Researcher:
Şenyüz, Simge

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Master Student

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Simge

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Şenyüz

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Şenyüz, Simge

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2021 - 20232

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Researcher Of Publications: search.filters.isAuthorOfPublication.931c66f4-901d-422a-9cd8-c6eb18e4383b

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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; Zeylan, Melisa Ece; Şenyüz, Simge; Gürsoy, Attila; Keskin, Özlem; PhD Student; Master Student; Faculty Member; Faculty Member; Department of Computer Engineering; 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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    PublicationOpen Access
    Mechanistic differences of activation of Rac1(P29S) and Rac1(A159V)
    (American Chemical Society (ACS), 2021) Jang, Hyunbum; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Şenyüz, Simge; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 26605; 8745
    Rac1 is a small GTPase that plays key roles in actin reorganization, cell motility, and cell survival/growth as well as in various cancer types and neurodegenerative diseases. Similar to other Ras superfamily GTPases, Rac1 switches between active GTP-bound and inactive GDP-bound states. Switch I and II regions open and close during GDP/GTP exchange. P29S and A159V (paralogous to K-Ras(A146)) mutations are the two most common somatic mutations of Rac1. Rac1(P2)(9S)( )is a known hotspot for melanoma, whereas Rac1(A159V) most commonly occurs in head and neck cancer. To investigate how these substitutions induce the Rac1 dynamics, we used atomistic molecular dynamics simulations on the wild-type Rac1 and two mutant systems (P29S and A159V) in the GTP bound state, and on the wild-type Rac1 and P29S mutated system in the GDP bound state. Here, we show that P29S and A159V mutations activate Rac1 with different mechanisms. In Rac1(P29S)-GTP, the substitution increases the flexibility of Switch I based on RMSF and dihedral angle calculations and leads to an open conformation. We propose that the open Switch I conformation is one of the underlying reasons for rapid GDP/GTP exchange of Rac1(P29S). On the other hand, in Rac1(A159V)-GTP, some of the contacts of the guanosine ring of GTP with Rac1 are temporarily lost, enabling the guanosine ring to move toward Switch I and subsequently close the switch. Rac1(A159V)-GTP adopts a Ras state 2 like conformation, where both switch regions are in closed conformation and Thr35 forms a hydrogen bond with the nucleotide.