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Publication Open Access Archaeogenetic analysis of Neolithic sheep from Anatolia suggests a complex demographic history since domestication(Nature Portfolio, 2021) Yurtman, Erinç; Özer, Onur; Yüncü, Eren; Dağtaş, Nihan Dilşad; Koptekin, Dilek; Çakan, Yasin Gökhan; Özkan, Mustafa; Akbaba, Ali; Kaptan, Damla; Atağ, Gözde; Vural, Kıvılcım Başak; Gündem, Can Yümni; Martin, Louise; Kılınç, Gülşah Merve; Ghalichi, Ayshin; Açan, Sinan Can; Yaka, Reyhan; Sağlıcan, Ekin; Lagerholm, Vendela Kempe; Krzewinska, Maja; Gunther, Torsten; Miranda, Pedro Morell; Pişkin, Evangelia; Sevketoğlu, Müge; Bilgin, C. Can; Atakuman, Ciğdem; Erdal, Yılmaz Selim; Sürer, Elif; Altınışık, N. Ezgi; Lenstra, Johannes A.; Yorulmaz, Sevgi; Abazari, Mohammad Foad; Hoseinzadeh, Javad; Baird, Douglas; Bıcakcı, Erhan; Çevik, Özlem; Gerritsen, Fokke; Gotherstrom, Anders; Somel, Mehmet; Togan, İnci; Özer, Füsun; Department of Archeology and History of Art; Özbal, Rana; Faculty Member; Department of Archeology and History of Art; College of Social Sciences and Humanities; 55583Sheep were among the first domesticated animals, but their demographic history is little understood. Here we analyzed nuclear polymorphism and mitochondrial data (mtDNA) from ancient central and west Anatolian sheep dating from Epipaleolithic to late Neolithic, comparatively with modern-day breeds and central Asian Neolithic/Bronze Age sheep (OBI). Analyzing ancient nuclear data, we found that Anatolian Neolithic sheep (ANS) are genetically closest to present-day European breeds relative to Asian breeds, a conclusion supported by mtDNA haplogroup frequencies. In contrast, OBI showed higher genetic affinity to present-day Asian breeds. These results suggest that the east-west genetic structure observed in present-day breeds had already emerged by 6000 BCE, hinting at multiple sheep domestication episodes or early wild introgression in southwest Asia. Furthermore, we found that ANS are genetically distinct from all modern breeds. Our results suggest that European and Anatolian domestic sheep gene pools have been strongly remolded since the Neolithic.
Publication Metadata only Bud14 function is crucial for spindle pole body size maintenance(TUBITAK, 2024) Department of Molecular Biology and Genetics; Girgin, Sevilay Münire; Çaydaşı, Ayşe Koca; Department of Molecular Biology and Genetics; College of Sciences; Graduate School of Sciences and EngineeringBackground/aim: Spindle pole bodies (SPB), the functional equivalent of centrosomes in yeast, duplicate through generation of a new SPB next to the old one. However, SPBs are dynamic structures that can grow and exchange, and mechanisms that regulate SPB size remain largely unknown. This study aims to elucidate the role of Bud14 in SPB size maintenance in Saccharomyces cerevisiae. Materials and methods: We employed quantitative fluorescence microscopy to assess the relative and absolute amounts of SPB structural proteins at SPBs of wildtype cells and in cells lacking BUD14 (bud14∆). Quantifications were performed using asynchronous cell cultures, as well as cultures synchronously progressing through the cell cycle and upon different cell cycle arrests. We also utilized mutants that allow the separation of Bud14 functions. Results: Our results indicate that higher levels of SPB inner, outer, and central plaque proteins are present at the SPBs of bud14∆ cells compared to wildtype cells during anaphase, as well as during nocodazole-induced M-phase arrest. However, during α-factor mediated G1 arrest, inner and outer plaque proteins responded differently to the absence of BUD14. A Bud14 mutant that cannot interact with the Protein Phosphatase 1 (Glc7) phenocopied bud14∆ in terms of SPB-bound levels of the inner plaque protein Spc110, whereas disruption of Bud14-Kel1-Kel2 complex did not alter Spc110 levels at SPBs. In cells synchronously released from α-factor arrest, lack of Bud14-Glc7 caused increase of Spc110 at the SPBs at early stages of the cell cycle. Conclusion: We identified Bud14 as a critical protein for SPB size maintenance. The interaction of Bud14 with Glc7, but not with the Kelch proteins, is indispensable for restricting levels of Spc110 incorporated into the SPBs. © TÜBİTAK.Publication Open Access CLIC4 and CLIC1 bridge plasma membrane and cortical actin network for a successful cytokinesis(Life Science Alliance LLC, 2020) Department of Molecular Biology and Genetics; Kagiali, Zeynep Cansu Üretmen; Şanal, Erdem; Değirmenci, Beste Senem; Mollaoğlu, Gürkan; Saner, Nazan; Master Student; Faculty Member; Researcher; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; N/A; N/A; 105301; 227757CLIC4 and CLIC1 are members of the well-conserved chloride intracellular channel proteins (CLICs) structurally related to glutathione-S-transferases. Here, we report new roles of CLICs in cytokinesis. At the onset of cytokinesis, CLIC4 accumulates at the cleavage furrow and later localizes to the midbody in a RhoA-dependent manner. The cell cycle-dependent localization of CLIC4 is abolished when its glutathione S-transferase activity-related residues (C35A and F37D) are mutated. Ezrin, anillin, and ALIX are identified as interaction partners of CLIC4 at the cleavage furrow and midbody. Strikingly, CLIC4 facilitates the activation of ezrin at the cleavage furrow and reciprocally inhibition of ezrin activation diminishes the translocation of CLIC4 to the cleavage furrow. Furthermore, knockouts of CLIC4 and CLIC1 cause abnormal blebbing at the polar cortex and regression of the cleavage furrow at late cytokinesis leading to multinucleated cells. We conclude that CLIC4 and CLIC1 function together with ezrin where they bridge plasma membrane and actin cytoskeleton at the polar cortex and cleavage furrow to promote cortical stability and successful completion of cytokinesis in mammalian cells.Publication Metadata only Computational design of a pentapeptide inhibitor for fibroblast growth factor receptor 3b (FGFR3b)(Tubitak Scientific & Technical Research Council Turkey, 2013) N/A; N/A; Öztürk, Mehmet Ali; Master Student; Graduate School of Sciences and Engineering; N/AFibroblast growth factor receptor ( FGFR) is a cell membrane protein and a member of the tyrosine kinase family. It has extracellular domains that can be activated by ligand binding, followed by receptor dimerization. FGFR3 has 2 isoforms, 3b and 3c. The R248C mutation in FGFR3b leads to ligand independent receptor dimerization and results in different kinds of dermatological diseases such as seborrheic keratoses, acanthosis nigricans, and epidermal nevi. In order to prevent the increased cellular signaling caused by the R248C mutation, a pentapeptide ligand was designed that recognizes the mutation and binds to the receptor dimerization site. Molecular docking and steered molecular dynamics simulations were conducted, and binding free energy was calculated. The identified pentapeptide sequence appears to be a possible drug candidate for FGFR3b R248C mutation-related skin diseases.Publication Open Access Cooperative allostery and structural dynamics of streptavidin at cryogenic- and ambient-temperature(Springer Nature, 2022) Yefanov, Oleksandr M.; Barty, Anton; Tolstikova, Alexandra; Ketawala, Gihan K.; Botha, Sabine; Dao, E. Han; Hayes, Brandon; Liang, Mengning; Seaberg, Matthew H.; Hunter, Mark S.; Batyuk, Alexander; Mariani, Valerio; Su, Zhen; Poitevin, Frederic; Yoon, Chun Hong; Kupitz, Christopher; Cohen, Aina; Doukov, Tzanko; Sierra, Raymond G.; Department of Molecular Biology and Genetics; Dağ, Çağdaş; Ayan, Esra; Yüksel, Büşra; Destan, Ebru; Ertem, Fatma Betül; Yıldırım, Günseli; Eren, Meryem; Demirci, Hasan; Faculty Member; PhD Student; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Engineering; N/A; N/A; N/A; N/A; N/A; N/A; N/A; 307350Ayan et al. report two structures of the protein streptavidin - one at ambient temperature determined using serial femtosecond crystallography and a second one determined at cryogenic temperature. These results provide insights into the structural dynamics of apo streptavidin and reveal a cooperative allostery between monomers for binding to biotin, and the findings are supported by GNM analysis. Multimeric protein assemblies are abundant in nature. Streptavidin is an attractive protein that provides a paradigm system to investigate the intra- and intermolecular interactions of multimeric protein complexes. Also, it offers a versatile tool for biotechnological applications. Here, we present two apo-streptavidin structures, the first one is an ambient temperature Serial Femtosecond X-ray crystal (Apo-SFX) structure at 1.7 angstrom resolution and the second one is a cryogenic crystal structure (Apo-Cryo) at 1.1 angstrom resolution. These structures are mostly in agreement with previous structural data. Combined with computational analysis, these structures provide invaluable information about structural dynamics of apo streptavidin. Collectively, these data further reveal a novel cooperative allostery of streptavidin which binds to substrate via water molecules that provide a polar interaction network and mimics the substrate biotin which displays one of the strongest affinities found in nature.Publication Open Access Crosstalk between autophagy and DNA repair systems(TÜBİTAK, 2021) Demirbağ Sarıkaya, Sinem; Çakır, Hatice; Gözüaçık, Devrim; Akkoç, Yunus; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 40248; N/AAutophagy and DNA repair are two essential biological mechanisms that maintain cellular homeostasis. Impairment of these mechanisms was associated with several pathologies such as premature aging, neurodegenerative diseases, and cancer. Intrinsic or extrinsic stress stimuli (e.g., reactive oxygen species or ionizing radiation) cause DNA damage. As a biological stress response, autophagy is activated following insults that threaten DNA integrity. Hence, in collaboration with DNA damage repair and response mechanisms, autophagy contributes to the maintenance of genomic stability and integrity. Yet, connections and interactions between these two systems are not fully understood. In this review article, current status of the associations and crosstalk between autophagy and DNA repair systems is documented and discussed.Publication Metadata only Dependence of erythrocyte deformability on mechanical stress and oxygenation(Federation amer Soc Exp Biol, 2017) N/A; N/A; N/A; Department of Physics; N/A; Yalçın, Özlem; Uğurel, Elif; Sağlam, Gökay; Erten, Ahmet Can; Aksu, Ali Cenk; Faculty Member; Researcher; Undergraduate Student; Teaching Faculty; PhD Student; Department of Physics; School of Medicine; School of Medicine; School of Medicine; College of Engineering; Graduate School of Health Sciences; 218440; N/A; N/A; N/A; N/AMechanical properties of erythrocytes are known to be affected by their oxygenation status. Several studies suggested that cytoskeletal rearrangements are carried out in an oxygen dependent manner. The structure of the cytoskeleton determines the mechanical properties of erythrocyte membrane. However, oxygen-dependent mechanical characteristics of erythrocyte are poorly studied whether oxygenated state could alter erythrocyte deformability. In this study, we investigated shear stress induced improvements in erythrocyte deformability through their oxygenation status. Venous blood was collected from male, healthy volunteers (n=10) between 25–50 ages. An informed written consent was obtained from each subject participated in the study according to Declaration of Helsinki. The hematocrit of blood samples adjusted to 0.4 l/l with autologous plasma. Whole blood samples were diluted with polyvinylpyrrolidone (PVP) solution (Mechatronics, Hoorn, Netherlands) with a dilution ratio of 1/200. Blood samples were equilibrated with either ambient air or nitrogen gas for at least 10 minutes at room temperature. Erythrocyte deformability was measured by a laser-assisted optical rotational cell analyzer (LORRCA MaxSis, Mechatronics, Netherlands) applying shear stresses (SS) ranging between 0.3 to 50 Pa. Then, a constant SS of 5, 10 and 20 Pa were applied continuously for 300 seconds and erythrocyte deformability was measured immediately afterwards. Maximal erythrocyte elongation index (EImax) and the SS required for one-half of this maximal deformation (SS1/2) were calculated by using the linear Lineweaver-Burke (LB) model. Deoxygenation of blood samples significantly decreased SS1/2 values both before and after SS applications (p < 0.001). EImax was significantly increased in deoxygenated blood before applying 5 Pa SS (p < 0.05). However, there were no significant differences after continuous SS in oxygenated and deoxygenated blood. Deoxygenation significantly decreased SS1/2/EImax values both before and after SS applications (p < 0.01). SS1/2/EImax values in both oxygenated and deoxygenated blood were significantly decreased after 5 and 10 Pa continuous SS applications although they were not significantly decreased after applying 20 Pa SS. Our study showed for the first time that erythrocyte deformability is improved in deoxygenated conditions in contrast to results presented in previous studies. This deformability improvement may control blood flow and consequently erythrocyte distribution within hypoxic tissues. Our study also demonstrated the relationship of oxygenation-deoxygenation shifts and magnitude of shear stress on erythrocyte deformability.Publication Open Access HMI-PRED 2.0: a biologist-oriented web application for prediction of host-microbe protein-protein interaction by interface mimicry(Oxford University Press (OUP), 2022) Lim, H., Tsai, C.J.; Nussinov, R.; Department of Computer Engineering; Department of Chemical and Biological Engineering; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Computer Engineering; Department of Chemical and Biological Engineering; College of Engineering; 26605; 8745HMI-PRED 2.0 is a publicly available web service for the prediction of host-microbe protein-protein interaction by interface mimicry that is intended to be used without extensive computational experience. A microbial protein structure is screened against a database covering the entire available structural space of complexes of known human proteins.Publication Open Access Proximity mapping of the microtubule plus-end tracking protein SLAIN2 using the BioID approach(TÜBİTAK, 2020) Department of Molecular Biology and Genetics; Karalar, Elif Nur Fırat; Faculty Member; Department of Molecular Biology and Genetics; College of Sciences; 206349The centrosome is the main microtubule-organizing center of animal cells, which plays key roles in critical cellular processes ranging from cell division to cellular signaling. Accordingly, defects in the structure and function of centrosomes cause various human diseases such as cancer and primary microcephaly. To elucidate the molecular defects underlying these diseases, the biogenesis and functions of the centrosomes have to be fully understood. An essential step towards addressing these questions is the identification and functional dissection of the full repertoire of centrosome proteins. Here, we used high-resolution imaging and showed that the microtubule plus-end tracking protein SLAIN2 localizes to the pericentriolar material at the proximal end of centrioles. To gain insight into its cellular functions and mechanisms, we applied in vivo proximity-dependent biotin identification to SLAIN2 and generated its proximity interaction map. Gene ontology analysis of the SLAIN2 interactome revealed extensive interactions with centriole duplication, ciliogenesis, and microtubule-associated proteins, including previously characterized and uncharacterized interactions. Collectively, our results define SLAIN2 as a component of pericentriolar material and provide an important resource for future studies aimed at elucidating SLAIN2 functions at the centrosome.Publication Metadata only SETD3 regulates endoderm differentiation of mouse embryonic stem cells through canonical Wnt signaling pathway(Wiley, 2024) Alganatay, Ceren; Balbasi, Emre; Sezginmert, Dersu; Cizmecioglu, Nihal Terzi; Department of Chemical and Biological Engineering; Tunçbağ, Nurcan; Department of Chemical and Biological Engineering; College of EngineeringWith self-renewal and pluripotency features, embryonic stem cells (ESCs) provide an invaluable tool to investigate early cell fate decisions. Pluripotency exit and lineage commitment depend on precise regulation of gene expression that requires coordination between transcription (TF) and chromatin factors in response to various signaling pathways. SET domain-containing 3 (SETD3 Delta) is a methyltransferase that can modify histones in the nucleus and actin in the cytoplasm. Through an shRNA screen, we previously identified SETD3 as an important factor in the meso/endodermal lineage commitment of mouse ESCs (mESC). In this study, we identified SETD3-dependent transcriptomic changes during endoderm differentiation of mESCs using time-course RNA-seq analysis. We found that SETD3 is involved in the timely activation of the endoderm-related gene network. The canonical Wnt signaling pathway was one of the markedly altered signaling pathways in the absence of SETD3. The assessment of Wnt transcriptional activity revealed a significant reduction in Setd3-deleted (setd3 increment ) mESCs coincident with a decrease in the nuclear pool of the key TF beta-catenin level, though no change was observed in its mRNA or total protein level. Furthermore, a proximity ligation assay (PLA) found an interaction between SETD3 and beta-catenin. We were able to rescue the differentiation defect by stably re-expressing SETD3 or activating the canonical Wnt signaling pathway by changing mESC culture conditions. Our results suggest that alterations in the canonical Wnt pathway activity and subcellular localization of beta-catenin might contribute to the endoderm differentiation defect of setd3 Delta increment mESCs.