Exploring PLAC1 Structure and Underlying Mechanisms to Design a Derivative Vaccine Against Breast Cancer Progression; In-Silico Study

2020 ◽  
Vol 17 (5) ◽  
pp. 379-391
Author(s):  
Farzaneh Afzali ◽  
Parisa Ghahremanifard ◽  
Mohammad Mehdi Ranjbar ◽  
Mahdieh Salimi
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
In Silico ◽  
Tertiary Structure ◽  
Specific Antigen ◽  
Docking Simulation ◽  
Post Translational Modification ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Underlying Mechanisms

Background: The tolerogenic homeostasis in Breast Cancer (BC) can be surpassed by rationally designed immune-encouraging constructs against tumor-specific antigens through immunoinformatics approach. Objective: Availability of high throughput data providing the underlying concept of diseases and awarded computational simulations, lead to screening the potential medications and strategies in less time and cost. Despite the extensive effects of Placenta Specific 1 (PLAC1) in BC progression, immune tolerance, invasion, cell cycle regulation, and being a tumor-specific antigen the fundamental mechanisms and regulatory factors were not fully explored. It is also worth to design an immune response inducing construct to surpass the hurdles of traditional anti-cancer treatments. Methods and Result: The study was initiated by predicting and modelling the PLAC1 secondary and tertiary structures and then engineering the fusion pattern of PLAC1 derived immunodominant predicted CD8+ and B-cell epitopes to form a multi-epitope immunogenic construct. The construct was analyzed considering the physiochemical characterization, safety, antigenicity, post-translational modification, solubility, and intrinsically disordered regions. After modelling its tertiary structure, proteinprotein docking simulation was carried out to ensure the attachment of construct with Toll-Like Receptor 4 (TLR4) as an immune receptor. To guarantee the highest expression of the designed construct in E. coli k12 as an expressional host, the codon optimization and in-silico cloning were performed. The PLAC1 related miRNAs in BC were excavated and validated through TCGA BC miRNA-sequencing and databases; the common pathways then were introduced as other probable mechanisms of PLAC1 activity. Conclusion: Regarding the obtained in-silico results, the designed anti-PLAC1 multi-epitope construct can probably trigger humoral and cellular immune responses and inflammatory cascades, therefore may have the potential of halting BC progression and invasion engaging predicted pathways.

CircPLK1 sponges miR-296-5p to facilitate triple-negative breast cancer progression

Epigenomics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1163-1176 ◽  
Author(s):  
Yanan Kong ◽  
Lu Yang ◽  
Weidong Wei ◽  
Ning Lyu ◽  
Yutian Zou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Expression Profiles ◽  
Proliferation And Metastasis ◽  
Underlying Mechanisms

Aim: To investigate the role of circRNAs in triple-negative breast cancer (TNBC) and the underlying mechanisms. Materials & methods: We performed circRNA microarrays to explore the expression profiles of TNBC cell lines. Experiments in vitro and in vivo were conducted to explore the effects of circPLK1 on tumor proliferation and metastasis as well as the interaction between circPLK1, miR-296-5p and PLK1 in TNBC. Results & conclusion: CircPLK1 was significantly upregulated in TNBC and associated with poor survivals. CircPLK1 knockdown inhibited cell growth and invasion in vitro as well as tumor occurrence and metastasis in vivo. CircPLK1-miR-296-5p- PLK1 axis regulates tumor progression by ceRNA mechanism in TNBC, indicating that circPLK1 may serve as a prognostic factor and novel therapeutic target for TNBC.

Eukaryotic transcription factors: paradigms of protein intrinsic disorder

2017 ◽  
Vol 474 (15) ◽  
pp. 2509-2532 ◽  
Author(s):  
Lasse Staby ◽  
Charlotte O'Shea ◽  
Martin Willemoës ◽  
Frederik Theisen ◽  
Birthe B. Kragelund ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Stress Responses ◽  
Tertiary Structure ◽  
Intrinsic Disorder ◽  
Molecular Structures ◽  
Sequence Motifs ◽  
Short Sequence ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Protein Intrinsic Disorder

Gene-specific transcription factors (TFs) are key regulatory components of signaling pathways, controlling, for example, cell growth, development, and stress responses. Their biological functions are determined by their molecular structures, as exemplified by their structured DNA-binding domains targeting specific cis-acting elements in genes, and by the significant lack of fixed tertiary structure in their extensive intrinsically disordered regions. Recent research in protein intrinsic disorder (ID) has changed our understanding of transcriptional activation domains from ‘negative noodles’ to ID regions with function-related, short sequence motifs and molecular recognition features with structural propensities. This review focuses on molecular aspects of TFs, which represent paradigms of ID-related features. Through specific examples, we review how the ID-associated flexibility of TFs enables them to participate in large interactomes, how they use only a few hydrophobic residues, short sequence motifs, prestructured motifs, and coupled folding and binding for their interactions with co-activators, and how their accessibility to post-translational modification affects their interactions. It is furthermore emphasized how classic biochemical concepts like allostery, conformational selection, induced fit, and feedback regulation are undergoing a revival with the appreciation of ID. The review also describes the most recent advances based on computational simulations of ID-based interaction mechanisms and structural analysis of ID in the context of full-length TFs and suggests future directions for research in TF ID.

scholarly journals Association of DNA Repair Gene APE1 Asp148Glu Polymorphism with Breast Cancer Risk

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Fatima AlMutairi ◽  
Akbar Ali Khan Pathan ◽  
Mohammed Alanazi ◽  
Manal Shalaby ◽  
Huda A. Alabdulkarim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Structure ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Cancer Progression ◽  
In Silico ◽  
Breast Cancer Progression ◽  
Saudi Population ◽  
Repair Gene ◽  
Ape1 Asp148glu

Objective. The aim of this study was to investigate the role of APE1 Asp148Glu polymorphism in breast cancer progression in Saudi population.Methods. We examined the genetic variations (rs1130409) in the DNA base excision repair gene APE1 at codon 148 (Asp148Glu) and its association with breast cancer risk using genotypic assays andin silicostructural as well as functional predictions.In silicostructural analysis was performed with Asp148Glu allele and compared with the predicted native protein structure. The wild and mutant 3D structures of APE1 were compared and analyzed using solvent accessibility models for protein stability confirmation.Results. Genotypic analysis of APE1 (rs1130409) showed statistically significant association of Asp148Glu with elevated susceptibility to breast cancer. Thein silicoanalysis results indicated that the nsSNP Asp148Glu may cause changes in the protein structure and is associated with breast cancer risk.Conclusion. Taken together, this is the first report that established that Asp148Glu variant has structural and functional effect on the APE1 and may play an important role in breast cancer progression in Saudi population.

scholarly journals Selection maintains signaling function of a highly diverged intrinsically disordered region

2017 ◽  
Vol 114 (8) ◽  
pp. E1450-E1459 ◽  
Author(s):  
Taraneh Zarin ◽  
Caressa N. Tsai ◽  
Alex N. Nguyen Ba ◽  
Alan M. Moses
Keyword(s):  
Tertiary Structure ◽  
Rapid Evolution ◽  
Stabilizing Selection ◽  
Phylogenetic Comparative Methods ◽  
Similar Function ◽  
Wild Type ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Signaling Function ◽  
Functional Implications

Intrinsically disordered regions (IDRs) are characterized by their lack of stable secondary or tertiary structure and comprise a large part of the eukaryotic proteome. Although these regions play a variety of signaling and regulatory roles, they appear to be rapidly evolving at the primary sequence level. To understand the functional implications of this rapid evolution, we focused on a highly diverged IDR inSaccharomyces cerevisiaethat is involved in regulating multiple conserved MAPK pathways. We hypothesized that under stabilizing selection, the functional output of orthologous IDRs could be maintained, such that diverse genotypes could lead to similar function and fitness. Consistent with the stabilizing selection hypothesis, we find that diverged, orthologous IDRs can mostly recapitulate wild-type function and fitness inS. cerevisiae. We also find that the electrostatic charge of the IDR is correlated with signaling output and, using phylogenetic comparative methods, find evidence for selection maintaining this quantitative molecular trait despite underlying genotypic divergence.

scholarly journals Defining binding motifs and dynamics of the multi-pocket FERM domain from ezrin, radixin, moesin and merlin

2020 ◽  
Author(s):  
Muhammad Ali ◽  
Alisa Khramushin ◽  
Vikash K Yadav ◽  
Ora Schueler-Furman ◽  
Ylva Ivarsson
Keyword(s):  
Conformational Changes ◽  
In Silico ◽  
Cell Cortex ◽  
List Type ◽  
Binding Assays ◽  
Ferm Domain ◽  
Binding Motifs ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions

AbstractThe ERMs (ezrin, radixin and moesin) and the closely related merlin (NF2) participate in signaling events at the cell cortex through interactions mediated by their conserved FERM domain. We systematically investigated the FERM domain mediated interactions with short linear motifs (SLiMs) by screening the FERM domains againsts a phage peptidome representing intrinsically disordered regions of the human proteome. We uncovered a diverse set of interacting partners with similar but distinct binding motifs (FYDF, xYxV, FY(D/E)L and LQE(I/L) that bind to distinct binding pockets. We validated interactions between moesin and merlin FERM domains and full-length FAM83G, HIF1A, LATS1, NOP53, PAK6, RRBP1 and ZNF622 through pull-down experiments. Using biophysical binding assays, we determined affinities of, and uncovered allosteric interdependencies between, different binding partners, suggesting that the FERM domain acts as a switchable interaction hub. Using Rosetta FlexPepDock computational peptide docking protocols, we investigated the energy landscapes of identified interactions, which provide a detailed molecular understanding of the binding of the distinct binding motifs, as well as possible allosteric interconnections. This study demonstrates how experimental and computational approaches together can unravel a complex system of protein-peptide interactions that includes a family of proteins with multiple binding sites that interact with similar but distinct binding motifs.HighlightsWe screened the human disorderome for motif-containing partners of the FERM domainsWe expand the ERM and merlin interactomes of the ERMs and merlinWe identify four distinct motif classes that bind the ERM and merlin FERM domains: FYDF, xYxV, FY(D/E)L and LQE(I/L)In-vitro and in-silico data suggest that the FYDF motif binds to the F3a site and that xYxV motif binds to the F3b siteIn-silico modelling sheds light on the underlying conformational changes responsible for ligand interdependenciesAbstract Figure

scholarly journals Regulation of ERα Stability and Estrogen Signaling in Breast Cancer by HOIL-1

2021 ◽  
Vol 11 ◽  
Author(s):  
Jianing Ding ◽  
Peng Kuang
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Estrogen Receptor Α ◽  
Good Prognosis ◽  
Estrogen Signaling ◽  
Breast Cancers ◽  
Post Translational Modification ◽  
Positive Breast Cancer

Estrogen receptor α (ERα) is the major driver for breast tumor carcinogenesis and progression, while ERα positive breast cancer is the major subtype in breast malignancies, which account for 70% breast cancers in patients. The success of endocrine therapy such as tamoxifen is one of the biggest breakthroughs in breast cancer treatments. However, the endocrine therapy resistance is a headache problem in breast cancer. Further mechanisms need to be identified to the effect of ERα signaling in controlling breast cancer progression and drug resistance. HOIL-1 was firstly identified as the ERα transcriptional co-activator in modulating estrogen signaling in breast cancer. In our current study, we showed that HOIL-1, which was elevated in breast cancer, related to good prognosis in ERα positive breast cancer, but correlated with poor outcome in endocrine-treated patients. HOIL-1 was required for ERα positive breast cancer proliferation and clone formation, which effect could be rescued by further ERα overexpression. Further mechanism studies showed that HOIL-1 is required for ERα signaling activity in breast cancer cells. HOIL-1 could interact with ERα in the cytosol and modulate ERα stability via inhibiting ERα K48-linked poly-ubiquitination. Thus, our study demonstrated a novel post-translational modification in ERα signaling, which could provide novel strategy for ERα-driven breast cancer therapy.

scholarly journals In silico study of lutein as anti-HER-2 receptors in breast cancer treatment

2021 ◽  
Vol 1 (1) ◽  
pp. 17
Author(s):  
Ni Ketut Nitya Cahyani ◽  
Wahyu Nadi Eka Putri ◽  
I Kadek Diva Dwivayana ◽  
Ni Putu Dinda Mirayanti ◽  
Ni Putu Linda Laksmiani
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Binding Energy ◽  
Cancer Progression ◽  
In Silico ◽  
Mechanism Of Inhibition ◽  
Docking Protocol ◽  
In Silico Study ◽  
Her 2 ◽  
In Silico Molecular Docking

Human Epidermal Receptor-2 (HER-2) overexpression is implicated in breast cancer progression; thus, HER-2 is widely used as the target of anticancer therapy. Lapatinib is a drug widely used to inhibit the HER-2 receptor and tyrosine kinase; however, it develops drug resistance. Lutein is promising to be developed as breast cancer therapy. This study aims to determine the mechanism of inhibition of HER-2 receptor overexpression by lutein in silico. Molecular docking was carried out by optimizing the lutein and lapatinib, preparing of protein target HER-2 (PDB ID 3PP0), validating of molecular docking protocol, and docking of lutein and lapatinib on HER-2. The study resulted in the binding energy of -12.37 kcal/mol, while the binding energy of the native ligand and lapatinib to HER-2 was -10.43 kcal/mol and -12.25 kcal/mol, respectively. The binding energy showed that lutein has potential as breast anticancer suggested from the stronger affinity to HER2.

scholarly journals The Arabidopsis autophagy cargo receptors ATI1 and ATI2 bind to ATG8 via intrinsically disordered regions and are post-translationally modified upon ATG8 interaction

2018 ◽  
Author(s):  
Ida Marie Zobbe Sjøgaard ◽  
Simon Bressendorff ◽  
Andreas Prestel ◽  
Swathi Kausika ◽  
Emilie Oksbjerg ◽  
...  
Keyword(s):  
Molten Globule ◽  
Resonance Spectroscopy ◽  
Wild Type ◽  
Post Translational Modification ◽  
Interacting Protein ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Specific Proteins ◽  
Modified Forms ◽  
Disordered Regions

AbstractSelective autophagy has emerged as an important mechanism by which eukaryotic cells control the abundance of specific proteins. This mechanism relies on cargo recruitment to autophagosomes by receptors that bind to both the ubiquitin-like AUTOPHAGY8 (ATG8) protein through ATG8 interacting motifs (AIMs) and to the cargo to be degraded. In plants, two autophagy cargo receptors, ATG8 Interacting Protein 1 (ATI1) and 2 (ATI2), were identified early on, but their molecular properties remain poorly understood. Here, we show that ATI1 and ATI2 are transmembrane proteins with long N-terminal intrinsically disordered regions (IDRs). The N-terminal IDRs contain the functional AIMs, and we use nuclear magnetic resonance spectroscopy to directly observe the disorder-order transition of the AIM upon ATG8 binding. Our analyses also show that the IDRs of ATI1 and ATI2 are not equivalent, because ATI2 has properties of a fully disordered polypeptide, while ATI1 has properties consistent with a collapsed pre-molten globule-like conformation Interestingly, wild type ATI1 and ATI2 exist as distinct post-translationally modified forms. Specifically, different forms are detectable upon mutation of the AIM, suggesting that interaction of ATI1 and ATI2 to ATG8 is coupled to a change in their post-translational modification.

scholarly journals Designing and Analyzing the Structure of DT-STXB Fusion Protein as an Anti-tumor Agent: An in Silico Approach

2019 ◽  
Vol 14 (4) ◽  
pp. 305-312 ◽  
Author(s):  
Zeynab Mohseni Moghadam ◽  
Raheleh Halabian ◽  
Hamid Sedighian ◽  
Elham Behzadi ◽  
Jafar Amani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fusion Protein ◽  
Shiga Toxin ◽  
In Silico ◽  
Tertiary Structure ◽  
Chimeric Protein ◽  
Human Tumors ◽  
Energy Calculation ◽  
Mrna Structure ◽  
The Stability

Background & Objective: A main contest in chemotherapy is to obtain regulator above the biodistribution of cytotoxic drugs. The utmost promising strategy comprises of drugs coupled with a tumor-targeting bearer that results in wide cytotoxic activity and particular delivery. The B-subunit of Shiga toxin (STxB) is nontoxic and possesses low immunogenicity that exactly binds to the globotriaosylceramide (Gb3/CD77). Gb3/CD77 extremely expresses on a number of human tumors such as pancreatic, colon, and breast cancer and acts as a functional receptor for Shiga toxin (STx). Then, this toxin can be applied to target Gb3-positive human tumors. In this study, we evaluated DT390-STXB chimeric protein as a new anti-tumor candidate via genetically fusing the DT390 fragment of DT538 (Native diphtheria toxin) to STxB. Methods: This study intended to investigate the DT390- STxB fusion protein structure in silico. Considering the Escherichia coli codon usage, the genomic construct was designed. The properties and the structure of the protein were determined by an in silico technique. The mRNA structure and the physicochemical characteristics, construction, and the stability of the designed chimeric protein were analyzed using computational and bioinformatics tools and servers. Hence, the GOR4 and I-TASSER online web servers were used to predict the secondary and tertiary structures of the designed protein. Results: The results demonstrated that codon adaptation index (CAI) of dt390-stxB chimeric gene raised from 0.6 in the wild type to 0.9 in the chimeric optimized gene. The mfold data revealed that the dt390-stxB mRNA was completely stable to be translated effectively in the novel host. The normal activity of the fusion protein determined by considering the secondary and tertiary structure of each construct. Energy calculation data indicated that the thermodynamic ensemble for mRNA structure was -427.40 kJ/mol. The stability index (SI) of DT390-STxB was 36.95, which is quite appropriate to preserve the stability of the construct. Ultimately, the DT390-STxB was classified as a steady fusion protein according to the Ramachandran plot. Conclusion: Our results showed that DT390-STXB was a stable chimeric protein and it can be recruited as a candidate of novel anti-tumor agents for the development of breast cancer treatment.

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