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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: closed (20 December 2023) | Viewed by 17836

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Dr. Luigi Russo

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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
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Dear Colleagues,

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 connect 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, entitled “Structure, Function and Dynamics in Proteins”, 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

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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 signalling
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 (11 papers)

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Research

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16 pages, 2762 KiB

Open AccessArticle

Structural and Dynamic-Based Characterization of the Recognition Patterns of E7 and TRP-2 Epitopes by MHC Class I Receptors through Computational Approaches

by Nicole Balasco, Maria Tagliamonte, Luigi Buonaguro, Luigi Vitagliano and Antonella Paladino

Int. J. Mol. Sci. 2024, 25(3), 1384; https://doi.org/10.3390/ijms25031384 - 23 Jan 2024

Viewed by 1043

Abstract

A detailed comprehension of MHC-epitope recognition is essential for the design and development of new antigens that could be effectively used in immunotherapy. Yet, the high variability of the peptide together with the large abundance of MHC variants binding makes the process highly specific and large-scale characterizations extremely challenging by standard experimental techniques. Taking advantage of the striking predictive accuracy of AlphaFold, we report a structural and dynamic-based strategy to gain insights into the molecular basis that drives the recognition and interaction of MHC class I in the immune response triggered by pathogens and/or tumor-derived peptides. Here, we investigated at the atomic level the recognition of E7 and TRP-2 epitopes to their known receptors, thus offering a structural explanation for the different binding preferences of the studied receptors for specific residues in certain positions of the antigen sequences. Moreover, our analysis provides clues on the determinants that dictate the affinity of the same epitope with different receptors. Collectively, the data here presented indicate the reliability of the approach that can be straightforwardly extended to a large number of related systems. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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12 pages, 4987 KiB

Open AccessArticle

Analysis of the Potassium-Solubilizing Priestia megaterium Strain NK851 and Its Potassium Feldspar-Binding Proteins

by Xinyue Wu, Zijian Zhao, Zirun Zhao, Youjun Zhang, Mingchun Li and Qilin Yu

Int. J. Mol. Sci. 2023, 24(18), 14226; https://doi.org/10.3390/ijms241814226 - 18 Sep 2023

Cited by 2 | Viewed by 1559

Abstract

Potassium-solubilizing bacteria are an important microbial group that play a critical role in releasing mineral potassium from potassium-containing minerals, e.g., potassium feldspar. Their application may reduce eutrophication caused by overused potassium fertilizers and facilitate plants to utilize environmental potassium. In this study, a high-efficiency potassium-solubilizing bacterium, named NK851, was isolated from the Astragalus sinicus rhizosphere soil. This bacterium can grow in the medium with potassium feldspar as the sole potassium source, releasing 157 mg/L and 222 mg/L potassium after 3 days and 5 days of incubation, respectively. 16S rDNA sequencing and cluster analysis showed that this strain belongs to Priestia megaterium. Genome sequencing further revealed that this strain has a genome length of 5,305,142 bp, encoding 5473 genes. Among them, abundant genes are related to potassium decomposition and utilization, e.g., the genes involved in adherence to mineral potassium, potassium release, and intracellular trafficking. Moreover, the strong potassium-releasing capacity of NK851 is not attributed to the acidic pH but is attributed to the extracellular potassium feldspar-binding proteins, such as the elongation factor TU and the enolase that contains potassium feldspar-binding cavities. This study provides new information for exploration of the bacterium-mediated potassium solubilization mechanisms. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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10 pages, 8375 KiB

Open AccessArticle

Immunohistochemical Identification and Assessment of the Location of Immunoproteasome Subunits LMP2 and LMP7 in Acquired Cholesteatoma

by Justyna Rutkowska, Irena Kasacka, Marek Rogowski and Ewa Olszewska

Int. J. Mol. Sci. 2023, 24(18), 14137; https://doi.org/10.3390/ijms241814137 - 15 Sep 2023

Viewed by 815

Abstract

Cholesteatoma, accompanied by chronic inflammatory response, is characterized by invasive growth and osteolytic activity. As specific proteasome isoforms, the immunoproteasomes serve as an important modulator of inflammatory responses. The aim of the present study was to determine the biological activity of cholesteatoma through the analysis of the expression and localization of immunoproteasome subunits of low molecule weight protein (LMP) 2 and LMP7. Cholesteatoma specimens were obtained from 15 adults who underwent ear surgery due to acquired attic cholesteatoma. Normal skin specimens were taken from retro-auricular skin incisions from the same patients. The specimens were stained with anti-LMP7 antibody, using immunohistochemistry techniques based on the binding of biotinylated secondary antibody with the enzyme-labeled streptavidin and the Envision FLEX system. In all specimens of cholesteatoma, the immunohistochemical reaction with the antibody against the LMP2 was positive, in both the cytoplasm of the cholesteatoma matrix and the perimatrix. A negative reaction with anti-LMP2 was observed in the cytoplasm and nuclei of control skin cells. A positive nuclear and cytoplasmic immunohistochemical reaction with anti-LMP7 has been demonstrated in numerous cells, in both the matrix and perimatrix of cholesteatoma. We present evidence of the presence of expressions of LMP2 and LMP7 within cholesteatoma tissue. Our results might bring new information concerning immunoproteasome-dependent pathophysiologic mechanisms in cholesteatoma. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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14 pages, 4755 KiB

Open AccessCommunication

Crystal Structures of Bacterial Pectin Methylesterases Pme8A and PmeC2 from Rumen Butyrivibrio

by Vincenzo Carbone, Kerri Reilly, Carrie Sang, Linley R. Schofield, Ron S. Ronimus, William J. Kelly, Graeme T. Attwood and Nikola Palevich

Int. J. Mol. Sci. 2023, 24(18), 13738; https://doi.org/10.3390/ijms241813738 - 6 Sep 2023

Viewed by 1285

Abstract

Pectin is a complex polysaccharide that forms a substantial proportion of the plant’s middle lamella of forage ingested by grazing ruminants. Methanol in the rumen is derived mainly from methoxy groups released from pectin by the action of pectin methylesterase (PME) and is subsequently used by rumen methylotrophic methanogens that reduce methanol to produce methane (CH₄). Members of the genus Butyrivibrio are key pectin-degrading rumen bacteria that contribute to methanol formation and have important roles in fibre breakdown, protein digestion, and the biohydrogenation of fatty acids. Therefore, methanol release from pectin degradation in the rumen is a potential target for CH₄ mitigation technologies. Here, we present the crystal structures of PMEs belonging to the carbohydrate esterase family 8 (CE8) from Butyrivibrio proteoclasticus and Butyrivibrio fibrisolvens, determined to a resolution of 2.30 Å. These enzymes, like other PMEs, are right-handed β-helical proteins with a well-defined catalytic site and reaction mechanisms previously defined in insect, plant, and other bacterial pectin methylesterases. Potential substrate binding domains are also defined for the enzymes. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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20 pages, 4047 KiB

Open AccessArticle

In Silico Structural Analysis Exploring Conformational Folding of Protein Variants in Alzheimer’s Disease

by Evangelos Efraimidis, Marios G. Krokidis, Themis P. Exarchos, Tamas Lazar and Panagiotis Vlamos

Int. J. Mol. Sci. 2023, 24(17), 13543; https://doi.org/10.3390/ijms241713543 - 31 Aug 2023

Cited by 2 | Viewed by 1998

Abstract

Accurate protein structure prediction using computational methods remains a challenge in molecular biology. Recent advances in AI-powered algorithms provide a transformative effect in solving this problem. Even though AlphaFold’s performance has improved since its release, there are still limitations that apply to its efficacy. In this study, a selection of proteins related to the pathology of Alzheimer’s disease was modeled, with Presenilin-1 (PSN1) and its mutated variants in the foreground. Their structural predictions were evaluated using the ColabFold implementation of AlphaFold, which utilizes MMseqs2 for the creation of multiple sequence alignments (MSAs). A higher number of recycles than the one used in the AlphaFold DB was selected, and no templates were used. In addition, prediction by RoseTTAFold was also applied to address how structures from the two deep learning frameworks match reality. The resulting conformations were compared with the corresponding experimental structures, providing potential insights into the predictive ability of this approach in this particular group of proteins. Furthermore, a comprehensive examination was performed on features such as predicted regions of disorder and the potential effect of mutations on PSN1. Our findings consist of highly accurate superpositions with little or no deviation from experimentally determined domain-level models. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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19 pages, 8343 KiB

Open AccessArticle

Dynamics of the Apo µ-Opioid Receptor in Complex with Gi Protein

by Mira Raya Paula de Lima, Rubem Francisco Silva Bezerra, David Denis Bento Serafim and Diniz Maciel Sena Junior

Int. J. Mol. Sci. 2023, 24(17), 13430; https://doi.org/10.3390/ijms241713430 - 30 Aug 2023

Cited by 1 | Viewed by 1076

Abstract

Opioid receptors, particularly the µ-opioid receptor (μOR), play a pivotal role in mediating the analgesic and addictive effects of opioid drugs. G protein signaling is an important pathway of μOR function, usually associated with painkilling effects. However, the molecular mechanisms underlying the interaction between the μOR and G protein remain poorly understood. In this study, we employed classical all-atom molecular dynamics simulations to investigate the structural changes occurring with the μOR-G protein complex under two different conditions: with the G protein in the apo form (open) and with the GDP bound G protein (closed, holo form). The receptor was in the apo form and active conformation in both cases, and the simulation time comprised 1µs for each system. In order to assess the effect of the G protein coupling on the receptor activation state, three parameters were monitored: the correlation of the distance between TM3 and TM6 and the RMSD of the NPxxYA motif; the universal activation index (A100); and the χ² dihedral distribution of residue W293^6.48. When complexed with the open G protein, receptor conformations with intermediate activation state prevailed throughout the molecular dynamics, whereas in the condition with the closed G protein, mostly inactive conformations of the receptor were observed. The major effect of the G protein in the receptor conformation comes from a steric hindrance involving an intracellular loop of the receptor and a β-sheet region of the G protein. This suggests that G-protein precoupling is essential for receptor activation, but this fact is not sufficient for complete receptor activation. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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14 pages, 2488 KiB

Open AccessArticle

New Approach for Studying of Isoforms and High-Homology Proteins in Mammalian Cells

by Nataliya V. Soshnikova, Yuriy P. Simonov, Alexey V. Feoktistov, Alvina I. Khamidullina, Margarita A. Yastrebova, Darya O. Bayramova, Victor V. Tatarskiy and Sofia G. Georgieva

Int. J. Mol. Sci. 2023, 24(15), 12153; https://doi.org/10.3390/ijms241512153 - 29 Jul 2023

Viewed by 1206

Abstract

In mammals, a large number of proteins are expressed as more than one isoform, resulting in the increased diversity of their proteome. Understanding the functions of isoforms is very important, since individual isoforms of the same protein can have oncogenic or pathogenic properties, or serve as disease markers. The high homology of isoforms with ubiquitous expression makes it difficult to study them. In this work, we propose a new approach for the study of protein isoforms in mammalian cells, which makes it possible to individually detect and investigate the functions of an individual isoform. The approach was developed to study the functions of isoforms of the PHF10 protein, a chromatin subunit of the PBAF remodeling complex. We demonstrated the possibility of induced simultaneous suppression of all endogenous PHF10 isoforms and the expression of a single recombinant FLAG-tagged isoform. For this purpose, we created constructs based on the pSLIK plasmid with a cloned cassette containing the recombinant gene of interest and miR30 with the corresponding shRNAs. The doxycycline-induced activation of the cassette allows on and off switching. Using this construct, we achieved the preferential expression of only one recombinant PHF10 isoform with a simultaneously reduced number of all endogenous isoforms. Our approach can be used to study the role of point mutations, the functions of individual domains and important sites, or to individually detect untagged isoforms with knockdown of all endogenous isoforms. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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19 pages, 33300 KiB

Open AccessArticle

Insights into the SARS-CoV-2 ORF6 Mechanism of Action

by Elena Krachmarova, Peicho Petkov, Elena Lilkova, Nevena Ilieva, Miroslav Rangelov, Nadezhda Todorova, Kristina Malinova, Rossitsa Hristova, Genoveva Nacheva, Anastas Gospodinov and Leandar Litov

Int. J. Mol. Sci. 2023, 24(14), 11589; https://doi.org/10.3390/ijms241411589 - 18 Jul 2023

Cited by 3 | Viewed by 1805

Abstract

ORF6 is responsible for suppressing the immune response of cells infected by the SARS-CoV-2 virus. It is also the most toxic protein of SARS-CoV-2, and its actions are associated with the viral pathogenicity. Here, we study in silico and in vitro the structure of the protein, its interaction with RAE1 and the mechanism of action behind its high toxicity. We show both computationally and experimentally that SARS-CoV-2 ORF6, embedded in the cytoplasmic membranes, binds to RAE1 and sequesters it in the cytoplasm, thus depleting its availability in the nucleus and impairing nucleocytoplasmic mRNA transport. This negatively affects the cellular genome stability by compromising the cell cycle progression into the S-phase and by promoting the accumulation of RNA–DNA hybrids. Understanding the multiple ways in which ORF6 affects DNA replication may also have important implications for elucidating the pathogenicity of SARS-CoV-2 and developing therapeutic strategies to mitigate its deleterious effects on host cells. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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20 pages, 26514 KiB

Open AccessArticle

Nitazoxanide Inhibits the Bifunctional Enzyme GlG6PD::6PGL of Giardia lamblia: Biochemical and In Silico Characterization of a New Druggable Target

by Víctor Martínez-Rosas, Beatriz Hernández-Ochoa, Laura Morales-Luna, Daniel Ortega-Cuellar, Abigail González-Valdez, Roberto Arreguin-Espinosa, Yadira Rufino-González, Ernesto Calderón-Jaimes, Rosa Angélica Castillo-Rodríguez, Carlos Wong-Baeza, Isabel Baeza-Ramírez, Verónica Pérez de la Cruz, Abraham Vidal-Limón and Saúl Gómez-Manzo

Int. J. Mol. Sci. 2023, 24(14), 11516; https://doi.org/10.3390/ijms241411516 - 15 Jul 2023

Viewed by 2117

Abstract

Giardiasis, which is caused by Giardia lamblia infection, is a relevant cause of morbidity and mortality worldwide. Because no vaccines are currently available to treat giardiasis, chemotherapeutic drugs are the main options for controlling infection. Evidence has shown that the nitro drug nitazoxanide (NTZ) is a commonly prescribed treatment for giardiasis; however, the mechanisms underlying NTZ’s antigiardial activity are not well-understood. Herein, we identified the glucose-6-phosphate::6-phosphogluconate dehydrogenase (GlG6PD::6PGL) fused enzyme as a nitazoxanide target, as NTZ behaves as a GlG6PD::6PGL catalytic inhibitor. Furthermore, fluorescence assays suggest alterations in the stability of GlG6PD::6PGL protein, whereas the results indicate a loss of catalytic activity due to conformational and folding changes. Molecular docking and dynamic simulation studies suggest a model of NTZ binding on the active site of the G6PD domain and near the structural NADP⁺ binding site. The findings of this study provide a novel mechanistic basis and strategy for the antigiardial activity of the NTZ drug. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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Review

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0 pages, 698 KiB

Open AccessReview

AMPK and Beyond: The Signaling Network Controlling RabGAPs and Contraction-Mediated Glucose Uptake in Skeletal Muscle

by Leon Peifer-Weiß, Hadi Al-Hasani and Alexandra Chadt

Int. J. Mol. Sci. 2024, 25(3), 1910; https://doi.org/10.3390/ijms25031910 - 5 Feb 2024

Cited by 2 | Viewed by 1927

Abstract

Impaired skeletal muscle glucose uptake is a key feature in the development of insulin resistance and type 2 diabetes. Skeletal muscle glucose uptake can be enhanced by a variety of different stimuli, including insulin and contraction as the most prominent. In contrast to the clearance of glucose from the bloodstream in response to insulin stimulation, exercise-induced glucose uptake into skeletal muscle is unaffected during the progression of insulin resistance, placing physical activity at the center of prevention and treatment of metabolic diseases. The two Rab GTPase-activating proteins (RabGAPs), TBC1D1 and TBC1D4, represent critical nodes at the convergence of insulin- and exercise-stimulated signaling pathways, as phosphorylation of the two closely related signaling factors leads to enhanced translocation of glucose transporter 4 (GLUT4) to the plasma membrane, resulting in increased cellular glucose uptake. However, the full network of intracellular signaling pathways that control exercise-induced glucose uptake and that overlap with the insulin-stimulated pathway upstream of the RabGAPs is not fully understood. In this review, we discuss the current state of knowledge on exercise- and insulin-regulated kinases as well as hypoxia as stimulus that may be involved in the regulation of skeletal muscle glucose uptake. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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21 pages, 4528 KiB

Open AccessReview

An Overall View of the Functional and Structural Characterization of Glucose-6-Phosphate Dehydrogenase Variants in the Mexican Population

by Beatriz Hernández-Ochoa, Daniel Ortega-Cuellar, Abigail González-Valdez, Víctor Martínez-Rosas, Laura Morales-Luna, Miriam Abigail Rojas-Alarcón, Montserrat Vázquez-Bautista, Roberto Arreguin-Espinosa, Verónica Pérez de la Cruz, Rosa Angélica Castillo-Rodríguez, Luis Miguel Canseco-Ávila, Abraham Vidal-Limón and Saúl Gómez-Manzo

Int. J. Mol. Sci. 2023, 24(16), 12691; https://doi.org/10.3390/ijms241612691 - 11 Aug 2023

Cited by 2 | Viewed by 1657

Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, affecting an estimated 500 million people worldwide, is a genetic disorder that causes human enzymopathies. Biochemical and genetic studies have identified several variants that produce different ranges of phenotypes; thus, depending on its severity, this enzymopathy is classified from the mildest (Class IV) to the most severe (Class I). Therefore, understanding the correlation between the mutation sites of G6PD and the resulting phenotype greatly enhances the current knowledge of enzymopathies’ phenotypic and genotypic heterogeneity, which will assist both clinical diagnoses and personalized treatments for patients with G6PD deficiency. In this review, we analyzed and compared the structural and functional data from 21 characterized G6PD variants found in the Mexican population that we previously characterized. In order to contribute to the knowledge regarding the function and structure of the variants associated with G6PD deficiency, this review aimed to determine the molecular basis of G6PD and identify how these mutations could impact the structure, stability, and function of the enzyme and its relation with the clinical manifestations of this disease. Full article

(This article belongs to the Special Issue Structure, Function and Dynamics in Proteins)

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