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Protein–Protein Interactions: Methods and Applications

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Special Issue Information
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Published Papers

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 27414

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Special Issue Editors

Prof. Dr. Ted Hupp

E-Mail Website
Section Board Member

International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland and the University of Edinburgh, Cancer Research Centre, Edinburgh 0131, UK
Interests: drug discovery in the ubiquitin-proteasome; antibody therapeutics; mass spectrometry and proteomics; interferon signaling in cancer
Special Issues, Collections and Topics in MDPI journals

Dr. M. Aiman Mohtar

E-Mail Website
Assistant Guest Editor

UKM Medical Molecular Biology Institute (UMBI),Universiti Kebangsaan Malaysia, Bangi, Malaysia
Interests: protein-protein interaction; cancer biology; cancer proteomics; synthetic biology; peptide motif; peptide therapeutics; oncogene

Special Issue Information

Dear Colleagues,

Metabolites, lipids, proteins, and RNA form the key chemical messengers of a genome. Proteins perhaps comprise the most well-studied therapeutic targets in biology due to their relatively high solubility in aqueous media, stable core structure, and high drugability using small molecules. In the past twenty years a paradigm shift has resulted in changing how the function of a protein is viewed. Proteins can have a surprisingly large number of interacting partners that function in their lifecycle, intrinsically non-structured regions, and structural domains, which can drive function, and weak interactions can create dynamic networks that regulate disease phenotypes. Thus, the vast diversity of proteins can be viewed to function inside tunable protein–protein interaction (PPI) networks, and these PPIs form a key bridge through which the genome interacts with its environment. PPIs have also emerged as compelling drivers of human disease under conditions in which these PPI networks are re-wired, resulting in a change in cell and tissue behavior. Fundamental sets of challenges remain in the PPI field including the following: (i) the role of intrinsically disordered regions, structural domains, linear motifs, and membraneless organelles in regulating signal transduction; (ii) how the PPI field can integrate combinatorial biology, computational science, and structural biology, including cryoEM, to clarify our understanding of how PPI networks produce normal and diseased phenotypes; and (iii) how we choose whether a PPI or a key PPI within a hub is “druggable”.

We invite the submission of reviews crossing several disciplines in the PPI field, such as informatics, synthetic biology, chemistry, virology, mass spectrometry, RNA biology, and cell or tissue imaging. These can be grouped into themes including the following: (i) methodologies and applications for discovering protein–protein interactions; (ii) defining protein–protein interaction networks at a systems level; (iii) modulating protein–protein interactions as potential therapeutics; (iv) applications for validating protein–protein interactions and their dynamics in vitro and in vivo; and (v) disease models regulated by dynamic shifts in protein–protein interaction networks.

Prof. Ted Hupp
Dr. M. Aiman Mohtar
Guest Editors

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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 networks
synthetic biology
computational protein science
mass spectrometry
intrinsically disordered proteins
structural biology of multi-protein complexes
peptide therapeutics and drug discovery
RNA–protein interactions
protein synthesis and degradation

Published Papers (6 papers)

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Research

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17 pages, 4446 KiB

Open AccessArticle

Can Glycosylation Mask the Detection of MHC Expressing p53 Peptides by T Cell Receptors?

by Thanh Binh Nguyen, David P. Lane and Chandra S. Verma

Biomolecules 2021, 11(7), 1056; https://doi.org/10.3390/biom11071056 - 19 Jul 2021

Cited by 1 | Viewed by 2617

Abstract

Proteins of the major histocompatibility complex (MHC) class I, or human leukocyte antigen (HLA) in humans interact with endogenous peptides and present them to T cell receptors (TCR), which in turn tune the immune system to recognize and discriminate between self and foreign (non-self) peptides. Of especial importance are peptides derived from tumor-associated antigens. T cells recognizing these peptides are found in cancer patients, but not in cancer-free individuals. What stimulates this recognition, which is vital for the success of checkpoint based therapy? A peptide derived from the protein p53 (residues 161–169 or p161) was reported to show this behavior. T cells recognizing this unmodified peptide could be further stimulated in vitro to create effective cancer killing CTLs (cytotoxic T lymphocytes). We hypothesize that the underlying difference may arise from post-translational glycosylation of p161 in normal individuals, likely masking it against recognition by TCR. Defects in glycosylation in cancer cells may allow the presentation of the native peptide. We investigate the structural consequences of such peptide glycosylation by investigating the associated structural dynamics. Full article

(This article belongs to the Special Issue Protein–Protein Interactions: Methods and Applications)

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12 pages, 1780 KiB

Open AccessArticle

Multivalent Display of SARS-CoV-2 Spike (RBD Domain) of COVID-19 to Nanomaterial, Protein Ferritin Nanocages

by Umesh Kalathiya, Monikaben Padariya, Robin Fahraeus, Soumyananda Chakraborti and Ted R. Hupp

Biomolecules 2021, 11(2), 297; https://doi.org/10.3390/biom11020297 - 17 Feb 2021

Cited by 19 | Viewed by 5555

Abstract

SARS-CoV-2, or COVID-19, has a devastating effect on our society, both in terms of quality of life and death rates; hence, there is an urgent need for developing safe and effective therapeutics against SARS-CoV-2. The most promising strategy to fight against this deadly virus is to develop an effective vaccine. Internalization of SARS-CoV-2 into the human host cell mainly occurs through the binding of the coronavirus spike protein (a trimeric surface glycoprotein) to the human angiotensin-converting enzyme 2 (ACE2) receptor. The spike-ACE2 protein–protein interaction is mediated through the receptor-binding domain (RBD) of the spike protein. Mutations in the spike RBD can significantly alter interactions with the ACE2 host receptor. Due to its important role in virus transmission, the spike RBD is considered to be one of the key molecular targets for vaccine development. In this study, a spike RBD-based subunit vaccine was designed by utilizing a ferritin protein nanocage as a scaffold. Several fusion protein constructs were designed in silico by connecting the spike RBD via a synthetic linker (different sizes) to different ferritin subunits (H-ferritin and L-ferritin). The stability and the dynamics of the engineered nanocage constructs were tested by extensive molecular dynamics simulation (MDS). Based on our MDS analysis, a five amino acid-based short linker (S-Linker) was the most effective for displaying the spike RBD over the surface of ferritin. The behavior of the spike RBD binding regions from the designed chimeric nanocages with the ACE2 receptor was highlighted. These data propose an effective multivalent synthetic nanocage, which might form the basis for new vaccine therapeutics designed against viruses such as SARS-CoV-2. Full article

(This article belongs to the Special Issue Protein–Protein Interactions: Methods and Applications)

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18 pages, 9030 KiB

Open AccessArticle

Temperature and Concentration Dependence of Human Whole Blood and Protein Drying Droplets

by Anusuya Pal, Amalesh Gope and Germano Iannacchione

Biomolecules 2021, 11(2), 231; https://doi.org/10.3390/biom11020231 - 05 Feb 2021

Cited by 12 | Viewed by 3623

Abstract

The drying of bio-colloidal droplets can be used in many medical and forensic applications. The whole human blood is the most complex bio-colloid system, whereas bovine serum albumin (BSA) is the simplest. This paper focuses on the drying characteristics and the final morphology of these two bio-colloids. The experiments were conducted by varying their initial concentrations, and the solutions were dried under various controlled substrate temperatures using optical and scanning electron microscopy. The droplet parameters (the contact angle, the fluid front, and the first-order image statistics) reveal the drying process’s unique features. Interestingly, both BSA and blood drying droplets’ contact angle measurements show evidence of a concentration-driven transition as the behavior changes from non-monotonic to monotonic decrease. This result indicates that this transition behavior is not limited to multi-component bio-colloid (blood) only, but may be a phenomenon of a bio-colloidal solution containing a large number of interacting components. The high dilution of blood behaves like the BSA solution. The ring-like deposition, the crack morphology, and the microstructures suggest that the components have enough time to segregate and deposit onto the substrate under ambient conditions. However, there is insufficient time for evaporative-driven segregation to occur at elevated temperatures, as expected. Full article

(This article belongs to the Special Issue Protein–Protein Interactions: Methods and Applications)

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Review

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29 pages, 4632 KiB

Open AccessReview

Functional Interfaces, Biological Pathways, and Regulations of Interferon-Related DNA Damage Resistance Signature (IRDS) Genes

by Monikaben Padariya, Alicja Sznarkowska, Sachin Kote, Maria Gómez-Herranz, Sara Mikac, Magdalena Pilch, Javier Alfaro, Robin Fahraeus, Ted Hupp and Umesh Kalathiya

Biomolecules 2021, 11(5), 622; https://doi.org/10.3390/biom11050622 - 22 Apr 2021

Cited by 21 | Viewed by 5466

Abstract

Interferon (IFN)-related DNA damage resistant signature (IRDS) genes are a subgroup of interferon-stimulated genes (ISGs) found upregulated in different cancer types, which promotes resistance to DNA damaging chemotherapy and radiotherapy. Along with briefly discussing IFNs and signalling in this review, we highlighted how different IRDS genes are affected by viruses. On the contrary, different strategies adopted to suppress a set of IRDS genes (STAT1, IRF7, OAS family, and BST2) to induce (chemo- and radiotherapy) sensitivity were deliberated. Significant biological pathways that comprise these genes were classified, along with their frequently associated genes (IFIT1/3, IFITM1, IRF7, ISG15, MX1/2 and OAS1/3/L). Major upstream regulators from the IRDS genes were identified, and different IFN types regulating these genes were outlined. Functional interfaces of IRDS proteins with DNA/RNA/ATP/GTP/NADP biomolecules featured a well-defined pharmacophore model for STAT1/IRF7-dsDNA and OAS1/OAS3/IFIH1-dsRNA complexes, as well as for the genes binding to GDP or NADP+. The Lys amino acid was found commonly interacting with the ATP phosphate group from OAS1/EIF2AK2/IFIH1 genes. Considering the premise that targeting IRDS genes mediated resistance offers an efficient strategy to resensitize tumour cells and enhances the outcome of anti-cancer treatment, this review can add some novel insights to the field. Full article

(This article belongs to the Special Issue Protein–Protein Interactions: Methods and Applications)

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27 pages, 3813 KiB

Open AccessReview

Interfaces with Structure Dynamics of the Workhorses from Cells Revealed through Cross-Linking Mass Spectrometry (CLMS)

by Umesh Kalathiya, Monikaben Padariya, Jakub Faktor, Etienne Coyaud, Javier A. Alfaro, Robin Fahraeus, Ted R. Hupp and David R. Goodlett

Biomolecules 2021, 11(3), 382; https://doi.org/10.3390/biom11030382 - 04 Mar 2021

Cited by 8 | Viewed by 4344

Abstract

The fundamentals of how protein–protein/RNA/DNA interactions influence the structures and functions of the workhorses from the cells have been well documented in the 20th century. A diverse set of methods exist to determine such interactions between different components, particularly, the mass spectrometry (MS) methods, with its advanced instrumentation, has become a significant approach to analyze a diverse range of biomolecules, as well as bring insights to their biomolecular processes. This review highlights the principal role of chemistry in MS-based structural proteomics approaches, with a particular focus on the chemical cross-linking of protein–protein/DNA/RNA complexes. In addition, we discuss different methods to prepare the cross-linked samples for MS analysis and tools to identify cross-linked peptides. Cross-linking mass spectrometry (CLMS) holds promise to identify interaction sites in larger and more complex biological systems. The typical CLMS workflow allows for the measurement of the proximity in three-dimensional space of amino acids, identifying proteins in direct contact with DNA or RNA, and it provides information on the folds of proteins as well as their topology in the complexes. Principal CLMS applications, its notable successes, as well as common pipelines that bridge proteomics, molecular biology, structural systems biology, and interactomics are outlined. Full article

(This article belongs to the Special Issue Protein–Protein Interactions: Methods and Applications)

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15 pages, 1448 KiB

Open AccessFeature PaperReview

Molecular and Biochemical Techniques for Deciphering p53-MDM2 Regulatory Mechanisms

by Konstantinos Karakostis, Ignacio López, Ana M. Peña-Balderas, Robin Fåhareus and Vanesa Olivares-Illana

Biomolecules 2021, 11(1), 36; https://doi.org/10.3390/biom11010036 - 30 Dec 2020

Cited by 7 | Viewed by 3953

Abstract

The p53 and Mouse double minute 2 (MDM2) proteins are hubs in extensive networks of interactions with multiple partners and functions. Intrinsically disordered regions help to adopt function-specific structural conformations in response to ligand binding and post-translational modifications. Different techniques have been used to dissect interactions of the p53-MDM2 pathway, in vitro, in vivo, and in situ each having its own advantages and disadvantages. This review uses the p53-MDM2 to show how different techniques can be employed, illustrating how a combination of in vitro and in vivo techniques is highly recommended to study the spatio-temporal location and dynamics of interactions, and to address their regulation mechanisms and functions. By using well-established techniques in combination with more recent advances, it is possible to rapidly decipher complex mechanisms, such as the p53 regulatory pathway, and to demonstrate how protein and nucleotide ligands in combination with post-translational modifications, result in inter-allosteric and intra-allosteric interactions that govern the activity of the protein complexes and their specific roles in oncogenesis. This promotes elegant therapeutic strategies that exploit protein dynamics to target specific interactions. Full article

(This article belongs to the Special Issue Protein–Protein Interactions: Methods and Applications)

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