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Advances in Protein-Protein Interactions 2.0
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Advances in Protein-Protein Interactions 2.0

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

Deadline for manuscript submissions: 31 July 2024 | Viewed by 6390

Special Issue Editor

Dr. Jessica Holien

E-Mail Website
Guest Editor
Biosciences and Food Technology, School of Science, College of Science, Engineering and Health, RMIT University, Melbourne, VIC 3053, Australia
Interests: drug discovery; protein-protein interactions; structural bioinformatics; molecular modelling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There are over 300,000 protein–protein interaction (PPI) pairs identified in the human genome. Thus, it is not surprising that modulators of PPIs—ideally small “drug-like” molecules—are urgently being sought and developed by the pharmaceutical industry to address the unmet medical needs. However, the physical characteristics of the PPI interface make this task non-trivial. Furthermore, unlike the traditional pharmaceutical approach of focusing on finding a ‘single switch that works’, it is clear that the phenotype of many diseases relies on complex networks of PPIs. Destabilising these networks for a successful therapeutic approach will require perturbing multiple key interactions.

This Special Issue focuses on recent studies aiming to investigate protien–protein interactions, with an additional aim of developing drugs to modulate these interactions. Specifically, this Special Issue will explore the latest computational and structural biology methods, and studies that further our understanding of protein– protein interfaces and how to better develop molecules to modulate these are welcomed.

Dr. Jessica Holien
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–protein interactions
  • structural biology
  • bioinformatics
  • network analysis
  • drug design
  • drug development
  • computational drug design
  • protein–ligand interactions
  • target identification

Related Special Issue

Published Papers (7 papers)

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Research

17 pages, 1230 KiB  
Article
Studies on the PII-PipX-NtcA Regulatory Axis of Cyanobacteria Provide Novel Insights into the Advantages and Limitations of Two-Hybrid Systems for Protein Interactions
by Paloma Salinas, Sirine Bibak, Raquel Cantos, Lorena Tremiño, Carmen Jerez, Trinidad Mata-Balaguer and Asunción Contreras
Int. J. Mol. Sci. 2024, 25(10), 5429; https://doi.org/10.3390/ijms25105429 - 16 May 2024
Viewed by 217
Abstract
Yeast two-hybrid approaches, which are based on fusion proteins that must co-localise to the nucleus to reconstitute the transcriptional activity of GAL4, have greatly contributed to our understanding of the nitrogen interaction network of cyanobacteria, the main hubs of which are the trimeric [...] Read more.
Yeast two-hybrid approaches, which are based on fusion proteins that must co-localise to the nucleus to reconstitute the transcriptional activity of GAL4, have greatly contributed to our understanding of the nitrogen interaction network of cyanobacteria, the main hubs of which are the trimeric PII and the monomeric PipX regulators. The bacterial two-hybrid system, based on the reconstitution in the E. coli cytoplasm of the adenylate cyclase of Bordetella pertussis, should provide a relatively faster and presumably more physiological assay for cyanobacterial proteins than the yeast system. Here, we used the bacterial two-hybrid system to gain additional insights into the cyanobacterial PipX interaction network while simultaneously assessing the advantages and limitations of the two most popular two-hybrid systems. A comprehensive mutational analysis of PipX and bacterial two-hybrid assays were performed to compare the outcomes between yeast and bacterial systems. We detected interactions that were previously recorded in the yeast two-hybrid system as negative, as well as a “false positive”, the self-interaction of PipX, which is rather an indirect interaction that is dependent on PII homologues from the E. coli host, a result confirmed by Western blot analysis with relevant PipX variants. This is, to our knowledge, the first report of the molecular basis of a false positive in the bacterial two-hybrid system. Full article
(This article belongs to the Special Issue Advances in Protein-Protein Interactions 2.0)
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17 pages, 2284 KiB  
Article
Analysing the Cyanobacterial PipX Interaction Network Using NanoBiT Complementation in Synechococcus elongatus PCC7942
by Carmen Jerez, Antonio Llop, Paloma Salinas, Sirine Bibak, Karl Forchhammer and Asunción Contreras
Int. J. Mol. Sci. 2024, 25(9), 4702; https://doi.org/10.3390/ijms25094702 - 25 Apr 2024
Viewed by 565
Abstract
The conserved cyanobacterial protein PipX is part of a complex interaction network with regulators involved in essential processes that include metabolic homeostasis and ribosome assembly. Because PipX interactions depend on the relative levels of their different partners and of the effector molecules binding [...] Read more.
The conserved cyanobacterial protein PipX is part of a complex interaction network with regulators involved in essential processes that include metabolic homeostasis and ribosome assembly. Because PipX interactions depend on the relative levels of their different partners and of the effector molecules binding to them, in vivo studies are required to understand the physiological significance and contribution of environmental factors to the regulation of PipX complexes. Here, we have used the NanoBiT complementation system to analyse the regulation of complex formation in Synechococcus elongatus PCC 7942 between PipX and each of its two best-characterized partners, PII and NtcA. Our results confirm previous in vitro analyses on the regulation of PipX-PII and PipX-NtcA complexes by 2-oxoglutarate and on the regulation of PipX-PII by the ATP/ADP ratio, showing the disruption of PipX-NtcA complexes due to increased levels of ADP-bound PII in Synechococcus elongatus. The demonstration of a positive role of PII on PipX-NtcA complexes during their initial response to nitrogen starvation or the impact of a PipX point mutation on the activity of PipX-PII and PipX-NtcA reporters are further indications of the sensitivity of the system. This study reveals additional regulatory complexities in the PipX interaction network, opening a path for future research on cyanobacteria. Full article
(This article belongs to the Special Issue Advances in Protein-Protein Interactions 2.0)
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14 pages, 1725 KiB  
Article
In Vivo Detection of Metabolic Fluctuations in Real Time Using the NanoBiT Technology Based on PII Signalling Protein Interactions
by Rokhsareh Rozbeh and Karl Forchhammer
Int. J. Mol. Sci. 2024, 25(6), 3409; https://doi.org/10.3390/ijms25063409 - 17 Mar 2024
Cited by 1 | Viewed by 798
Abstract
New protein-fragment complementation assays (PCA) have successfully been developed to characterize protein–protein interactions in vitro and in vivo. Notably, the NanoBiT technology, employing fragment complementation of NanoLuc luciferase, stands out for its high sensitivity, wide dynamic range, and straightforward read out. Previously, we [...] Read more.
New protein-fragment complementation assays (PCA) have successfully been developed to characterize protein–protein interactions in vitro and in vivo. Notably, the NanoBiT technology, employing fragment complementation of NanoLuc luciferase, stands out for its high sensitivity, wide dynamic range, and straightforward read out. Previously, we explored the in vitro protein interaction dynamics of the PII signalling protein using NanoBiT, revealing significant modulation of luminescence signals generated by the interaction between PII and its receptor protein NAGK by 2-oxoglutarate levels. In the current work, we investigated this technology in vivo, to find out whether recombinantly expressed NanoBiT constructs using the NanoLuc large fragment fused to PII and PII-interaction partners NAGK or PipX-fused to the NanoLuc Small BiT are capable of detecting the metabolic fluctuations in Escherichia coli. Therefore, we devised an assay capable of capturing the metabolic responses of E. coli cells, demonstrating real-time metabolic perturbation upon nitrogen upshift or depletion treatments. In particular, the PII-NAGK NanoBitT sensor pair reported these changes in a highly sensitive manner. Full article
(This article belongs to the Special Issue Advances in Protein-Protein Interactions 2.0)
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11 pages, 2417 KiB  
Communication
Structured Tandem Repeats in Protein Interactions
by Juan Mac Donagh, Abril Marchesini, Agostina Spiga, Maximiliano José Fallico, Paula Nazarena Arrías, Alexander Miguel Monzon, Aimilia-Christina Vagiona, Mariane Gonçalves-Kulik, Pablo Mier and Miguel A. Andrade-Navarro
Int. J. Mol. Sci. 2024, 25(5), 2994; https://doi.org/10.3390/ijms25052994 - 5 Mar 2024
Viewed by 812
Abstract
Tandem repeats (TRs) in protein sequences are consecutive, highly similar sequence motifs. Some types of TRs fold into structural units that pack together in ensembles, forming either an (open) elongated domain or a (closed) propeller, where the last unit of the ensemble packs [...] Read more.
Tandem repeats (TRs) in protein sequences are consecutive, highly similar sequence motifs. Some types of TRs fold into structural units that pack together in ensembles, forming either an (open) elongated domain or a (closed) propeller, where the last unit of the ensemble packs against the first one. Here, we examine TR proteins (TRPs) to see how their sequence, structure, and evolutionary properties favor them for a function as mediators of protein interactions. Our observations suggest that TRPs bind other proteins using large, structured surfaces like globular domains; in particular, open-structured TR ensembles are favored by flexible termini and the possibility to tightly coil against their targets. While, intuitively, open ensembles of TRs seem prone to evolve due to their potential to accommodate insertions and deletions of units, these evolutionary events are unexpectedly rare, suggesting that they are advantageous for the emergence of the ancestral sequence but are early fixed. We hypothesize that their flexibility makes it easier for further proteins to adapt to interact with them, which would explain their large number of protein interactions. We provide insight into the properties of open TR ensembles, which make them scaffolds for alternative protein complexes to organize genes, RNA and proteins. Full article
(This article belongs to the Special Issue Advances in Protein-Protein Interactions 2.0)
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22 pages, 3659 KiB  
Article
Comparative Analysis of Cyclization Techniques in Stapled Peptides: Structural Insights into Protein–Protein Interactions in a SARS-CoV-2 Spike RBD/hACE2 Model System
by Sára Ferková, Ulrike Froehlich, Marie-Édith Nepveu-Traversy, Alexandre Murza, Taha Azad, Michel Grandbois, Philippe Sarret, Pierre Lavigne and Pierre-Luc Boudreault
Int. J. Mol. Sci. 2024, 25(1), 166; https://doi.org/10.3390/ijms25010166 - 21 Dec 2023
Viewed by 1239
Abstract
Medicinal chemistry is constantly searching for new approaches to develop more effective and targeted therapeutic molecules. The design of peptidomimetics is a promising emerging strategy that is aimed at developing peptides that mimic or modulate the biological activity of proteins. Among these, stapled [...] Read more.
Medicinal chemistry is constantly searching for new approaches to develop more effective and targeted therapeutic molecules. The design of peptidomimetics is a promising emerging strategy that is aimed at developing peptides that mimic or modulate the biological activity of proteins. Among these, stapled peptides stand out for their unique ability to stabilize highly frequent helical motifs, but they have failed to be systematically reported. Here, we exploit chemically diverse helix-inducing i, i + 4 constraints—lactam, hydrocarbon, triazole, double triazole and thioether—on two distinct short sequences derived from the N-terminal peptidase domain of hACE2 upon structural characterization and in silico alanine scan. Our overall objective was to provide a sequence-independent comparison of α-helix-inducing staples using circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. We identified a 9-mer lactam stapled peptide derived from the hACE2 sequence (His34-Gln42) capable of reaching its maximal helicity of 55% with antiviral activity in bioreporter- and pseudovirus-based inhibition assays. To the best of our knowledge, this study is the first comprehensive investigation comparing several cyclization methods with the goal of generating stapled peptides and correlating their secondary structures with PPI inhibitions using a highly topical model system (i.e., the interaction of SARS-CoV-2 Spike RBD with hACE2). Full article
(This article belongs to the Special Issue Advances in Protein-Protein Interactions 2.0)
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21 pages, 17776 KiB  
Article
Inhibiting Intracellular α2C-Adrenoceptor Surface Translocation Using Decoy Peptides: Identification of an Essential Role of the C-Terminus in Receptor Trafficking
by Aisha Raza, Saima Mohsin, Fasiha Saeed, Syed Abid Ali and Maqsood A. Chotani
Int. J. Mol. Sci. 2023, 24(24), 17558; https://doi.org/10.3390/ijms242417558 - 16 Dec 2023
Viewed by 1052
Abstract
The G protein-coupled α2-adrenoceptor subtype C (abbreviated α2C-AR) has been implicated in peripheral vascular conditions and diseases such as cold feet–hands, Raynaud’s phenomenon, and scleroderma, contributing to morbidity and mortality. Microvascular α2C-adrenoceptors are expressed in specialized smooth [...] Read more.
The G protein-coupled α2-adrenoceptor subtype C (abbreviated α2C-AR) has been implicated in peripheral vascular conditions and diseases such as cold feet–hands, Raynaud’s phenomenon, and scleroderma, contributing to morbidity and mortality. Microvascular α2C-adrenoceptors are expressed in specialized smooth muscle cells and mediate constriction under physiological conditions and the occlusion of blood supply involving vasospastic episodes and tissue damage under pathological conditions. A crucial step for receptor biological activity is the cell surface trafficking of intracellular receptors, triggered by cAMP-Epac-Rap1A GTPase signaling, which involves protein–protein association with the actin-binding protein filamin-2, mediated by critical amino acid residues in the last 14 amino acids of the receptor carboxyl (C)-terminus. This study assessed the role of the C-terminus in Rap1A GTPase coupled receptor trafficking by domain-swapping studies using recombinant tagged receptors in transient co-transfections and compared with wild-type receptors using immunofluorescence microscopy. We further tested the biological relevance of the α2C-AR C-terminus, when introduced as competitor peptides, to selectively inhibit intracellular α2C-AR surface translocation in transfected as well as in microvascular smooth muscle cells expressing endogenous receptors. These studies contribute to establishing proof of principle to target intracellular α2C-adrenoceptors to reduce biological activity, which in clinical conditions can be a target for therapy. Full article
(This article belongs to the Special Issue Advances in Protein-Protein Interactions 2.0)
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20 pages, 2516 KiB  
Article
Endoplasmic Reticulum Protein TXNDC5 Interacts with PRDX6 and HSPA9 to Regulate Glutathione Metabolism and Lipid Peroxidation in the Hepatic AML12 Cell Line
by Seyed Hesamoddin Bidooki, Javier Sánchez-Marco, Roberto Martínez-Beamonte, Tania Herrero-Continente, María A. Navarro, María J. Rodríguez-Yoldi and Jesús Osada
Int. J. Mol. Sci. 2023, 24(24), 17131; https://doi.org/10.3390/ijms242417131 - 5 Dec 2023
Cited by 2 | Viewed by 1282
Abstract
Non-alcoholic fatty liver disease or steatosis is an accumulation of fat in the liver. Increased amounts of non-esterified fatty acids, calcium deficiency, or insulin resistance may disturb endoplasmic reticulum (ER) homeostasis, which leads to the abnormal accumulation of misfolded proteins, activating the unfolded [...] Read more.
Non-alcoholic fatty liver disease or steatosis is an accumulation of fat in the liver. Increased amounts of non-esterified fatty acids, calcium deficiency, or insulin resistance may disturb endoplasmic reticulum (ER) homeostasis, which leads to the abnormal accumulation of misfolded proteins, activating the unfolded protein response. The ER is the primary location site for chaperones like thioredoxin domain-containing 5 (TXNDC5). Glutathione participates in cellular oxidative stress, and its interaction with TXNDC5 in the ER may decrease the disulfide bonds of this protein. In addition, glutathione is utilized by glutathione peroxidases to inactivate oxidized lipids. To characterize proteins interacting with TXNDC5, immunoprecipitation and liquid chromatography–mass spectrometry were used. Lipid peroxidation, reduced glutathione, inducible phospholipase A2 (iPLA2) and hepatic transcriptome were assessed in the AML12 and TXNDC5-deficient AML12 cell lines. The results showed that HSPA9 and PRDX6 interact with TXNDC5 in AML12 cells. In addition, TXNDC5 deficiency reduced the protein levels of PRDX6 and HSPA9 in AML12. Moreover, lipid peroxidation, glutathione and iPLA2 activities were significantly decreased in TXNDC5-deficient cells, and to find the cause of the PRDX6 protein reduction, proteasome suppression revealed no considerable effect on it. Finally, hepatic transcripts connected to PRDX6 and HSPA9 indicated an increase in the Dnaja3, Mfn2 and Prdx5 and a decrease in Npm1, Oplah, Gstp3, Gstm6, Gstt1, Serpina1a, Serpina1b, Serpina3m, Hsp90aa1 and Rps14 mRNA levels in AML12 KO cells. In conclusion, the lipid peroxidation system and glutathione mechanism in AML12 cells may be disrupted by the absence of TXNDC5, a novel protein–protein interacting partner of PRDX6 and HSPA9. Full article
(This article belongs to the Special Issue Advances in Protein-Protein Interactions 2.0)
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