Researcher:
Muratçıoğlu, Serena

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PhD Student

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Serena

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Muratçıoğlu

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Muratçıoğlu, Serena

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2014 - 2019152020 - 20212

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    Membrane-associated Ras dimers are isoform-specific: K-Ras dimers differ from H-Ras dimers
    (Portland Press Ltd, 2016) Nussinov, Ruth; Jang, Hyunbum; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745
    Are the dimer structures of active Ras isoforms similar? This question is significant since Ras can activate its effectors as a monomer; however, as a dimer, it promotes Raf's activation and MAPK (mitogen-activated protein kinase) cell signalling. In the present study, we model possible catalytic domain dimer interfaces of membrane-anchored GTP-bound K-Ras4B and H-Ras, and compare their conformations. The active helical dimers formed by the allosteric lobe are isoform-specific: K-Ras4B-GTP favours the alpha 3 and alpha 4 interface; H-Ras-GTP favours alpha 4 and alpha 5. Both isoforms also populate a stable beta-sheet dimer interface formed by the effector lobe; a less stable beta-sandwich interface is sustained by salt bridges of the beta-sheet side chains. Raf's high-affinity beta-sheet interaction is promoted by the active helical interface. Collectively, Ras isoforms' dimer conformations are not uniform; instead, the isoform-specific dimers reflect the favoured interactions of the HVRs (hypervariable regions) with cell membrane microdomains, biasing the effector-binding site orientations, thus isoform binding selectivity.
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    Interactions and dynamics of ras
    (Wiley, 2017) Jang, H.; Nussinov, R.; Department of Chemical and Biological Engineering; N/A; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Keskin, Özlem; Muratçıoğlu, Serena; Gürsoy, Attila; Faculty Member; PhD Student; Faculty Member; College of Engineering; Graduate School of Sciences and Engineering; College of Engineering; 26605; N/A; 8745
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    Anti-apoptotic bag-1S isoform is involved in endoplasmic reticulum associated degradation
    (Wiley, 2018) Can, Nisan Denizce; Akgun, Tugba Kizilboga; Dingiloglu, Baran; Doganay, Gizem Dinler; N/A; N/A; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Muratçıoğlu, Serena; Elbeyli, Efe; Keskin, Özlem; PhD Student; PhD Student; Faculty Member; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; N/A; 26605
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    GTP-dependent K-Ras dimerization
    (Cell Press, 2015) Chavan, Tanmay S.; Freed, Benjamin C.; Jang, Hyunbum; Khavrutskii, Lyuba; Freed, R. Natasha; Dyba, Marzena A.; Stefanisko, Karen; Tarasov, Sergey G.; Gursoy, Attila; Keskin, Ozlem; Tarasova, Nadya I.; Gaponenko, Vadim; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745
    Ras proteins recruit and activate effectors, including Raf, that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, activation of Raf requires its dimerization. It has been suspected that dimeric Ras may promote dimerization and activation of Raf. Here, we show that the GTP-bound catalytic domain of K-Ras4B, a highly oncogenic splice variant of the K-Ras isoform, forms stable homodimers. We observe two major dimer interfaces. The first, highly populated beta-sheet dimer interface is at the Switch I and effector binding regions, overlapping the binding surfaces of Raf, PI3K, RalGDS, and additional effectors. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps the binding sites of some effectors. This interface may promote activation of Raf. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf signaling in cancer.
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    The key role of calmodulin in kras-driven adenocarcinomas
    (Amer Assoc Cancer Research, 2015) Nussinov, Ruth; Tsai, Chung-Jung; Jang, Hyunbum; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745
    KRAS4B is a highly oncogenic splice variant of the KRAS isoform. It is the only isoform associated with initiation of adenocarcinomas. Insight into why and how KRAS4B can mediate ductal adenocarcinomas, particularly of the pancreas, is vastly important for its therapeutics. Here we point out the overlooked critical role of calmodulin (CaM). Calmodulin selectively binds to GTP-bound K-Ras4B; but not to other Ras isoforms. Cell proliferation and growth require the MAPK (Raf/MEK/ERK) and PI3K/Akt pathways. We propose that Ca2+/calmodulin promote PI3K alpha/Akt signaling, and suggest how. The elevated calcium levels clinically observed in adenocarcinomas may explain calmodulin's involvement in recruiting and stimulating PI3K alpha through interaction with its n/cSH2 domains as well as K-Ras4B; importantly, it also explains why K-Ras4B specifically is a key player in ductal carcinomas, such as pancreatic (PDAC), colorectal (CRC), and lung cancers. We hypothesize that calmodulin recruits and helps activate PI3K alpha at the membrane, and that this is the likely reason for Ca2+/calmodulin dependence in adenocarcinomas. Calmodulin can contribute to initiation/progression of ductal cancers via both PI3K alpha/Akt and Raf/MEK/ERK pathways. Blocking the K-Ras4B/MAPK pathway and calmodulin/PI3Ka binding in a K-Ras4B/calmodulin/PI3K alpha trimer could be a promising adenocarcinoma-specific therapeutic strategy.
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    Elucidating structural details of ras-effector interactions
    (Marmara Üniversitesi, 2019) Özbabacan, Saliha Ece Acuner; N/A; Muratçıoğlu, Serena; PhD Student; Graduate School of Sciences and Engineering; N/A
    Small membrane-associated Ras proteins mediate a wide range of cellular functions, such as cell proliferation, migration, survival, and differentiation; through binding and activating numerous effectors. Constitutively active mutant Ras proteins are detected in various types of human cancer and Ras community seeks approaches other than small-molecule Ras inhibitors; such as targeting the protein-protein interactions in the downstream Ras effector pathways and preventing its membrane localization. Although the most studied effectors of Ras, i.e. Raf, PI3K and RalGDS, bind Ras through the same site, they elicit opposing signaling pathways and thus, the temporal and spatial decision of the cell among them is critical. Elucidating the structural details of Ras-effector interactions can help us understand the cell decision and target the protein-protein interactions precisely. However, only a few crystal structures of Ras in complex with an effector are deposited in PDB. Here, the 3D structures of Ras/effector complexes were modeled with the PRISM algorithm and important binding sites as well as hot spot residues on Ras were identified. The effectors were also classified according to the binding regions on Ras, to determine the competitive pathways and the binding regions other than the “effector lobe”. The modeled complexes reveal important information about the interfaces between Ras and its partners with the potential of guiding drug design studies to block oncogenic Ras signaling. / Hücre zarıyla ilintili küçük Ras proteinleri pek çok efektöre bağlanıp onları aktif hale getirerek hücre çoğalması, göçü, hayatta kalma ve farklılaşması gibi çeşitli hücresel işlevleri kontrol ederler. Ras üzerindeki mutasyonlar, yapısal olarak aktif proteine sebebiyet verir ve insandaki birçok kanser tipinde tespit edilmişlerdir ve Ras topluluğu Ras’ı hedef alan küçük moleküllü inhibitörler tasarlamak yerine Ras’ın efektör yolaklarındaki protein-protein etkileşimlerini hedef alarak Ras’ın zar üzerindeki lokalizasyonunu engellemeyi amaçlamaktadır. Ras’ın en çok çalışılan efektörleri, Raf, PI3K ve RalGDS, Ras’a aynı yüzeyden bağlanmasına rağmen karşıt sinyal yolaklarını ortaya çıkarırlar ve dolayısıyla hücrenin bu yolaklar arasındaki zamansal ve mekansal kararları kritik öneme sahiptir. Ras/efektör etkileşimlerinin yapısal detaylarını açığa çıkarmak, hücrenin karar mekanizmasını anlamamıza ve protein-protein etkileşimlerini hassas olarak hedeflememize yardımcı olabilir. Bununla birlikte, sadece birkaç Ras/efektör kompleksinin kristal yapısı PDB’de bulunmaktadır. Bu çalışmada, Ras/ efektör komplekslerinin 3 boyutlu yapıları PRISM algoritması ile modellenmiştir ve Ras üzerindeki sıcak nokta kalıntılarının yanı sıra önemli bağlanma bölgeleri belirlenmiştir. Efektörler ayrıca, rekabetçi yolları ve “efektör lobu” dışındaki bağlayıcı bölgeleri belirlemek için Ras’daki bağlayıcı bölgelere göre sınıflandırılmıştır. Modellenen kompleksler, Ras ve ortakları arasındaki arayüzeyler hakkında onkojenik Ras sinyal iletimini bloke etmek için ilaç tasarım çalışmalarına rehberlik etme potansiyeli olan önemli bilgiler ortaya koymaktadır.
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    Structural modeling of GR interactions with the SWI/SNF chromatin remodeling complex and C/EBP
    (Cell Press, 2015) Presman, Diego M.; Pooley, John R.; Grontved, Lars; Hager, Gordon L.; Nussinov, Ruth; Department of Chemical and Biological Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745
    The glucocorticoid receptor (GR) is a steroid-hormone-activated transcription factor that modulates gene expression. Transcriptional regulation by the GR requires dynamic receptor binding to specific target sites located across the genome. This binding remodels the chromatin structure to allow interaction with other transcription factors. Thus, chromatin remodeling is an essential component of GR-mediated transcriptional regulation, and understanding the interactions between these molecules at the structural level provides insights into the mechanisms of how GR and chromatin remodeling cooperate to regulate gene expression. This study suggests models for the assembly of the SWI/SNF-A (SWItch/Sucrose-NonFermentable) complex and its interaction with the GR. We used the PRISM algorithm (PRotein Interactions by Structural Matching) to predict the three-dimensional complex structures of the target proteins. The structural models indicate that BAF57 and/or BAF250 mediate the interaction between the GR and the SWI/SNF-A complex, corroborating experimental data. They further suggest that a BAF60a/BAF155 and/or BAF60a/BAF170 interaction is critical for association between the core and variant subunits. Further, we model the interaction between GR and CCAAT-enhancer-binding proteins (C/EBPs), since the GR can regulate gene expression indirectly by interacting with other transcription factors like C/EBPs. We observe that GR can bind to bZip domains of the C/EBPa homodimer as both a monomer and dimer of the DNA-binding domain. In silico mutagenesis of the predicted interface residues confirm the importance of these residues in binding. In vivo analysis of the computationally suggested mutations reveals that double mutations of the leucine residues (L317D+L335D) may disrupt the interaction between GR and C/EBPa. Determination of the complex structures of the GR is of fundamental relevance to understanding its interactions and functions, since the function of a protein or a complex is dictated by its structure. In addition, it may help us estimate the effects of mutations on GR interactions and signaling.
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    Plasma membrane regulates ras signaling networks
    (Taylor & Francis, 2016) Chavan, Tanmay Sanjeev; Marszalek, Richard; Jang, Hyunbum; Nussinov, Ruth; Gaponenko, Vadim; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; The Center for Computational Biology and Bioinformatics (CCBB); Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745
    Ras GTPases activate more than 20 signaling pathways, regulating such essential cellular functions as proliferation, survival, and migration. How Ras proteins control their signaling diversity is still a mystery. Several pieces of evidence suggest that the plasma membrane plays a critical role. Among these are: (1) selective recruitment of Ras and its effectors to particular localities allowing access to Ras regulators and effectors; (2) specific membrane-induced conformational changes promoting Ras functional diversity; and (3) oligomerization of membrane-anchored Ras to recruit and activate Raf. Taken together, the membrane does not only attract and retain Ras but also is a key regulator of Ras signaling. This can already be gleaned from the large variability in the sequences of Ras membrane targeting domains, suggesting that localization, environment and orientation are important factors in optimizing the function of Ras isoforms.
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    PDEδ binding to ras isoforms provides a route to proper membrane localization
    (Amer Chemical Soc, 2017) Jang, Hyunbum; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Department of Chemical and Biological Engineering; Department of Computer Engineering; Muratçıoğlu, Serena; Keskin, Özlem; Gürsoy, Attila; PhD Student; Faculty Member; Faculty Member; Graduate School of Sciences and Engineering; College of Engineering; College of Engineering; N/A; 26605; 8745
    To signal, Ras isoforms must be enriched at the plasma membrane (PM). It was suggested that phosphodies-terase-delta (PDE delta) can bind and shuttle some farnesylated Ras isoforms to the PM, but not all. Among these, interest focused on K-Ras4B, the most abundant oncogenic Ras isoform. To study PDE delta/Ras interactions, we modeled and simulated the PDE delta/K-Ras4B complex. We obtained structures, which were similar to two subsequently determined crystal structures. We next modeled and simulated complexes of PDE delta with the farnesylated hypervariable regions K-Ras4A and N-Ras. Earlier data suggested that PDE delta extracts K-Ras4B and N-Ras from the PM, but surprisingly not K-kas4A. Earlier analysis of the crystal structures advanced that the presence of large/charged residues adjacent to the farnesylated site precludes the PDE delta interaction. Here, we show that PDE delta can bind to farnesylated K-Ras4A and N-Ras like K-Ras4B, albeit not as strongly. This weaker binding, coupled with the stronger anchoring of K-Ras4A in the membrane (but not of electrostatically neutral N-Ras), can explain the observation why PDE delta is unable to effectively extract K-Ras4A. We thus propose that farnesylated Ras isoforms can bind PDE delta to fulfill the required PM enrichment, and argue that the different environments, PM versus solution, can resolve apparently puzzling Ras observations. These are novel insights that would not be expected based on the crystal structures alone, which provide an elegant rationale for previously puzzling observations of the differential effects of PDE delta on farnesylated Ras family proteins.
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    Ras conformational ensembles, allostery, and signaling
    (American Chemical Society (ACS), 2016) Lu, Shaoyong; Jang, Hyunbum; Nussinov, Ruth; Zhang, Jian; Department of Chemical and Biological Engineering; Department of Computer Engineering; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Keskin, Özlem; Gürsoy, Attila; Muratçıoğlu, Serena; Faculty Member; Faculty Member; PhD Student; College of Engineering; College of Engineering; Graduate School of Sciences and Engineering; 26605; 8745
    Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. In this review, we focus on data that have accumulated over the past few years pertaining to the conformational ensembles and the allosteric regulation of Ras proteins and their interpretation from our conformational landscape standpoint. The Ras ensemble embodies all states, including the ligand-bound conformations, the activated (or inactivated) allosteric modulated states, post-translationally modified states, mutational states, transition states, and nonfunctional states serving as a reservoir for emerging functions. The ensemble is shifted by distinct mutational events, cofactors, post-translational modifications, and different membrane compositions. A better understanding of Ras biology can contribute to therapeutic strategies.