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Cancers
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Protein Structure and Cancer
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Protein Structure and Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 21063

Special Issue Editor

Dr. Michalis Aivaliotis

E-Mail Website
Guest Editor
Laboratory of Biological Chemistry, Medical School, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
Interests: functional proteomics; cancer biology; neurodegenerative diseases; system biology; bioinformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins are fundamental molecules to all living organisms and the remarkable way they fold into complex three-dimensional (3D) structures strongly defines organism’s functional capabilities and phenotype. Protein structure is highly dynamic and defines protein function and interactions. The dynamic feature of protein structure enhances and supports the amazing flexibility of cellular and extracellular biochemistry and cells’ inherent capability for autoregulation and adaptation to different conditions. On the other hand, a problematic protein structure may lead to protein deregulation, dysfunction, or no function, and consequently to disease or even death. Protein structural alterations are a hallmark of several diseases, including cancer. In addition, such alterations in cancer lead to diverse protein functions that can significantly promote cancerous transformation and phenotype. Local concentrations of mutations are well known in human cancers affecting protein function and interactions enhancing cancer development and progression, contributing to tumor heterogeneity and tumorigenesis. However, their 3D spatial relationships in the encoded proteins have yet to be systematically investigated. It is expected that the elucidation of protein structural alterations resulting from such driver mutations is of paramount importance for obtaining an in-depth understanding of the molecular mechanisms leading to cancer. Such an understanding can provide more direct and clinically relevant knowledge and evidence of disease states than genetic signatures alone.

We are excited to invite authors to submit original research and review articles that address the progress and current standing of protein-structure-based studies in cancer research. Research areas may include various aspects and approaches that have been developed for understanding and predicting the role of protein structure alterations in the development, progression, and resistance to therapy of different cancers, as well as their potential application in developing precision cancer therapies.

Prof. Dr. Michalis Aivaliotis
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 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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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 structure dynamics
  • structural cancer biology
  • protein pathways in cancer
  • structure–function alterations
  • in silico protein structure prediction
  • protein interactions
  • cancer mutations and protein structure alterations

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Published Papers (7 papers)

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Research

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27 pages, 18527 KiB  
Article
Interruption of p53-MDM2 Interaction by Nutlin-3a in Human Lymphoma Cell Models Initiates a Cell-Dependent Global Effect on Transcriptome and Proteome Level
by Konstantina Psatha, Laxmikanth Kollipara, Elias Drakos, Elena Deligianni, Konstantinos Brintakis, Eustratios Patsouris, Albert Sickmann, George Z. Rassidakis and Michalis Aivaliotis
Cancers 2023, 15(15), 3903; https://doi.org/10.3390/cancers15153903 - 31 Jul 2023
Cited by 7 | Viewed by 2240
Abstract
In most lymphomas, p53 signaling pathway is inactivated by various mechanisms independent to p53 gene mutations or deletions. In many cases, p53 function is largely regulated by alterations in the protein abundance levels by the action of E3 ubiquitin-protein ligase MDM2, targeting p53 [...] Read more.
In most lymphomas, p53 signaling pathway is inactivated by various mechanisms independent to p53 gene mutations or deletions. In many cases, p53 function is largely regulated by alterations in the protein abundance levels by the action of E3 ubiquitin-protein ligase MDM2, targeting p53 to proteasome-mediated degradation. In the present study, an integrating transcriptomics and proteomics analysis was employed to investigate the effect of p53 activation by a small-molecule MDM2-antagonist, nutlin-3a, on three lymphoma cell models following p53 activation. Our analysis revealed a system-wide nutlin-3a-associated effect in all examined lymphoma types, identifying in total of 4037 differentially affected proteins involved in a plethora of pathways, with significant heterogeneity among lymphomas. Our findings include known p53-targets and novel p53 activation effects, involving transcription, translation, or degradation of protein components of pathways, such as a decrease in key members of PI3K/mTOR pathway, heat-shock response, and glycolysis, and an increase in key members of oxidative phoshosphorylation, autophagy and mitochondrial translation. Combined inhibition of HSP90 or PI3K/mTOR pathway with nutlin-3a-mediated p53-activation enhanced the apoptotic effects suggesting a promising strategy against human lymphomas. Integrated omic profiling after p53 activation offered novel insights on the regulatory role specific proteins and pathways may have in lymphomagenesis. Full article
(This article belongs to the Special Issue Protein Structure and Cancer)
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21 pages, 3455 KiB  
Article
Mutation in the Common Docking Domain Affects MAP Kinase ERK2 Catalysis and Stability
by Leonore Novak, Maria Petrosino, Alessandra Pasquo, Apirat Chaikuad, Roberta Chiaraluce, Stefan Knapp and Valerio Consalvi
Cancers 2023, 15(11), 2938; https://doi.org/10.3390/cancers15112938 - 26 May 2023
Cited by 3 | Viewed by 1759
Abstract
The extracellular-signal-regulated kinase 2 (ERK2), a mitogen-activated protein kinase (MAPK) located downstream of the Ras-Raf-MEK-ERK signal transduction cascade, is involved in the regulation of a large variety of cellular processes. The ERK2, activated by phosphorylation, is the principal effector of a central signaling [...] Read more.
The extracellular-signal-regulated kinase 2 (ERK2), a mitogen-activated protein kinase (MAPK) located downstream of the Ras-Raf-MEK-ERK signal transduction cascade, is involved in the regulation of a large variety of cellular processes. The ERK2, activated by phosphorylation, is the principal effector of a central signaling cascade that converts extracellular stimuli into cells. Deregulation of the ERK2 signaling pathway is related to many human diseases, including cancer. This study reports a comprehensive biophysical analysis of structural, function, and stability data of pure, recombinant human non-phosphorylated (NP-) and phosphorylated (P-) ERK2 wild-type and missense variants in the common docking site (CD-site) found in cancer tissues. Because the CD-site is involved in interaction with protein substrates and regulators, a biophysical characterization of missense variants adds information about the impact of point mutations on the ERK2 structure–function relationship. Most of the P-ERK2 variants in the CD-site display a reduced catalytic efficiency, and for the P-ERK2 D321E, D321N, D321V and E322K, changes in thermodynamic stability are observed. The thermal stability of NP-ERK2 and P-ERK2 D321E, D321G, and E322K is decreased with respect to the wild-type. In general, a single residue mutation in the CD-site may lead to structural local changes that reflects in alterations in the global ERK2 stability and catalysis. Full article
(This article belongs to the Special Issue Protein Structure and Cancer)
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22 pages, 20801 KiB  
Article
E2 Partner Tunes the Ubiquitylation Specificity of Arkadia E3 Ubiquitin Ligase
by Georgia N. Delegkou, Maria Birkou, Nefeli Fragkaki, Tamara Toro, Konstantinos D. Marousis, Vasso Episkopou and Georgios A. Spyroulias
Cancers 2023, 15(4), 1040; https://doi.org/10.3390/cancers15041040 - 7 Feb 2023
Viewed by 2339
Abstract
Arkadia (RNF111) is a positive regulator of the TGF-β signaling that mediates the proteasome-dependent degradation of negative factors of the pathway. It is classified as an E3 ubiquitin ligase and a SUMO-targeted ubiquitin ligase (STUBL), implicated in various pathological conditions [...] Read more.
Arkadia (RNF111) is a positive regulator of the TGF-β signaling that mediates the proteasome-dependent degradation of negative factors of the pathway. It is classified as an E3 ubiquitin ligase and a SUMO-targeted ubiquitin ligase (STUBL), implicated in various pathological conditions including cancer and fibrosis. The enzymatic (ligase) activity of Arkadia is located at its C-terminus and involves the RING domain. Notably, E3 ligases require E2 enzymes to perform ubiquitylation. However, little is known about the cooperation of Arkadia with various E2 enzymes and the type of ubiquitylation that they mediate. In the present work, we study the interaction of Arkadia with the E2 partners UbcH5B and UbcH13, as well as UbcH7. Through NMR spectroscopy, we found that the E2–Arkadia interaction surface is similar in all pairs examined. Nonetheless, the requirements and factors that determine an enzymatically active E2–Arkadia complex differ in each case. Furthermore, we revealed that the cooperation of Arkadia with different E2s results in either monoubiquitylation or polyubiquitin chain formation via K63, K48, or K11 linkages, which can determine the fate of the substrate and lead to distinct biological outcomes. Full article
(This article belongs to the Special Issue Protein Structure and Cancer)
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17 pages, 4755 KiB  
Article
2,2-Diphenethyl Isothiocyanate Enhances Topoisomerase Inhibitor-Induced Cell Death and Suppresses Multi-Drug Resistance 1 in Breast Cancer Cells
by Monika Aggarwal
Cancers 2023, 15(3), 928; https://doi.org/10.3390/cancers15030928 - 1 Feb 2023
Cited by 2 | Viewed by 2232
Abstract
We previously reported that phenethyl isothiocyanate (PEITC), a dietary-related compound, can rescue mutant p53. A structure–activity relationships study showed that the synthetic analog 2,2-diphenylethyl isothiocyanate (DPEITC) is a more potent inducer of apoptosis than natural or synthetic ITCs. Here, we showed that DPEITC [...] Read more.
We previously reported that phenethyl isothiocyanate (PEITC), a dietary-related compound, can rescue mutant p53. A structure–activity relationships study showed that the synthetic analog 2,2-diphenylethyl isothiocyanate (DPEITC) is a more potent inducer of apoptosis than natural or synthetic ITCs. Here, we showed that DPEITC inhibited the growth of triple-negative breast cancer cells (MDA-MB-231, MDA-MB-468, and Hs578T) expressing “hotspot” p53 mutants, structural (p53R280K, p53R273H) or contact (p53V157F), at IC50 values significantly lower than PEITC. DPEITC inhibited the growth of HER2+ (p53R175H SK-BR-3, p53R175H AU565) and Luminal A (p53L194F T47D) breast cancer (BC) cells harboring a p53 structural mutant. DPEITC induced apoptosis, irrespective of BC subtypes, by rescuing p53 mutants. Accordingly, the rescued p53 mutants induced apoptosis by activating canonical WT p53 targets and delaying the cell cycle. DPEITC acted synergistically with doxorubicin and camptothecin to inhibit proliferation and induce apoptosis. Under these conditions, DPEITC delayed BC cells in the G1 phase, activated p53 canonical targets, and enhanced pS1981-ATM. DPEITC reduced the expression of MDR1 and ETS1. These findings are the first report of synergism between a synthetic ITC and a chemotherapy drug via mutant p53 rescue. Furthermore, our data demonstrate that ITCs suppress the expression of cellular proteins that play a role in chemoresistance. Full article
(This article belongs to the Special Issue Protein Structure and Cancer)
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Review

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39 pages, 10589 KiB  
Review
Human Aldehyde Dehydrogenases: A Superfamily of Similar Yet Different Proteins Highly Related to Cancer
by Vasileios Xanthis, Theodora Mantso, Anna Dimtsi, Aglaia Pappa and Vasiliki E. Fadouloglou
Cancers 2023, 15(17), 4419; https://doi.org/10.3390/cancers15174419 - 4 Sep 2023
Cited by 5 | Viewed by 3755
Abstract
The superfamily of human aldehyde dehydrogenases (hALDHs) consists of 19 isoenzymes which are critical for several physiological and biosynthetic processes and play a major role in the organism’s detoxification via the NAD(P) dependent oxidation of numerous endogenous and exogenous aldehyde substrates to their [...] Read more.
The superfamily of human aldehyde dehydrogenases (hALDHs) consists of 19 isoenzymes which are critical for several physiological and biosynthetic processes and play a major role in the organism’s detoxification via the NAD(P) dependent oxidation of numerous endogenous and exogenous aldehyde substrates to their corresponding carboxylic acids. Over the last decades, ALDHs have been the subject of several studies as it was revealed that their differential expression patterns in various cancer types are associated either with carcinogenesis or promotion of cell survival. Here, we attempt to provide a thorough review of hALDHs’ diverse functions and 3D structures with particular emphasis on their role in cancer pathology and resistance to chemotherapy. We are especially interested in findings regarding the association of structural features and their changes with effects on enzymes’ functionalities. Moreover, we provide an updated outline of the hALDHs inhibitors utilized in experimental or clinical settings for cancer therapy. Overall, this review aims to provide a better understanding of the impact of ALDHs in cancer pathology and therapy from a structural perspective. Full article
(This article belongs to the Special Issue Protein Structure and Cancer)
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20 pages, 2193 KiB  
Review
The Structural Dynamics, Complexity of Interactions, and Functions in Cancer of Multi-SAM Containing Proteins
by Christopher M. Clements, Morkos A. Henen, Beat Vögeli and Yiqun G. Shellman
Cancers 2023, 15(11), 3019; https://doi.org/10.3390/cancers15113019 - 1 Jun 2023
Cited by 2 | Viewed by 1808
Abstract
SAM domains are crucial mediators of diverse interactions, including those important for tumorigenesis or metastasis of cancers, and thus SAM domains can be attractive targets for developing cancer therapies. This review aims to explore the literature, especially on the recent findings of the [...] Read more.
SAM domains are crucial mediators of diverse interactions, including those important for tumorigenesis or metastasis of cancers, and thus SAM domains can be attractive targets for developing cancer therapies. This review aims to explore the literature, especially on the recent findings of the structural dynamics, regulation, and functions of SAM domains in proteins containing more than one SAM (multi-SAM containing proteins, MSCPs). The topics here include how intrinsic disorder of some SAMs and an additional SAM domain in MSCPs increase the complexity of their interactions and oligomerization arrangements. Many similarities exist among these MSCPs, including their effects on cancer cell adhesion, migration, and metastasis. In addition, they are all involved in some types of receptor-mediated signaling and neurology-related functions or diseases, although the specific receptors and functions vary. This review also provides a simple outline of methods for studying protein domains, which may help non-structural biologists to reach out and build new collaborations to study their favorite protein domains/regions. Overall, this review aims to provide representative examples of various scenarios that may provide clues to better understand the roles of SAM domains and MSCPs in cancer in general. Full article
(This article belongs to the Special Issue Protein Structure and Cancer)
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12 pages, 678 KiB  
Review
Mining the Immunopeptidome for Antigenic Peptides in Cancer
by Ricardo A. León-Letelier, Hiroyuki Katayama and Sam Hanash
Cancers 2022, 14(20), 4968; https://doi.org/10.3390/cancers14204968 - 11 Oct 2022
Cited by 11 | Viewed by 4960
Abstract
Although harnessing the immune system for cancer therapy has shown success, response to immunotherapy has been limited. The immunopeptidome of cancer cells presents an opportunity to discover novel antigens for immunotherapy applications. These neoantigens bind to MHC class I and class II molecules. [...] Read more.
Although harnessing the immune system for cancer therapy has shown success, response to immunotherapy has been limited. The immunopeptidome of cancer cells presents an opportunity to discover novel antigens for immunotherapy applications. These neoantigens bind to MHC class I and class II molecules. Remarkably, the immunopeptidome encompasses protein post-translation modifications (PTMs) that may not be evident from genome or transcriptome profiling. A case in point is citrullination, which has been demonstrated to induce a strong immune response. In this review, we cover how the immunopeptidome, with a special focus on PTMs, can be utilized to identify cancer-specific antigens for immunotherapeutic applications. Full article
(This article belongs to the Special Issue Protein Structure and Cancer)
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