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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 38398

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Prof. Dr. Yuriy F. Zuev

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Kazan Institute of Biochemistry and Biophysics of FRC Kazan Scientific Center of Rassian Academy of Sciences, 420111 Kazan, Russia
Interests: biophysics and physical chemistry of biomacromolecules, structure and functions
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Dr. Igor Sedov

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Chemical Institute, Kazan Federal University, 420008 Kazan, Russia
Interests: biophysical chemistry; computer simulations; solution thermodynamics
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Dear Colleagues,

Intermolecular interactions of naturally structured and intrinsically unstructured proteins is an important research field, which has been extensively studied for many years. Different types of specific and non-specific protein–protein interactions are involved in most biological processes. Permanently improved biophysical and computational methods provide quantitative characteristics of protein interactions and functioning. They allow assessing molecular recognition, binding affinities, molecular interaction maps, structural information including complete atomic structure of complexes, aggregate size and shape, and thermodynamic and kinetic interaction parameters. This information is crucial in unraveling protein functions, cellular or intercellular pathways and in fighting diseases. The effects of intermolecular interactions increase sharply in the crowded milieu, altering protein behavior.

The present Special Issue entitled “Recent Advances in Protein-Protein interactions” aims to highlight the research developments to the large community involved in this field. We welcome contributions in the field of protein interactions which is at the intersection of physics, biology, chemistry, and/or materials science.

Prof. Dr. Yuriy F. Zuev
Dr. Igor Sedov
Guest Editors

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Keywords

Protein–protein interactions
Protein antibodies
Interactomes
Protein complexes
Protein aggregation
Macromolecular crowding
Protein functions
Biophysical methods
Biomolecular spectroscopy
Computational methods in biology

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Published Papers (13 papers)

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Editorial

Jump to: Research, Review

3 pages, 188 KiB

Open AccessEditorial

Recent Advances in Protein–Protein Interactions

by Igor A. Sedov and Yuriy F. Zuev

Int. J. Mol. Sci. 2023, 24(2), 1282; https://doi.org/10.3390/ijms24021282 - 9 Jan 2023

Cited by 8 | Viewed by 2794

Abstract

Protein-protein interactions (PPIs) lead to formation of complexes and aggregates between a pair or multiple protein molecules [...] Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

Research

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19 pages, 3630 KiB

Open AccessArticle

The β₂-Subunit (AMOG) of Human Na⁺, K⁺-ATPase Is a Homophilic Adhesion Molecule

by María Luisa Roldán, Gema Lizbeth Ramírez-Salinas, Marlet Martinez-Archundia, Francisco Cuellar-Perez, Claudia Andrea Vilchis-Nestor, Juan Carlos Cancino-Diaz and Liora Shoshani

Int. J. Mol. Sci. 2022, 23(14), 7753; https://doi.org/10.3390/ijms23147753 - 14 Jul 2022

Cited by 4 | Viewed by 2170

Abstract

The β₂ subunit of Na⁺, K⁺-ATPase was originally identified as the adhesion molecule on glia (AMOG) that mediates the adhesion of astrocytes to neurons in the central nervous system and that is implicated in the regulation of neurite outgrowth and neuronal migration. While β₁ isoform have been shown to trans-interact in a species-specific mode with the β₁ subunit on the epithelial neighboring cell, the β₂ subunit has been shown to act as a recognition molecule on the glia. Nevertheless, none of the works have identified the binding partner of β₂ or described its adhesion mechanism. Until now, the interactions pronounced for β₂/AMOG are heterophilic cis-interactions. In the present report we designed experiments that would clarify whether β₂ is a cell–cell homophilic adhesion molecule. For this purpose, we performed protein docking analysis, cell–cell aggregation, and protein–protein interaction assays. We observed that the glycosylated extracellular domain of β₂/AMOG can make an energetically stable trans-interacting dimer. We show that CHO (Chinese Hamster Ovary) fibroblasts transfected with the human β₂ subunit become more adhesive and make large aggregates. The treatment with Tunicamycin in vivo reduced cell aggregation, suggesting the participation of N-glycans in that process. Protein–protein interaction assay in vivo with MDCK (Madin-Darby canine kidney) or CHO cells expressing a recombinant β₂ subunit show that the β₂ subunits on the cell surface of the transfected cell lines interact with each other. Overall, our results suggest that the human β₂ subunit can form trans-dimers between neighboring cells when expressed in non-astrocytic cells, such as fibroblasts (CHO) and epithelial cells (MDCK). Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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17 pages, 1801 KiB

Open AccessArticle

Network-Based Approaches for Disease-Gene Association Prediction Using Protein-Protein Interaction Networks

by Yoonbee Kim, Jong-Hoon Park and Young-Rae Cho

Int. J. Mol. Sci. 2022, 23(13), 7411; https://doi.org/10.3390/ijms23137411 - 3 Jul 2022

Cited by 19 | Viewed by 3704

Abstract

Genome-wide association studies (GWAS) can be used to infer genome intervals that are involved in genetic diseases. However, investigating a large number of putative mutations for GWAS is resource- and time-intensive. Network-based computational approaches are being used for efficient disease-gene association prediction. Network-based methods are based on the underlying assumption that the genes causing the same diseases are located close to each other in a molecular network, such as a protein-protein interaction (PPI) network. In this survey, we provide an overview of network-based disease-gene association prediction methods based on three categories: graph-theoretic algorithms, machine learning algorithms, and an integration of these two. We experimented with six selected methods to compare their prediction performance using a heterogeneous network constructed by combining a genome-wide weighted PPI network, an ontology-based disease network, and disease-gene associations. The experiment was conducted in two different settings according to the presence and absence of known disease-associated genes. The results revealed that HerGePred, an integrative method, outperformed in the presence of known disease-associated genes, whereas PRINCE, which adopted a network propagation algorithm, was the most competitive in the absence of known disease-associated genes. Overall, the results demonstrated that the integrative methods performed better than the methods using graph-theory only, and the methods using a heterogeneous network performed better than those using a homogeneous PPI network only. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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17 pages, 2292 KiB

Open AccessArticle

Structure-Functional Characteristics of the Svx Protein—The Virulence Factor of the Phytopathogenic Bacterium Pectobacterium atrosepticum

by Natalia Tendiuk, Tatiana Konnova, Olga Petrova, Elena Osipova, Timur Mukhametzyanov, Olga Makshakova and Vladimir Gorshkov

Int. J. Mol. Sci. 2022, 23(13), 6914; https://doi.org/10.3390/ijms23136914 - 21 Jun 2022

Cited by 4 | Viewed by 2460

Abstract

The Svx proteins are virulence factors of phytopathogenic bacteria of the Pectobacterium genus. The specific functions of these proteins are unknown. Here we show that most of the phytopathogenic species of Pectobacterium, Dickeya, and Xanthomonas genera have genes encoding Svx proteins, as well as some plant-non-associated species of different bacterial genera. As such, the Svx-like proteins of phytopathogenic species form a distinct clade, pointing to the directed evolution of these proteins to provide effective interactions with plants. To get a better insight into the structure and functions of the Svx proteins, we analyzed the Svx of Pectobacterium atrosepticum (Pba)—an extracellular virulence factor secreted into the host plant cell wall (PCW). Using in silico analyses and by obtaining and analyzing the recombinant Pba Svx and its mutant forms, we showed that this protein was a gluzincin metallopeptidase. The 3D structure model of the Pba Svx was built and benchmarked against the experimental overall secondary structure content. Structure-based substrate specificity analysis using molecular docking revealed that the Pba Svx substrate-binding pocket might accept α-glycosylated proteins represented in the PCW by extensins—proteins that strengthen the PCW. Thus, these results elucidate the way in which the Pba Svx may contribute to the Pba virulence. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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18 pages, 2067 KiB

Open AccessArticle

Effect of Betaine and Arginine on Interaction of αB-Crystallin with Glycogen Phosphorylase b

by Tatiana B. Eronina, Valeriya V. Mikhaylova, Natalia A. Chebotareva, Kristina V. Tugaeva and Boris I. Kurganov

Int. J. Mol. Sci. 2022, 23(7), 3816; https://doi.org/10.3390/ijms23073816 - 30 Mar 2022

Cited by 5 | Viewed by 1757

Abstract

Protein–protein interactions (PPIs) play an important role in many biological processes in a living cell. Among them chaperone–client interactions are the most important. In this work PPIs of αB-crystallin and glycogen phosphorylase b (Phb) in the presence of betaine (Bet) and arginine (Arg) at 48 °C and ionic strength of 0.15 M were studied using methods of dynamic light scattering, differential scanning calorimetry, and analytical ultracentrifugation. It was shown that Bet enhanced, while Arg reduced both the stability of αB-crystallin and its adsorption capacity (AC₀) to the target protein at the stage of aggregate growth. Thus, the anti-aggregation activity of αB-crystallin increased in the presence of Bet and decreased under the influence of Arg, which resulted in inhibition or acceleration of Phb aggregation, respectively. Our data show that chemical chaperones can influence the tertiary and quaternary structure of both the target protein and the protein chaperone. The presence of the substrate protein also affects the quaternary structure of αB-crystallin, causing its disassembly. This is inextricably linked to the anti-aggregation activity of αB-crystallin, which in turn affects its PPI with the target protein. Thus, our studies contribute to understanding the mechanism of interaction between chaperones and proteins. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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17 pages, 1564 KiB

Open AccessArticle

Complex of HIV-1 Integrase with Cellular Ku Protein: Interaction Interface and Search for Inhibitors

by Ekaterina Ilgova, Simon Galkin, Maria Khrenova, Marina Serebryakova, Marina Gottikh and Andrey Anisenko

Int. J. Mol. Sci. 2022, 23(6), 2908; https://doi.org/10.3390/ijms23062908 - 8 Mar 2022

Cited by 5 | Viewed by 2888

Abstract

The interaction of HIV-1 integrase and the cellular Ku70 protein is necessary for HIV replication due to its positive effect on post-integration DNA repair. We have previously described in detail the Ku70 binding site within integrase. However, the integrase binding site in Ku70 remained poorly characterized. Here, using a peptide fishing assay and site-directed mutagenesis, we have identified residues I72, S73, and I76 of Ku70 as key for integrase binding. The molecular dynamics studies have revealed a possible way for IN to bind to Ku70, which is consistent with experimental data. According to this model, residues I72 and I76 of Ku70 form a “leucine zipper” with integrase residues, and, therefore, their concealment by low-molecular-weight compounds should impede the Ku70 interaction with integrase. We have identified such compounds by molecular docking and have confirmed their capacity to inhibit the formation of the integrase complex with Ku70. Our data demonstrate that the site of IN binding within Ku70 identified in the present work may be used for further search for inhibitors of the integrase binding to Ku70. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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13 pages, 2282 KiB

Open AccessArticle

Refolding of Lysozyme in Glycerol as Studied by Fast Scanning Calorimetry

by Alisa Fatkhutdinova, Timur Mukhametzyanov and Christoph Schick

Int. J. Mol. Sci. 2022, 23(5), 2773; https://doi.org/10.3390/ijms23052773 - 2 Mar 2022

Cited by 7 | Viewed by 2063

Abstract

The folding of lysozyme in glycerol was monitored by the fast scanning calorimetry technique. Application of a temperature–time profile with an isothermal segment for refolding allowed assessment of the state of the non-equilibrium protein ensemble and gave information on the kinetics of folding. We found that the non-equilibrium protein ensemble mainly contains a mixture of unfolded and folded protein forms and partially folded intermediates, and enthalpic barriers control the kinetics of the process. Lysozyme folding in glycerol follows the same or similar triangular mechanism described in the literature for folding in water. The unfolding enthalpy of the intermediate must be no lower than 70% of the folded form, while the activation barrier for the unfolding of the intermediate (ca. 140 kJ/mol) is about 100 kJ/mol lower than that of the folded form (ca. 240–260 kJ/mol). Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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14 pages, 38120 KiB

Open AccessArticle

Structural and Functional Differences between Homologous Bacterial Ribonucleases

by Vera Ulyanova, Alsu Nadyrova, Elena Dudkina, Aleksandra Kuznetsova, Albina Ahmetgalieva, Dzhigangir Faizullin, Yulia Surchenko, Darya Novopashina, Yuriy Zuev, Nikita Kuznetsov and Olga Ilinskaya

Int. J. Mol. Sci. 2022, 23(3), 1867; https://doi.org/10.3390/ijms23031867 - 7 Feb 2022

Cited by 4 | Viewed by 1998

Abstract

Small cationic guanyl-preferring ribonucleases (RNases) produced by the Bacillus species share a similar protein tertiary structure with a high degree of amino acid sequence conservation. However, they form dimers that differ in conformation and stability. Here, we have addressed the issues (1) whether the homologous RNases also have distinctions in catalytic activity towards different RNA substrates and interactions with the inhibitor protein barstar, and (2) whether these differences correlate with structural features of the proteins. Circular dichroism and dynamic light scattering assays revealed distinctions in the structures of homologous RNases. The activity levels of the RNases towards natural RNA substrates, as measured spectrometrically by acid-soluble hydrolysis products, were similar and decreased in the row high-polymeric RNA >>> transport RNA > double-stranded RNA. However, stopped flow kinetic studies on model RNA substrates containing the guanosine residue in a hairpin stem or a loop showed that the cleavage rates of these enzymes were different. Moreover, homologous RNases were inhibited by the barstar with diverse efficiency. Therefore, minor changes in structure elements of homologous proteins have a potential to significantly effect molecule stability and functional activities, such as catalysis or ligand binding. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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29 pages, 1166 KiB

Open AccessArticle

Fibrosis Protein-Protein Interactions from Google Matrix Analysis of MetaCore Network

by Ekaterina Kotelnikova, Klaus M. Frahm, Dima L. Shepelyansky and Oksana Kunduzova

Int. J. Mol. Sci. 2022, 23(1), 67; https://doi.org/10.3390/ijms23010067 - 22 Dec 2021

Cited by 3 | Viewed by 3441

Abstract

Protein–protein interactions is a longstanding challenge in cardiac remodeling processes and heart failure. Here, we use the MetaCore network and the Google matrix algorithms for prediction of protein–protein interactions dictating cardiac fibrosis, a primary cause of end-stage heart failure. The developed algorithms allow identification of interactions between key proteins and predict new actors orchestrating fibroblast activation linked to fibrosis in mouse and human tissues. These data hold great promise for uncovering new therapeutic targets to limit myocardial fibrosis. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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Review

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18 pages, 2847 KiB

Open AccessReview

Effect of Protein–Protein Interactions on Translational Diffusion of Spheroidal Proteins

by Aleksandra M. Kusova, Aleksandr E. Sitnitsky, Vladimir N. Uversky and Yuriy F. Zuev

Int. J. Mol. Sci. 2022, 23(16), 9240; https://doi.org/10.3390/ijms23169240 - 17 Aug 2022

Cited by 8 | Viewed by 2376

Abstract

One of the commonly accepted approaches to estimate protein–protein interactions (PPI) in aqueous solutions is the analysis of their translational diffusion. The present review article observes a phenomenological approach to analyze PPI effects via concentration dependencies of self- and collective translational diffusion coefficient for several spheroidal proteins derived from the pulsed field gradient NMR (PFG NMR) and dynamic light scattering (DLS), respectively. These proteins are rigid globular α-chymotrypsin (ChTr) and human serum albumin (HSA), and partly disordered α-casein (α-CN) and β-lactoglobulin (β-Lg). The PPI analysis enabled us to reveal the dominance of intermolecular repulsion at low ionic strength of solution (0.003–0.01 M) for all studied proteins. The increase in the ionic strength to 0.1–1.0 M leads to the screening of protein charges, resulting in the decrease of the protein electrostatic potential. The increase of the van der Waals potential for ChTr and α-CN characterizes their propensity towards unstable weak attractive interactions. The decrease of van der Waals interactions for β-Lg is probably associated with the formation of stable oligomers by this protein. The PPI, estimated with the help of interaction potential and idealized spherical molecular geometry, are in good agreement with experimental data. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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15 pages, 1405 KiB

Open AccessReview

Microscale Thermophoresis as a Tool to Study Protein Interactions and Their Implication in Human Diseases

by Romain Magnez, Christian Bailly and Xavier Thuru

Int. J. Mol. Sci. 2022, 23(14), 7672; https://doi.org/10.3390/ijms23147672 - 12 Jul 2022

Cited by 15 | Viewed by 4784

Abstract

The review highlights how protein–protein interactions (PPIs) have determining roles in most life processes and how interactions between protein partners are involved in various human diseases. The study of PPIs and binding interactions as well as their understanding, quantification and pharmacological regulation are crucial for therapeutic purposes. Diverse computational and analytical methods, combined with high-throughput screening (HTS), have been extensively used to characterize multiple types of PPIs, but these procedures are generally laborious, long and expensive. Rapid, robust and efficient alternative methods are proposed, including the use of Microscale Thermophoresis (MST), which has emerged as the technology of choice in drug discovery programs in recent years. This review summarizes selected case studies pertaining to the use of MST to detect therapeutically pertinent proteins and highlights the biological importance of binding interactions, implicated in various human diseases. The benefits and limitations of MST to study PPIs and to identify regulators are discussed. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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18 pages, 948 KiB

Open AccessReview

Regulation by Different Types of Chaperones of Amyloid Transformation of Proteins Involved in the Development of Neurodegenerative Diseases

by Vladimir I. Muronetz, Sofia S. Kudryavtseva, Evgeniia V. Leisi, Lidia P. Kurochkina, Kseniya V. Barinova and Elena V. Schmalhausen

Int. J. Mol. Sci. 2022, 23(5), 2747; https://doi.org/10.3390/ijms23052747 - 2 Mar 2022

Cited by 5 | Viewed by 2939

Abstract

The review highlights various aspects of the influence of chaperones on amyloid proteins associated with the development of neurodegenerative diseases and includes studies conducted in our laboratory. Different sections of the article are devoted to the role of chaperones in the pathological transformation of alpha-synuclein and the prion protein. Information about the interaction of the chaperonins GroE and TRiC as well as polymer-based artificial chaperones with amyloidogenic proteins is summarized. Particular attention is paid to the effect of blocking chaperones by misfolded and amyloidogenic proteins. It was noted that the accumulation of functionally inactive chaperones blocked by misfolded proteins might cause the formation of amyloid aggregates and prevent the disassembly of fibrillar structures. Moreover, the blocking of chaperones by various forms of amyloid proteins might lead to pathological changes in the vital activity of cells due to the impaired folding of newly synthesized proteins and their subsequent processing. The final section of the article discusses both the little data on the role of gut microbiota in the propagation of synucleinopathies and prion diseases and the possible involvement of the bacterial chaperone GroE in these processes. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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17 pages, 2641 KiB

Open AccessReview

The Role of Natural Polymorphic Variants of DNA Polymerase β in DNA Repair

by Olga A. Kladova, Olga S. Fedorova and Nikita A. Kuznetsov

Int. J. Mol. Sci. 2022, 23(4), 2390; https://doi.org/10.3390/ijms23042390 - 21 Feb 2022

Cited by 13 | Viewed by 3174

Abstract

DNA polymerase β (Polβ) is considered the main repair DNA polymerase involved in the base excision repair (BER) pathway, which plays an important part in the repair of damaged DNA bases usually resulting from alkylation or oxidation. In general, BER involves consecutive actions of DNA glycosylases, AP endonucleases, DNA polymerases, and DNA ligases. It is known that protein–protein interactions of Polβ with enzymes from the BER pathway increase the efficiency of damaged base repair in DNA. However natural single-nucleotide polymorphisms can lead to a substitution of functionally significant amino acid residues and therefore affect the catalytic activity of the enzyme and the accuracy of Polβ action. Up-to-date databases contain information about more than 8000 SNPs in the gene of Polβ. This review summarizes data on the in silico prediction of the effects of Polβ SNPs on DNA repair efficacy; available data on cancers associated with SNPs of Polβ; and experimentally tested variants of Polβ. Analysis of the literature indicates that amino acid substitutions could be important for the maintenance of the native structure of Polβ and contacts with DNA; others affect the catalytic activity of the enzyme or play a part in the precise and correct attachment of the required nucleotide triphosphate. Moreover, the amino acid substitutions in Polβ can disturb interactions with enzymes involved in BER, while the enzymatic activity of the polymorphic variant may not differ significantly from that of the wild-type enzyme. Therefore, investigation regarding the effect of Polβ natural variants occurring in the human population on enzymatic activity and protein–protein interactions is an urgent scientific task. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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