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Now showing 1 - 10 of 49
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    A genome-wide functional screen identifies enhancer and protective genes for amyloid beta-peptide toxicity
    (Multidisciplinary Digital Publishing Institute (MDPI), 2023) Picon-Pages, Pol; Bosch-Morato, Monica; Subirana, Laia; Rubio-Moscardo, Francisca; Guivernau, Biuse; Fanlo-Ucar, Hugo; Herrera-Fernandez, Victor; Vicente, Ruben; Fernandez-Fernandez, Jose M.; Garcia-Ojalvo, Jordi; Oliva, Baldomero; Posas, Francesc; de Nadal, Eulalia; Munoz, Francisco J.; N/A; N/A; N/A; Department of Computer Engineering; Department of Computer Engineering; Department of Computer Engineering; Zeylan, Melisa Ece; Şenyüz, Simge; Gürsoy, Attila; Keskin, Özlem; PhD Student; Master Student; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; N/A; 8745; 26605
    Alzheimer's disease (AD) is known to be caused by amyloid beta-peptide (A beta) misfolded into beta-sheets, but this knowledge has not yet led to treatments to prevent AD. To identify novel molecular players in A beta toxicity, we carried out a genome-wide screen in Saccharomyces cerevisiae, using a library of 5154 gene knock-out strains expressing A beta(1-42). We identified 81 mammalian orthologue genes that enhance A beta(1-42) toxicity, while 157 were protective. Next, we performed interactome and text-mining studies to increase the number of genes and to identify the main cellular functions affected by A beta oligomers (oA beta). We found that the most affected cellular functions were calcium regulation, protein translation and mitochondrial activity. We focused on SURF4, a protein that regulates the store-operated calcium channel (SOCE). An in vitro analysis using human neuroblastoma cells showed that SURF4 silencing induced higher intracellular calcium levels, while its overexpression decreased calcium entry. Furthermore, SURF4 silencing produced a significant reduction in cell death when cells were challenged with oA beta(1-42), whereas SURF4 overexpression induced A beta(1-42) cytotoxicity. In summary, we identified new enhancer and protective activities for A beta toxicity and showed that SURF4 contributes to oA beta(1-42) neurotoxicity by decreasing SOCE activity.
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    A new recognizable recessive syndrome with distinct dysmorphism, lymphedema and sensorineural hearing loss caused by carboxypeptidase D mutations
    (Nature Publishing Group, 2018) Altunoğlu, U.; Laupheimer, S.; Bonnard, C.; N/A; Kayserili, Hülya; Reversade, Bruno; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 7945; 274182
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    A novel and promising multi-enzyme co-embedded organicinorganic hybrid nanoflower with enhanced stability and catalytic activity
    (Wiley, 2019) Gecili, Firdevs; Ozdemir, Nalan; N/A; Aydemir, Duygu; Ulusu, Nuriye Nuray; PhD Student; Faculty Member; Graduate School of Health Sciences; School of Medicine; N/A; 6807
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    Abnormal high-energy phosphate molecule metabolism during regional brain activation in patients with bipolar disorder
    (Nature Publishing Group (NPG), 2015) Yuksel, C.; Du, F.; Ravichandran, C.; Goldbach, J. R.; Thida, T.; Lin, P.; Gelda, J.; O'Connor, L.; Sehovic, S.; Gruber, S.; Ongur, D.; Cohen, B. M.; Department of Psychology; Department of Psychology; Dora, Begüm; PhD Student; College of Social Sciences and Humanities; N/A
    Converging evidence suggests bioenergetic abnormalities in bipolar disorder (BD). In the brain, phosphocreatine (PCr) acts a reservoir of high-energy phosphate (HEP) bonds, and creatine kinases (CK) catalyze the transfer of HEP from adenosine triphosphate (ATP) to PCr and from PCr back to ATP, at times of increased need. This study examined the activity of this mechanism in BD by measuring the levels of HEP molecules during a stimulus paradigm that increased local energy demand. Twenty-three patients diagnosed with BD-I and 22 healthy controls (HC) were included. Levels of phosphorus metabolites were measured at baseline and during visual stimulation in the occipital lobe using P-31 magnetic resonance spectroscopy at 4T. Changes in metabolite levels showed different patterns between the groups. During stimulation, HC had significant reductions in PCr but not in ATP, as expected. In contrast, BD patients had significant reductions in ATP but not in PCr. In addition, PCr/ATP ratio was lower at baseline in patients, and there was a higher change in this measure during stimulation. This pattern suggests a disease-related failure to replenish ATP from PCr through CK enzyme catalysis during tissue activation. Further studies measuring the CK flux in BD are required to confirm and extend this finding.
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    PublicationOpen 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 Medicine
    Over 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.
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    Application of exosomes for the alleviation of COVID-19-related pathologies
    (Wiley, 2022) Rezabakhsh, Aysa; Mahdipour, Mahdi; Nourazarian, Alireza; Habibollahi, Paria; Avcı, Çığır Biray; Rahbarghazi, Reza; Sokullu, Emel; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 163024
    The pandemic of COVID-19 caused worldwide concern. Due to the lack of appropriate medications and the inefficiency of commercially available vaccines, lots of efforts are being made to develop de novo therapeutic modalities. Besides this, the possibility of several genetic mutations in the viral genome has led to the generation of resistant strains such as Omicron against neutralizing antibodies and vaccines, leading to worsening public health status. Exosomes (Exo), nanosized vesicles, possess several therapeutic properties that participate in intercellular communication. The discovery and application of Exo in regenerative medicine have paved the way for the alleviation of several pathologies. These nanosized particles act as natural bioshuttles and transfer several biomolecules and anti-inflammatory cytokines. To date, several approaches are available for the administration of Exo into the targeted site inside the body, although the establishment of standard administration routes remains unclear. As severe acute respiratory syndrome coronavirus 2 primarily affects the respiratory system, we here tried to highlight the transplantation of Exo in the alleviation of COVID-19 pathologies.
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    Architectures and functional coverage of protein-protein interfaces
    (Elsevier, 2008) Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Tunçbağ, Nurcan; Gürsoy, Attila; Güney, Emre; Keskin, Özlem; Faculty Member; Faculty Member; Master Student; Faculty Member; College of Engineering; College of Engineering; Graduate School of Sciences and Engineering; College of Engineering; 245513; 8745; N/A; 26605
    The diverse range of cellular functions is performed by a limited number of protein folds existing in nature. One may similarly expect that cellular functional diversity would be covered by a limited number of protein-protein interface architectures. Here, we present 8205 interface clusters, each representing a unique interface architecture. This data set of protein-protein interfaces is analyzed and compared with older data sets. We observe that the number of both biological and crystal interfaces increases significantly compared to the number of Protein Data Bank entries. Furthermore, we find that the number of distinct interface architectures grows at a much faster rate than the number of folds and is yet to level off. We further analyze the growth trend of the functional coverage by constructing functional interaction networks from interfaces. The functional coverage is also found to steadily increase. Interestingly, we also observe that despite the diversity of interface architectures, some are more favorable and frequently used, and of particular interest, are the ones that are also preferred in single chains.
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    PublicationOpen 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; Department of Chemical and Biological Engineering; Keskin, Özlem; Faculty Member; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; 26605
    gp120 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.
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    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; Department of Physics; Reşat, Haluk; Faculty Member; College of Sciences; N/A
    Even 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.
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    De novo gain-of-function mutations in the epigenetic regulator SMCHD1 cause Bosma arhinia microphthalmia syndrome
    (NATURE PUBLISHING GROUP, 2018) Gordon, C. T.; Xue, S.; Yigit, G.; Filali, H.; Chen, K.; Rosin, N.; Yoshiura, K.; Oufadem, M.; Beck, T.; Dion, C.; Sefiani, A.; Murphy, J.; Chatdokmaiprai, C.; Hillmer, A.; Wattanasirichaigoon, D.; Lyonnet, S.; Magdinier, F.; Javed, A.; Blewitt, M.; Amiel, J.; Wollnik, B.; Reversade, B.; N/A; Kayserili, Hülya; Faculty Member; School of Medicine; 7945
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