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Protein Structure Research 2024

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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 November 2024 | Viewed by 12202

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Special Issue Editors

Prof. Dr. Istvan Simon

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Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network, 1117 Budapest, Hungary
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
* We dedicate the memory of the editor, Prof. Dr. Istvan Simon, who passed away during this special issue period.
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Dr. Csaba Magyar

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Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, 1117 Budapest, Hungary
Interests: protein bioinformatics; protein stability; intrinsically disordered proteins; protein structure; protein structure modeling; protein dynamics; molecular dynamics simulation; protein conformation; computational structural biology; structural bioinformatics; drug design; structure based drug design
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Special Issue Information

Dear Colleagues,

In recent years, new frontiers have opened up in protein structure research. Besides the traditional forms of proteins, such as folded water-soluble proteins, transmembrane- and membrane-associated proteins, and disordered proteins which are able to fold on the surface of folded proteins or other stable mac romolecules, new forms of proteins and protein complexes have emerged. Among others, fuzzy complexes in which, during physiological function, at least one protein component is still in disordered form; and mutual synergistic folding complexes, in which two or more disordered proteins help each other to fold, are new subclasses of proteins. Combinations of the above-mentioned proteins, such as partially disordered proteins or proteins participating in liquid–liquid phase separation, represent new forms of proteins. These all encompass new and interesting fields of protein structure research.

As the guest editors of this Special Issue of IJMS titled “Protein Structure Research 2024”, we would like to invite you to contribute a paper related to protein structures.

Prof. Dr. Istvan Simon
Dr. Csaba Magyar
Guest Editors

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Keywords

fuzzy complexes
intrinsically disordered proteins
liquid-liquid phase separation
mutual synergistic folding
protein folding
protein structure
protein-protein interactions
transmembrane proteins

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Published Papers (9 papers)

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Research

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17 pages, 3167 KiB

Open AccessArticle

Prediction of Protein Secondary Structures Based on Substructural Descriptors of Molecular Fragments

by Oleg S. Zakharov, Anastasia V. Rudik, Dmitry A. Filimonov and Alexey A. Lagunin

Int. J. Mol. Sci. 2024, 25(23), 12525; https://doi.org/10.3390/ijms252312525 - 21 Nov 2024

Viewed by 420

Abstract

The accurate prediction of secondary structures of proteins (SSPs) is a critical challenge in molecular biology and structural bioinformatics. Despite recent advancements, this task remains complex and demands further exploration. This study presents a novel approach to SSP prediction using atom-centric substructural multilevel neighborhoods of atoms (MNA) descriptors for protein molecular fragments. A dataset comprising over 335,000 SSPs, annotated by the Dictionary of Secondary Structure in Proteins (DSSP) software from 37,000 proteins, was constructed from Protein Data Bank (PDB) records with a resolution of 2 Å or better. Protein fragments were converted into structural formulae using the RDKit Python package and stored in SD files using the MOL V3000 format. Classification sequence–structure–property relationships (SSPR) models were developed with varying levels of MNA descriptors and a Bayesian algorithm implemented in MultiPASS software. The average prediction accuracy (AUC) for eight SSP types, calculated via leave-one-out cross-validation, was 0.902. For independent test sets (ASTRAL and CB513 datasets), the best SSPR models achieved AUC, Q3, and Q8 values of 0.860, 77.32%, 70.92% and 0.889, 78.78%, 74.74%, respectively. Based on the created models, a freely available web application MNA-PSS-Pred was developed. Full article

(This article belongs to the Special Issue Protein Structure Research 2024)

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14 pages, 3275 KiB

Open AccessArticle

Structural Catalytic Core in Subtilisin-like Proteins and Its Comparison to Trypsin-like Serine Proteases and Alpha/Beta-Hydrolases

by Alexander I. Denesyuk, Konstantin Denessiouk, Mark S. Johnson and Vladimir N. Uversky

Int. J. Mol. Sci. 2024, 25(22), 11858; https://doi.org/10.3390/ijms252211858 - 5 Nov 2024

Viewed by 423

Abstract

Subtilisin-like proteins are serine proteases that use two types of catalytic triads: Ser-His-Asp and Ser-Glu-Asp. Here, we investigate the two known families of subtilisin-like proteins, the subtilases (Ser-His-Asp triad) and the serine-carboxyl proteinases (Ser-Glu-Asp triad), and describe the local structural arrangements (cores) that govern the catalytic residues in these proteins. We show the separation of the cores into conserved structural zones, which can be repeatedly found in different structures, and compare the structural cores in subtilisin-like proteins with those in trypsin-like serine proteases and alpha/beta-hydrolases. Full article

(This article belongs to the Special Issue Protein Structure Research 2024)

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26 pages, 4428 KiB

Open AccessArticle

Modular Structure and Polymerization Status of GABA_A Receptors Illustrated with EM Analysis and AlphaFold2 Prediction

by Chloe Kan, Ata Ullah, Shangyu Dang and Hong Xue

Int. J. Mol. Sci. 2024, 25(18), 10142; https://doi.org/10.3390/ijms251810142 - 21 Sep 2024

Viewed by 880

Abstract

Type-A γ-aminobutyric acid (GABA_A) receptors are channel proteins crucial to mediating neuronal balance in the central nervous system (CNS). The structure of GABA_A receptors allows for multiple binding sites and is key to drug development. Yet the formation mechanism of the receptor’s distinctive pentameric structure is still unknown. This study aims to investigate the role of three predominant subunits of the human GABA_A receptor in the formation of protein pentamers. Through purifying and refolding the protein fragments of the GABA_A receptor α1, β2, and γ2 subunits, the particle structures were visualised with negative staining electron microscopy (EM). To aid the analysis, AlphaFold2 was used to compare the structures. Results show that α1 and β2 subunit fragments successfully formed homo-oligomers, particularly homopentameric structures, while the predominant heteropentameric GABA_A receptor was also replicated through the combination of the three subunits. However, homopentameric structures were not observed with the γ2 subunit proteins. A comparison of the AlphaFold2 predictions and the previously obtained cryo-EM structures presents new insights into the subunits’ modular structure and polymerization status. By performing experimental and computational studies, a deeper understanding of the complex structure of GABA_A receptors is provided. Hopefully, this study can pave the way to developing novel therapeutics for neuropsychiatric diseases. Full article

(This article belongs to the Special Issue Protein Structure Research 2024)

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15 pages, 2512 KiB

Open AccessArticle

Protein Microarrays for High Throughput Hydrogen/Deuterium Exchange Monitored by FTIR Imaging

by Joëlle De Meutter and Erik Goormaghtigh

Int. J. Mol. Sci. 2024, 25(18), 9989; https://doi.org/10.3390/ijms25189989 - 16 Sep 2024

Viewed by 659

Abstract

Proteins form the fastest-growing therapeutic class. Due to their intrinsic instability, loss of native structure is common. Structure alteration must be carefully evaluated as structural changes may jeopardize the efficiency and safety of the protein-based drugs. Hydrogen deuterium exchange (HDX) has long been used to evaluate protein structure and dynamics. The rate of exchange constitutes a sensitive marker of the conformational state of the protein and of its stability. It is often monitored by mass spectrometry. Fourier transform infrared (FTIR) spectroscopy is another method with very promising capabilities. Combining protein microarrays with FTIR imaging resulted in high throughput HDX FTIR measurements. BaF₂ slides bearing the protein microarrays were covered by another slide separated by a spacer, allowing us to flush the cell continuously with a flow of N₂ gas saturated with ²H₂O. Exchange occurred simultaneously for all proteins and single images covering ca. 96 spots of proteins that could be recorded on-line at selected time points. Each protein spot contained ca. 5 ng protein, and the entire array covered 2.5 × 2.5 mm². Furthermore, HDX could be monitored in real time, and the experiment was therefore not subject to back-exchange problems. Analysis of HDX curves by inverse Laplace transform and by fitting exponential curves indicated that quantitative comparison of the samples is feasible. The paper also demonstrates how the whole process of analysis can be automatized to yield fast analyses. Full article

(This article belongs to the Special Issue Protein Structure Research 2024)

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17 pages, 3517 KiB

Open AccessArticle

Exploring the Structurally Conserved Regions and Functional Significance in Bacterial N-Terminal Nucleophile (Ntn) Amide-Hydrolases

by Israel Quiroga, Juan Andrés Hernández-González, Elizabeth Bautista-Rodríguez and Alfredo C. Benítez-Rojas

Int. J. Mol. Sci. 2024, 25(13), 6850; https://doi.org/10.3390/ijms25136850 - 21 Jun 2024

Viewed by 1546

Abstract

The initial adoption of penicillin as an antibiotic marked the start of exploring other compounds essential for pharmaceuticals, yet resistance to penicillins and their side effects has compromised their efficacy. The N-terminal nucleophile (Ntn) amide-hydrolases S45 family plays a key role in catalyzing amide bond hydrolysis in various compounds, including antibiotics like penicillin and cephalosporin. This study comprehensively analyzes the structural and functional traits of the bacterial N-terminal nucleophile (Ntn) amide-hydrolases S45 family, covering penicillin G acylases, cephalosporin acylases, and D-succinylase. Utilizing structural bioinformatics tools and sequence analysis, the investigation delineates structurally conserved regions (SCRs) and substrate binding site variations among these enzymes. Notably, sixteen SCRs crucial for substrate interaction are identified solely through sequence analysis, emphasizing the significance of sequence data in characterizing functionally relevant regions. These findings introduce a novel approach for identifying targets to enhance the biocatalytic properties of N-terminal nucleophile (Ntn) amide-hydrolases, while facilitating the development of more accurate three-dimensional models, particularly for enzymes lacking structural data. Overall, this research advances our understanding of structure–function relationships in bacterial N-terminal nucleophile (Ntn) amide-hydrolases, providing insights into strategies for optimizing their enzymatic capabilities. Full article

(This article belongs to the Special Issue Protein Structure Research 2024)

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16 pages, 3619 KiB

Open AccessArticle

Channel Formation in Cry Toxins: An Alphafold-2 Perspective

by Jaume Torres, Wahyu Surya and Panadda Boonserm

Int. J. Mol. Sci. 2023, 24(23), 16809; https://doi.org/10.3390/ijms242316809 - 27 Nov 2023

Cited by 1 | Viewed by 1434

Abstract

Bacillus thuringiensis (Bt) strains produce pore-forming toxins (PFTs) that attack insect pests. Information for pre-pore and pore structures of some of these Bt toxins is available. However, for the three-domain (I-III) crystal (Cry) toxins, the most used Bt toxins in pest control, this crucial information is still missing. In these Cry toxins, biochemical data have shown that 7-helix domain I is involved in insertion in membranes, oligomerization and formation of a channel lined mainly by helix α4, whereas helices α1 to α3 seem to have a dynamic role during insertion. In the case of Cry1Aa, toxic against Manduca sexta larvae, a tetrameric oligomer seems to precede membrane insertion. Given the experimental difficulty in the elucidation of the membrane insertion steps, we used Alphafold-2 (AF2) to shed light on possible oligomeric structural intermediates in the membrane insertion of this toxin. AF2 very accurately (<1 Å RMSD) predicted the crystal monomeric and trimeric structures of Cry1Aa and Cry4Ba. The prediction of a tetramer of Cry1Aa, but not Cry4Ba, produced an ‘extended model’ where domain I helices α3 and α2b form a continuous helix and where hydrophobic helices α1 and α2 cluster at the tip of the bundle. We hypothesize that this represents an intermediate that binds the membrane and precedes α4/α5 hairpin insertion, together with helices α6 and α7. Another Cry1Aa tetrameric model was predicted after deleting helices α1 to α3, where domain I produced a central cavity consistent with an ion channel, lined by polar and charged residues in helix α4. We propose that this second model corresponds to the ‘membrane-inserted’ structure. AF2 also predicted larger α4/α5 hairpin n-mers (14 ≤n ≤ 17) with high confidence, which formed even larger (~5 nm) pores. The plausibility of these models is discussed in the context of available experimental data and current paradigms. Full article

(This article belongs to the Special Issue Protein Structure Research 2024)

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20 pages, 3694 KiB

Open AccessArticle

The Intrinsically Disordered N Terminus in Atg12 from Yeast Is Necessary for the Functional Structure of the Protein

by Hana Popelka, Vikramjit Lahiri, Wayne D. Hawkins, Felipe da Veiga Leprevost, Alexey I. Nesvizhskii and Daniel J. Klionsky

Int. J. Mol. Sci. 2023, 24(20), 15036; https://doi.org/10.3390/ijms242015036 - 10 Oct 2023

Cited by 1 | Viewed by 1539

Abstract

The Atg12 protein in yeast is an indispensable polypeptide in the highly conserved ubiquitin-like conjugation system operating in the macroautophagy/autophagy pathway. Atg12 is covalently conjugated to Atg5 through the action of Atg7 and Atg10; the Atg12–Atg5 conjugate binds Atg16 to form an E3 ligase that functions in a separate conjugation pathway involving Atg8. Atg12 is comprised of a ubiquitin-like (UBL) domain preceded at the N terminus by an intrinsically disordered protein region (IDPR), a domain that comprises a major portion of the protein but remains elusive in its conformation and function. Here, we show that the IDPR in unconjugated Atg12 is positioned in proximity to the UBL domain, a configuration that is important for the functional structure of the protein. A major deletion in the IDPR disrupts intactness of the UBL domain at the unconjugated C terminus, and a mutation in the predicted α0 helix in the IDPR prevents Atg12 from binding to Atg7 and Atg10, which ultimately affects the protein function in the ubiquitin-like conjugation cascade. These findings provide evidence that the IDPR is an indispensable part of the Atg12 protein from yeast. Full article

(This article belongs to the Special Issue Protein Structure Research 2024)

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Review

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17 pages, 1710 KiB

Open AccessReview

Could Targeting NPM1c+ Misfolding Be a Promising Strategy for Combating Acute Myeloid Leukemia?

by Daniele Florio and Daniela Marasco

Int. J. Mol. Sci. 2024, 25(2), 811; https://doi.org/10.3390/ijms25020811 - 9 Jan 2024

Cited by 1 | Viewed by 1826

Abstract

Acute myeloid leukemia (AML) is a heterogeneous group of diseases classified into various types on the basis of distinct features concerning the morphology, cytochemistry and cytogenesis of leukemic cells. Among the different subtypes, the group “AML with gene mutations” includes the variations of the gene of the multifunctional protein nucleophosmin 1 (NPM1). These mutations are the most frequent (~30–35% of AML adult patients and less in pediatric ones) and occur predominantly in the C-terminal domain (CTD) of NPM1. The most important mutation is the insertion at W288, which determines the frame shift W288Cfs12/Ffs12/Lfs*12 and leads to the addition of 2–12 amino acids, which hamper the correct folding of NPM1. This mutation leads to the loss of the nuclear localization signal (NoLS) and to aberrant cytoplasmic localization, denoted as NPM1c+. Many investigations demonstrated that interfering with the cellular location and oligomerization status of NPM1 can influence its biological functions, including the proper buildup of the nucleolus, and therapeutic strategies have been proposed to target NPM1c+, particularly the use of drugs able to re-direct NPM1 localization. Our studies unveiled a direct link between AML mutations and the neat amyloidogenic character of the CTDs of NPM1c+. Herein, with the aim of exploiting these conformational features, novel therapeutic strategies are proposed that rely on the induction of the selective self-cytotoxicity of leukemic blasts by focusing on agents such as peptides, peptoids or small molecules able to enhance amyloid aggregation and targeting selectively AML–NPM1c+ mutations. Full article

(This article belongs to the Special Issue Protein Structure Research 2024)

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25 pages, 5971 KiB

Open AccessReview

Analyzing Current Trends and Possible Strategies to Improve Sucrose Isomerases’ Thermostability

by Amado Javier Sardiña-Peña, Liber Mesa-Ramos, Blanca Flor Iglesias-Figueroa, Lourdes Ballinas-Casarrubias, Tania Samanta Siqueiros-Cendón, Edward Alexander Espinoza-Sánchez, Norma Rosario Flores-Holguín, Sigifredo Arévalo-Gallegos and Quintín Rascón-Cruz

Int. J. Mol. Sci. 2023, 24(19), 14513; https://doi.org/10.3390/ijms241914513 - 25 Sep 2023

Viewed by 1971

Abstract

Due to their ability to produce isomaltulose, sucrose isomerases are enzymes that have caught the attention of researchers and entrepreneurs since the 1950s. However, their low activity and stability at temperatures above 40 °C have been a bottleneck for their industrial application. Specifically, the instability of these enzymes has been a challenge when it comes to their use for the synthesis and manufacturing of chemicals on a practical scale. This is because industrial processes often require biocatalysts that can withstand harsh reaction conditions, like high temperatures. Since the 1980s, there have been significant advancements in the thermal stabilization engineering of enzymes. Based on the literature from the past few decades and the latest achievements in protein engineering, this article systematically describes the strategies used to enhance the thermal stability of sucrose isomerases. Additionally, from a theoretical perspective, we discuss other potential mechanisms that could be used for this purpose. Full article

(This article belongs to the Special Issue Protein Structure Research 2024)

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