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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/3
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Publication Metadata only A homozygous pathogenic missense variant broadens the phenotypic and mutational spectrum of CREB3L1-related osteogenesis imperfecta(Oxford Univ Press, 2019) Guillemyn, Brecht; Demuynck, Lynn; Sips, Patrick; De Paepe, Anne; Syx, Delfien; Coucke, Paul J.; Malfait, Fransiska; Symoens, Sofie; N/A; Kayserili, Hülya; Faculty Member; School of Medicine; 7945The cyclic adenosine monophosphate responsive element binding protein 3-like 1 (CREB3L1) gene codes for the endoplasmic reticulum stress transducer old astrocyte specifically induced substance (OASIS), which has an important role in osteoblast differentiation during bone development. Deficiency of OASIS is linked to a severe form of autosomal recessive osteogenesis imperfecta (OI), but only few patients have been reported. We identified the first homozygous pathogenic missense variant [p.(Ala304Val)] in a patient with lethal OI, which is located within the highly conserved basic leucine zipper domain, four amino acids upstream of the DNA binding domain. In vitro structural modeling and luciferase assays demonstrate that this missense variant affects a critical residue in this functional domain, thereby decreasing the type I collagen transcriptional binding ability. In addition, overexpression of the mutant OASIS protein leads to decreased transcription of the SEC23A and SEC24D genes, which code for components of the coat protein complex type II (COPII), and aberrant OASIS signaling also results in decreased protein levels of SEC24D. Our findings therefore provide additional proof of the potential involvement of the COPII secretory complex in the context of bone-associated disease.Publication Metadata only Proteome analysis of the circadian clock protein PERIOD2(Wiley, 2022) Gül, Hüseyin; Selvi, Saba; Yılmaz, Fatma; Özçelik, Gözde; Olfaz-Aslan, Senanur; Yazan, Şeyma; Tiryaki, Büşra; Gül, Şeref; Öztürk, Nuri; N/A; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Yurtseven, Ali; Kavaklı, İbrahim Halil; Master Student; Faculty Member; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Engineering; College of Sciences; N/A; 40319; 105301Circadian rhythms are a series of endogenous autonomous 24-h oscillations generated by the circadian clock. At the molecular level, the circadian clock is based on a transcription-translation feedback loop, in which BMAL1 and CLOCK transcription factors of the positive arm activate the expression of CRYPTOCHROME (CRY) and PERIOD (PER) genes of the negative arm as well as the circadian clock-regulated genes. There are three PER proteins, of which PER2 shows the strongest oscillation at both stability and cellular localization level. Protein-protein interactions (PPIs) or interactome of the circadian clock proteins have been investigated using classical methods such as two-dimensional gel electrophoresis, immunoprecipitation-coupled mass spectrometry, and yeast-two hybrid assay where the dynamic and weak interactions are difficult to catch. To identify the interactome of PER2 we have adopted proximity-dependent labeling with biotin and mass spectrometry-based identification of labeled proteins (BioID). In addition to known interactions with such as CRY1 and CRY2, we have identified several new PPIs for PER2 and confirmed some of them using co-immunoprecipitation technique. This study characterizes the PER2 protein interactions in depth, and it also implies that using a fast BioID method with miniTurbo or TurboID coupled to other major circadian clock proteins might uncover other interactors in the clock that have yet to be discovered.Publication Metadata only Effect of long noncoding RNAs on epithelial-mesenchymal transition in A549 cells and fibrotic human lungs(Wiley, 2021) Yıldırım, Merve; Öztay, Füsun; Taşçı, Ahmet Erdal; N/A; Kayalar, Özgecan; Researcher; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; N/ALong noncoding RNAs (LncRNAs) regulate epithelial-mesenchymal transition (EMT). EMT involves myofibroblast differentiation and pulmonary fibrosis (PF). We aimed to determine the expression profiles of HOTAIR, CARLo-5, and CD99P1 LncRNAs in EMT-mediated myofibroblast differentiation in A549 cells and fibrotic human lungs and to explain their roles. A group of A549s was stimulated with transforming growth factor beta (TGF-beta; 5 ng/ml) to induce EMT. The remaining A549s were incubated with 20 mu M FH535 after 24 h of TGF-beta treatment to inhibit EMT. A549s were collected at 0, 24, 36, and 48 h. Expressions of three LncRNAs and protein/genes related to EMT, myofibroblast differentiation, and PF were assayed by quantitative reverse-transcription polymerase chain reaction and Western blot analysis in A549s and fibrotic human lungs. The targets of three LncRNAs were investigated by bioinformatics methods. TGF-beta stimulation resulted in increased expressions of three LncRNAs, ACTA2, COL1A1, SNAI1, CTNNB1, TCF4, LEF1, alpha-SMA, and active-beta-catenin, and decreased E-cadherin at 24, 36, and 48 h in A549s. FH535 treatment regressed these alterations. But it increased HOTAIR expression at 36 h and did not increase E-cadherin at 48 h. Fibrotic human lungs were characterized by increased expressions of HOTAIR, CARLo-5, CD99P1, and miR-214, decreased expressions of miR-148b, miR-218-1, miR-7-1, and the presence of CARLo-5 and CD99P1 in HDAC1-LncRNAs coprecipitation products, but not HOTAIR. Bioinformatic analysis showed the interactions of three LncRNAs with both proteins and at least 13 microRNAs related to EMT and PF. In conclusion, HOTAIR, CARLo-5, and CD99P1 can regulate EMT-mediated myofibroblast differentiation through interacting with proteins and miRNAs associated with EMT and PF. These LncRNAs can be considered as potential targets to decrease EMT for treating PF.Publication Metadata only Quasi-harmonic fluctuations of two bound peptides(Wiley-Blackwell, 2012) N/A; Department of Chemical and Biological Engineering; Gür, Mert; Erman, Burak; PhD Student; Faculty Member; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; College of Engineering; 216930; 179997Binding of two short peptides of sequences ASN-ASP-MET-PHE-ARG-LEU and LEU-LEU-PHE-MET-GLN-HIS and their bound complex structures is studied. Molecular dynamic simulations of the three structures around their respective minimum energy conformations are performed and a quasi-harmonic analysis is performed over the trajectories generated. The fluctuation correlation matrix is constructed for all C-alpha-atoms of the peptides for the full trajectory. The spring constant matrix between peptide C-alpha-atoms is obtained from the correlation matrix. Statistical thermodynamics of fluctuations, the energies, entropies, and the free energies of binding are discussed in terms of the quasi-harmonic model. Sites contributing to the stability of the system and presenting high affinity for binding are determined. Contribution of hydrophobic forces to binding is discussed. Quasi-harmonic approximation identifies the essential subspace of motions, the important interactions, and binding sites, gives the energetic contribution of each individual interaction, and filters out noise observed in molecular dynamics owing to uncorrelated motions. Comparison of the molecular dynamics results with those of the quasi-harmonic model shows the importance of entropy change, resulting from water molecules being liberated from the surfaces of the two peptides upon binding.Publication Metadata only Investigation of the factors affecting the photothermal therapy potential of small iron oxide nanoparticles over the 730-840 nm spectral region(Royal Soc Chemistry, 2018) N/A; N/A; N/A; Department of Physics; Department of Chemistry; Bilici, Kübra; Muti, Abdullah; Duman, Fatma Demir; Sennaroğlu, Alphan; Acar, Havva Funda Yağcı; PhD Student; PhD Student; PhD Student; Faculty Member; Faculty Member; Department of Physics; Department of Chemistry; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Sciences; College of Sciences; N/A; N/A; N/A; 23851; 178902The use of superparamagnetic iron oxide nanoparticles (SPIONs) as a sensitizer in photothermal therapy (PTT) is relatively new and the origin of such a phenomenon is not known. Usually, large crystals and aggregated particles are preferred in the literature, suggesting that these increase the absorbance of particles at the irradiation wavelength, and hence, provide a larger temperature increase. This study has two major goals: identification of the key factors that affect the photo-induced temperature increase in well-controlled experiments and the influence of laser irradiation on nanoparticle properties. Small, biocompatible poly(acrylic acid) coated SPIONs (PAA/SPIONs) were used since they are more practical for future medical use than large aggregates. We studied the impact of three major laser-dependent variables, namely the wavelength (between 728 and 838 nm), intensity (1.85-9.76 W cm(-2)) and power (105-800 mW) as well as attenuation at the irradiation wavelength, on photothermal heating achieved with PAA/SPIONs. Within the studied range of these variables, only the laser power plays a critical role on the magnitude of photothermal heating in solutions. There is no strong correlation between the attenuation at the excitation wavelength and the temperature increase. In addition, extensive characterization of SPIONs before and after irradiation revealed no significant difference, which supports the re-usability of SPIONs. Lastly, the PTT potential of these small PAA/SPIONs was demonstrated in vitro on HeLa cells. At these low laser powers no temperature increase in SPION-free water or cell death in SPION-free cells was detected. Hence, this study provides a new insight into the photothermal effect of SPIONs, provides a clear and repeatable experimental procedure and demonstrates great potential for small SPIONs to be exploited in PTT.Publication Metadata only Understanding follicle growth in vitro: are we getting closer to obtaining mature oocytes from in vitro-grown follicles in human?(Wiley, 2017) Güzel, Yılmaz; N/A; Öktem, Özgür; Faculty Member; School of Medicine; 102627Obtaining and fertilizing mature oocytes from immature follicles that were grown outside the body has conceptually attracted scientists for centuries, with initial attempts first documented in the 19th century. Significant progress has been made since then, due in part to a better understanding of folliculogenesis and improved techniques of in vitro follicle growth. Indeed, in vitro growth is now considered a reasonable approach to preserve or restore fertility when immature follicles and their oocytes need to be grown and matured outside the body. Certain patients would benefit from in vitro follicle growth, particularly those who carry a risk of cancer re-seeding after grafting of frozen-thawed ovarian tissue or who are at the risk of premature ovarian failure due to several intrinsic ovarian defects and genetic mutations that lead to accelerated follicle atresia and early exhaustion of the ovarian reserve. This review provides an update on the current status of in vitro growth of preantral human follicles, from initial efforts to the most recent achievements.Publication Metadata only Clinical and molecular findings of seven Turkish nonphotosensitive trichothiodystrophy patients with two novel mutations in MPLKIP(Nature Publishing Group, 2018) Kalayci, T.; Altunoglu, U.; Karaman, B.; Uyguner, Z.; N/A; Kayserili, Hülya; Faculty Member; School of Medicine; 7945N/APublication Metadata only Enriching the human apoptosis pathway by predicting the structures of protein-protein complexes(Elsevier, 2012) Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Computer Engineering; N/A; Keskin, Özlem; Gürsoy, Attila; Özbabacan, Saliha Ece Acuner; Faculty Member; Faculty Member; PhD Student; Department of Chemical and Biological Engineering; Department of Computer Engineering; The Center for Computational Biology and Bioinformatics (CCBB); College of Engineering; College of Engineering; Graduate School of Sciences and Engineering; 26605; 8745; 264351Apoptosis is a matter of life and death for cells and both inhibited and enhanced apoptosis may be involved in the pathogenesis of human diseases. The structures of protein-protein complexes in the apoptosis signaling pathway are important as the structural pathway helps in understanding the mechanism of the regulation and information transfer, and in identifying targets for drug design. Here, we aim to predict the structures toward a more informative pathway than currently available. Based on the 3D structures of complexes in the target pathway and a protein-protein interaction modeling tool which allows accurate and proteome-scale applications, we modeled the structures of 29 interactions, 21 of which were previously unknown. Next, 27 interactions which were not listed in the KEGG apoptosis pathway were predicted and subsequently validated by the experimental data in the literature. Additional interactions are also predicted. The multi-partner hub proteins are analyzed and interactions that can and cannot co-exist are identified. Overall, our results enrich the understanding of the pathway with interactions and provide structural details for the human apoptosis pathway. They also illustrate that computational modeling of protein-protein interactions on a large scale can help validate experimental data and provide accurate, structural atom-level detail of signaling pathways in the human cell.Publication Metadata only Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase(Nature Publishing Group (NPG), 2018) Ruess, Dietrich A.; Heynen, Guus J.; Ciecielski, Katrin J.; Ai, Jiaoyu; Berninger, Alexandra; Kabacaoglu, Derya; Goerguelue, Kivanc; Dantes, Zahra; Woermann, Sonja M.; Diakopoulos, Kalliope N.; Karpathaki, Angeliki F.; Kowalska, Marlena; Kaya-Aksoy, Ezgi; Song, Liang; van der Laan, Eveline A. Zeeuw; Lopez-Alberca, Maria P.; Nazare, Marc; Reichert, Maximilian; Saur, Dieter; Hopt, Ulrich T.; Sainz, Bruno, Jr.; Birchmeier, Walter; Schmid, Roland M.; Lesina, Marina; Alguel, Hana; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors(1). Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways(1-7). Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro(8). Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.Publication Metadata only Hot spots in protein-protein interfaces: towards drug discovery(Elsevier, 2014) N/A; N/A; Department of Computer Engineering; Department of Chemical and Biological Engineering; Çukuroğlu, Engin; Engin, Hatice Billur; Gürsoy, Attila; Keskin, Özlem; PhD Student; PhD Student; Faculty Member; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; Graduate School of Sciences and Engineering; N/A; College of Engineering; College of Engineering; N/A; N/A; 8745; 26605Identification of drug-like small molecules that alter protein-protein interactions might be a key step in drug discovery. However, it is very challenging to find such molecules that target interface regions in protein complexes. Recent findings indicate that such molecules usually target specifically energetically favored residues (hot spots) in protein protein interfaces. These residues contribute to the stability of protein-protein complexes. Computational prediction of hot spots on bound and unbound structures might be useful to find druggable sites on target interfaces. We review the recent advances in computational hot spot prediction methods in the first part of the review and then provide examples on how hot spots might be crucial in drug design. (C) 2014 Published by Elsevier Ltd.