteins Interacting with hACE2 Enzyme
by Jiawei Chen, Lingtao Chen, Heng Quan, Soongoo Lee, Kaniz Fatama Khan, Ying Xie, Qiaomu Li, Maria Valero, Zhiyu Dai and Yixin Xie
Int. J. Mol. Sci. 2024, 25(15), 8032; https://doi.org/10.3390/ijms25158032 - 23 Jul 2024
Viewed by 702
Abstract
In late 2019, the emergence of a novel coronavirus led to its identification as SARS-CoV-2, precipitating the onset of the COVID-19 pandemic. Many experimental and computational studies were performed on SARS-CoV-2 to understand its behavior and patterns. In this research, Molecular Dynamic (MD) [...] Read more.
In late 2019, the emergence of a novel coronavirus led to its identification as SARS-CoV-2, precipitating the onset of the COVID-19 pandemic. Many experimental and computational studies were performed on SARS-CoV-2 to understand its behavior and patterns. In this research, Molecular Dynamic (MD) simulation is utilized to compare the behaviors of SARS-CoV-2 and its Variants of Concern (VOC)-Alpha, Beta, Gamma, Delta, and Omicron-with the hACE2 protein. Protein structures from the Protein Data Bank (PDB) were aligned and trimmed for consistency using Chimera, focusing on the receptor-binding domain (RBD) responsible for ACE2 interaction. MD simulations were performed using Visual Molecular Dynamics (VMD) and Nanoscale Molecular Dynamics (NAMD2), and salt bridges and hydrogen bond data were extracted from the results of these simulations. The data extracted from the last 5 ns of the 10 ns simulations were visualized, providing insights into the comparative stability of each variant’s interaction with ACE2. Moreover, electrostatics and hydrophobic protein surfaces were calculated, visualized, and analyzed. Our comprehensive computational results are helpful for drug discovery and future vaccine designs as they provide information regarding the vital amino acids in protein-protein interactions (PPIs). Our analysis reveals that the Original and Omicron variants are the two most structurally similar proteins. The Gamma variant forms the strongest interaction with hACE2 through hydrogen bonds, while Alpha and Delta form the most stable salt bridges; the Omicron is dominated by positive potential in the binding site, which makes it easy to attract the hACE2 receptor; meanwhile, the Original, Beta, Delta, and Omicron variants show varying levels of interaction stability through both hydrogen bonds and salt bridges, indicating that targeted therapeutic agents can disrupt these critical interactions to prevent SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins: 2nd Edition)
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18 pages, 3499 KiB  
Article
NMR Dynamic View of the Destabilization of WW4 Domain by Chaotropic GdmCl and NaSCN
by Liang-Zhong Lim and Jianxing Song
Int. J. Mol. Sci. 2024, 25(13), 7344; https://doi.org/10.3390/ijms25137344 - 4 Jul 2024
Cited by 1 | Viewed by 529
Abstract
GdmCl and NaSCN are two strong chaotropic salts commonly used in protein folding and stability studies, but their microscopic mechanisms remain enigmatic. Here, by CD and NMR, we investigated their effects on conformations, stability, binding and backbone dynamics on ps-ns and µs-ms time [...] Read more.
GdmCl and NaSCN are two strong chaotropic salts commonly used in protein folding and stability studies, but their microscopic mechanisms remain enigmatic. Here, by CD and NMR, we investigated their effects on conformations, stability, binding and backbone dynamics on ps-ns and µs-ms time scales of a 39-residue but well-folded WW4 domain at salt concentrations ≤200 mM. Up to 200 mM, both denaturants did not alter the tertiary packing of WW4, but GdmCl exerted more severe destabilization than NaSCN. Intriguingly, GdmCl had only weak binding to amide protons, while NaSCN showed extensive binding to both hydrophobic side chains and amide protons. Neither denaturant significantly affected the overall ps-ns backbone dynamics, but they distinctively altered µs-ms backbone dynamics. This study unveils that GdmCl and NaSCN destabilize a protein before the global unfolding occurs with differential binding properties and µs-ms backbone dynamics, implying the absence of a simple correlation between thermodynamic stability and backbone dynamics of WW4 at both ps-ns and µs-ms time scales. Full article
(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins: 2nd Edition)
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Review

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18 pages, 2526 KiB  
Review
Emerging Roles of B56 Phosphorylation and Binding Motif in PP2A-B56 Holoenzyme Biological Function
by Yanqiao Zhang, Haonan Jiang, Haimeng Yin, Xinyuan Zhao and Yali Zhang
Int. J. Mol. Sci. 2024, 25(6), 3185; https://doi.org/10.3390/ijms25063185 - 10 Mar 2024
Viewed by 1388
Abstract
Protein serine/threonine phosphatase 2A (PP2A) regulates diverse cellular processes via the formation of ~100 heterotrimeric holoenzymes. However, a scarcity of knowledge on substrate recognition by various PP2A holoenzymes has greatly prevented the deciphering of PP2A function in phosphorylation-mediated signaling in eukaryotes. The review [...] Read more.
Protein serine/threonine phosphatase 2A (PP2A) regulates diverse cellular processes via the formation of ~100 heterotrimeric holoenzymes. However, a scarcity of knowledge on substrate recognition by various PP2A holoenzymes has greatly prevented the deciphering of PP2A function in phosphorylation-mediated signaling in eukaryotes. The review summarized the contribution of B56 phosphorylation to PP2A-B56 function and proposed strategies for intervening B56 phosphorylation to treat diseases associated with PP2A-B56 dysfunction; it especially analyzed recent advancements in LxxIxEx B56-binding motifs that provide the molecular details of PP2A-B56 binding specificity and, on this basis, explored the emerging role of PP2A-B56 in the mitosis process, virus attack, and cancer development through LxxIxE motif-mediated PP2A-B56 targeting. This review provides theoretical support for discriminatingly targeting specific PP2A holoenzymes to guide PP2A activity against specific pathogenic drivers. Full article
(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins: 2nd Edition)
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