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Publication Metadata only A fast approximate method of identifying paths of allosteric communication in proteins(Wiley, 2013) Department of Chemical and Biological Engineering; Erman, Burak; Faculty Member; Department of Chemical and Biological Engineering; College of Engineering; 179997Fluctuations of the distance between a pair of residues i and j may be correlated with the fluctuations of the distance between another pair k and l. In this case, information may be transmitted among these four residues. Allosteric activity is postulated to proceed through such correlated paths. In this short communication a fast method for calculating correlations among all possible pairs ij and kl leading to a pathway of correlated residues of a protein is proposed. The method is based on the alpha carbon centered Gaussian Network Model. The model is applied to Glutamine Amidotransferase and pathways of allosteric activity are identified and compared with literature. Proteins 2013; 81:1097-1101. (c) 2013 Wiley Periodicals, Inc.Publication Open Access AKT signaling modifies the balance between cell proliferation and migration in neural crest cells from patients affected with Bosma Arhinia and Microphthalmia Syndrome(Multidisciplinary Digital Publishing Institute (MDPI), 2021) Laberthonnière, C.; Novoa-Del-Toro, E. M.; Chevalier, R.; Broucqsault, N.; Rao, V. V.; Trani, J. P.; Nguyen, K.; Xue, S.; Robin, J. D.; Baudot, A.; Magdinier, F.; Reversade, Bruno; Faculty Member; School of MedicineOver the recent years, the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain Containing 1) chromatin-associated factor has triggered increasing interest after the identification of variants in three rare and unrelated diseases, type 2 Facio Scapulo Humeral Dystrophy (FSHD2), Bosma Arhinia and Microphthalmia Syndrome (BAMS), and the more recently isolated hypogonadotrophic hypogonadism (IHH) combined pituitary hormone deficiency (CPHD) and septo-optic dysplasia (SOD). However, it remains unclear why certain mutations lead to a specific muscle defect in FSHD while other are associated with severe congenital anomalies. To gain further insights into the specificity of SMCHD1 variants and identify pathways associated with the BAMS phenotype and related neural crest defects, we derived induced pluripotent stem cells from patients carrying a mutation in this gene. We differentiated these cells in neural crest stem cells and analyzed their transcriptome by RNA-Seq. Besides classical differential expression analyses, we analyzed our data using MOGAMUN, an algorithm allowing the extraction of active modules by integrating differential expression data with biological networks. We found that in BAMS neural crest cells, all subnetworks that are associated with differentially expressed genes converge toward a predominant role for AKT signaling in the control of the cell proliferation-migration balance. Our findings provide further insights into the distinct mechanism by which defects in neural crest migration might contribute to the craniofacial anomalies in BAMS.Publication Metadata only An integrative analysis of transcriptomic response of ethanol tolerant strains to ethanol in Saccharomyces cerevisiae(Royal Soc Chemistry, 2016) Kasavi, Ceyda; Oner, Ebru Toksoy; Kirdar, Betul; N/A; Eraslan, Serpil; Researcher; School of Medicine; N/AThe accumulation of ethanol is one of the main environmental stresses that Saccharomyces cerevisiae cells are exposed to in industrial alcoholic beverage and bioethanol production processes. Despite the known impacts of ethanol, the molecular mechanisms underlying ethanol tolerance are still not fully understood. Novel gene targets leading to ethanol tolerance were previously identified via a network approach and the investigations of the deletions of these genes resulted in the improved ethanol tolerance of pmt7 Delta/pmt7 Delta and yhl042w Delta/yhl042w Delta strains. In the present study, an integrative system based approach was used to investigate the global transcriptional changes in these two ethanol tolerant strains in response to ethanol and hence to elucidate the mechanisms leading to the observed tolerant phenotypes. In addition to strain specific biological processes, a number of common and already reported biological processes were found to be affected in the reference and both ethanol tolerant strains. However, the integrative analysis of the transcriptome with the transcriptional regulatory network and the ethanol tolerance network revealed that each ethanol tolerant strain had a specific organization of the transcriptomic response. Transcription factors around which most important changes occur were determined and active subnetworks in response to ethanol and functional clusters were identified in all strains.Publication Metadata only Atorvastatin attenuates pulmonary fibrosis in mice and human lung fibroblasts, by the regulation of myofibroblast differentiation and apoptosis(Wiley, 2022) Yıldırım, Merve; Atahan, Ersan; Öztay, Füsun; N/A; Kayalar, Özgecan; Researcher; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/AStatins have anti-inflammatory and antifibrotic effects in addition to cholesterol-lowering effect. We aimed to investigate the effect of atorvastatin (ATR) in fibrotic mouse lung and human lung fibroblasts (MRCSs). Pulmonary fibrosis was induced by a single dose of bleomycin by intratracheal instillation in adult mice. ATR was administered (20 mg/kg ip) to mice with healthy and pulmonary fibrosis for 10 days from Day 7 of the experiment. Mice were dissected on the 21st day. The levels of alpha-smooth muscle actin (alpha-SMA), pSMAD2/3, LOXL2, and p-Src were determined by Western blot analysis in the lungs. Furthermore, a group of MRC5 was differentiated into myofibroblasts by transforming growth factor-beta (TGF-beta). Another group of MRCSs was treated with 10 mu M ATR at 24 h after TGF-beta stimulation. Cells were collected at 0, 24, 48, and 72 h. The effects of ATR on myofibroblast differentiation, apoptosis, and TGF-beta and Wnt/beta-catenin signaling activations were examined by Western blot analysis and flow cytometry in MRC5s. ATR attenuated pulmonary fibrosis by regulating myofibroblast differentiation and interstitial accumulation of collagen, by acting on LOXL2, p-Src, and pSMAD2/3 in mice lungs. Additionally, it blocked myofibroblast differentiation via reduced TGF-beta and Wnt/beta-catenin signaling and decreased alpha-SMA in MRCSs stimulated with TGF-beta. Moreover, ATR caused myofibroblast apoptosis via caspase-3 activation. ATR treatment attenuates pulmonary fibrosis in mice treated with bleomycin. It also inhibits fibroblast/myofibroblast activation, by both reducing myofibroblasts differentiation and inducing myofibroblast apoptosis.Publication Metadata only Cabazitaxel exhibits more favorable molecular changes compared to other taxanes in androgen-independent prostate cancer cells(Wiley, 2020) Çevik, Özge; Acidereli, Hilal; Turut, Fatma Aysun; Yıldırım, Şahin; Ayhan, Ceyda Açılan; Faculty Member; School of Medicine; 219658Taxane-based chemotherapy drugs (cabazitaxel, docetaxel, and paclitaxel) are microtubule inhibitors, which are effectively and frequently used to treat metastatic prostate cancer (PCa). Among these, cabazitaxel is offered as a new therapeutic option for patients with metastatic castration-resistant PC as that are resistant to other taxanes. Here, we investigated the cellular and molecular changes in response to cabazitaxel in comparison with docetaxel and paclitaxel in androgen-independent human PCas. The androgen-independent human PCa cell lines, PC3 and DU145, were treated with 1 to 5nM cabazitaxel, docetaxel, or paclitaxel, and assessed for cell viability (MTT assay), colony forming ability and migration (scratch assay). The induction of apoptosis was determined through measurement of mitochondrial membrane potential (JC-1 assay) and caspase-3 activity assay. The protein expression changes (caspase-3, caspase-8, Bax, Bcl-2, beta-tubulin, nuclear factor-kappa B [NF-kappa B/p50, NF-kappa B/p65], vascular endothelial growth factor, WNT1-inducible signaling pathway protein-1 [WISP1], transforming growth factor beta [TGF-beta]) in response to drug treatment were screened via western blotting. Under our experimental conditions, all taxanes significantly reduced WISP1 and TGF-beta expressions, suggesting an anti-metastatic/antiangiogenic effect for these drugs. On the other hand, cabazitaxel induced more cell death and inhibited colony formation compared to docetaxel or paclitaxel. The highest fold change in caspase-3 activity and Bax/Bcl-2 ratio was also detected in response to cabazitaxel. Furthermore, the induction of beta-tubulin expression was lower in cabazitaxel-treated cells relative to the other taxanes. In summary, cabazitaxel shows molecular changes in favor of killing PCa cells compared to other taxanes, at least for the parameters analyzed herein. The differences with other taxanes may be important while designing other studies or in clinical settings.Publication Metadata only CGRP induces myofibroblast differentiation and the production of extracellular matrix in MRC5s via autocrine and paracrine signalings(Wiley, 2022) Öztay, Füsun; N/A; Kayalar, Özgecan; Researcher; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/AThere are contradictory views on which calcitonin gene-related peptide (CGRP) causes pulmonary fibrosis. Fibrotic potency of CGRP was tested and compared to that of transforming growth factor-beta (TGF-beta). Myofibroblast differentiation, cell proliferation, and activations of TGF-beta and Writ pathways were examined for 24, 48, and 72 h in A549 and MRC5 cell lines stimulated with CGRP and TGF-beta. CGRP-induced cell proliferation in MRC5s early on while cell proliferation in A549 occurred progressively. CGRP promoted fibroblast-myofibroblast differentiation by inducing the transcription of ACTA2, COL1A1, SMAD2/3, and SMAD4 genes, the production of collagen, fibronectin, alpha-smooth muscle actin, and activation of TGF-beta signaling starting from 24 h. Additionally, TGF-beta signaling induced by CGRP decreased the DKK1 level and activated the Wnt signaling in MRC5s. After CGRP stimulation, Wnt7a levels were increased from 24 to 72 h, while Wnt5a levels were elevated at 72 h in MRC5s. CGRP did not induce epithelial-mesenchymal transition in A549s, unlike TGF-beta. A comparison of fibrotic potency of CGRP and TGF-beta showed that TGF-beta is a powerful profibrotic molecule and induces earlier myofibroblast differentiation. Even so, CGRP promotes myofibroblast differentiation and extra-cellular matrix production by inducing Smad-dependent-TGF-beta and Wnt signalings via autocrine and paracrine signalings in MRC5s.Publication Open Access Characterization of the conformational state and flexibility of HIV-1 glycoprotein gp120 core domain(American Society for Biochemistry and Molecular Biology (ASBMB), 2004) Pan, Yongping.; Ma, Buyong; Nussinov, Ruth; Department of Chemical and Biological Engineering; Keskin, Özlem; Faculty Member; Department of Chemical and Biological Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; 26605gp120 is key to the human immunodeficiency virus type 1 viral cell entry. Knowledge of the detailed conformational states of gp120 is crucial to intervention, yet the unbound form is still resistant to structural characterization probably because of its flexibility. Toward this goal, we performed molecular dynamics simulations on the wild type gp120 core domain extracted from its ternary crystal structure and on a modeled mutant, S375W, that experimentally has a significantly different phenotype from the wild type. Although the mutant retained a bound-like conformation, the wild type drifted to a different conformational state. The wild type beta strands 2 and 3 of the bridging sheet were very mobile and partially unfolded, and the organization among the inner and outer domains and beta strands 20 and 21 of the bridging sheet, near the mutation site, was more open than in the bound form, although the overall structure was maintained. These differences were apparently a result of the strengthening of the hydrophobic core in the mutant. This stabilization further explains the experimentally significantly different thermodynamic properties between the wild type and the mutant. Taken together, our results suggest that the free form, although different from the bound state, shares many of the bound structural features. The observed loss of freedom near the binding site, rather than the previously hypothesized more dramatic conformational transition from the unbound to the bound state, appears to be the major contributor to the large entropy cost for the CD4 binding to the wild type.Publication Metadata only Computer-aided drug discovery for DNA photolyase: with an emphasis on biomolecular interaction analysis in drug discovery using surface plasmon resonance'(Wiley-Blackwell, 2011) N/A; Department of Chemical and Biological Engineering; Azizoğlu, Selimcan; Kızılel, Seda; Master Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 28376N/APublication Metadata only Conformational properties of amphotericin b amide derivatives - impact on selective toxicity(Springer, 2000) Sungur, F. Aylin; Baginski, Maciej; Borowski, Edward; Aviyente, Viktorya; Department of Physics; Reşat, Haluk; Faculty Member; Department of Physics; College of Sciences; N/AEven though it is highly toxic, Amphotericin B (AmB), an amphipathic polyene macrolide antibiotic, is used in the treatment of severe systemic fungal infections as a life-saving drug. To examine the influence of conformational factors on selective toxicity of these compounds, we have investigated the conformational properties of five AmB amide derivatives. It was found that the extended conformation with torsional angles (phi,psi)=(290 degrees,180 degrees ) is a common minimum of the potential energy surfaces (PES) of unsubstituted AmB and its amide derivatives. The extended conformation of the studied compounds allows for the formation of an intermolecular hydrogen bond network between adjacent antibiotic molecules in the open channel configuration. Therefore, the extended conformation is expected to be the dominant conformer in an open AmB (or its amide derivatives) membrane channel. The derivative compounds for calculations were chosen according to their selective toxicity compared to AmB and they had a wide range of selective toxicity. Except for two AmB derivatives, the PES maps of the derivatives reveal that the molecules can coexist in more than one conformer. Taking into account the cumulative conclusions drawn from the earlier MD simulation studies of AmB membrane channel, the results of the potential energy surface maps, and the physical considerations of the molecular structures, we hypothesize a new model of structure-selective toxicity of AmB derivatives. In this proposed model the presence of the extended conformation as the only well defined global conformer for AmB derivatives is taken as the indicator of their higher selective toxicity. This model successfully explains our results. To further test our model, we also investigated an AmB derivative whose selective toxicity has not been experimentally measured before. Our prediction for the selective toxicity of this compound can be tested in experiments to validate or invalidate the proposed model.Publication Metadata only Conformational properties of amphotericin B amide derivatives - impact on selective toxicity(Springer, 2000) Sungur, Fethiye Aylin; Beginski, Maciej; Borowski, Edward; Aviyente, Viktorya; Department of Physics; Reşat, Haluk; Faculty Member; Department of Physics; College of Sciences; N/AEven though it is highly toxic, Amphotericin B (AmB), an amphipathic polyene macrolide antibiotic, is used in the treatment of severe systemic fungal infections as a life-saving drug. To examine the influence of conformational factors on selective toxicity of these compounds, we have investigated the conformational properties of five AmB amide derivatives. It was found that the extended conformation with torsional angles (ΦΨ)=(290°, 180°) is a common minimum of the potential energy surfaces (PES) of unsubstituted AmB and its amide derivatives. The extended conformation of the studied compounds allows for the formation of an intermolecular hydrogen bond network between adjacent antibiotic molecules in the open channel configuration. Therefore, the extended conformation is expected to be the dominant conformer in an open AmB (or its amide derivatives) membrane channel. The derivative compounds for calculations were chosen according to their selective toxicity compared to AmB and they had a wide range of selective toxicity. Except for two AmB derivatives, the PES maps of the derivatives reveal that the molecules can coexist in more than one conformer. Taking into account the cumulative conclusions drawn from the earlier MD simulation studies of AmB membrane channel, the results of the potential energy surface maps, and the physical considerations of the molecular structures, we hypothesize a new model of structure-selective toxicity of AmB derivatives. In this proposed model the presence of the extended conformation as the only well defined global conformer for AmB derivatives is taken as the indicator of their higher selective toxicity. This model successfully explains our results. To further test our model, we also investigated an AmB derivative whose selective toxicity has not been experimentally measured before. Our prediction for the selective toxicity of this compound can be tested in experiments to validate or invalidate the proposed model.