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Dive into the research topics where Cristina V. Iancu is active.

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Featured researches published by Cristina V. Iancu.


Proceedings of the National Academy of Sciences of the United States of America | 2009

Universal architecture of bacterial chemoreceptor arrays

Ariane Briegel; Davi R. Ortega; Elitza I. Tocheva; Kristin Wuichet; Zhuo Li; Songye Chen; Axel Müller; Cristina V. Iancu; Gavin E. Murphy; Megan J. Dobro; Igor B. Zhulin; Grant J. Jensen

Chemoreceptors are key components of the high-performance signal transduction system that controls bacterial chemotaxis. Chemoreceptors are typically localized in a cluster at the cell pole, where interactions among the receptors in the cluster are thought to contribute to the high sensitivity, wide dynamic range, and precise adaptation of the signaling system. Previous structural and genomic studies have produced conflicting models, however, for the arrangement of the chemoreceptors in the clusters. Using whole-cell electron cryo-tomography, here we show that chemoreceptors of different classes and in many different species representing several major bacterial phyla are all arranged into a highly conserved, 12-nm hexagonal array consistent with the proposed “trimer of dimers” organization. The various observed lengths of the receptors confirm current models for the methylation, flexible bundle, signaling, and linker sub-domains in vivo. Our results suggest that the basic mechanism and function of receptor clustering is universal among bacterial species and was thus conserved during evolution.


Journal of Molecular Biology | 2010

Organization, Structure, and Assembly of α-Carboxysomes Determined by Electron Cryotomography of Intact Cells

Cristina V. Iancu; Dylan M. Morris; Zhicheng Dou; Sabine Heinhorst; Gordon C. Cannon; Grant J. Jensen

Carboxysomes are polyhedral inclusion bodies that play a key role in autotrophic metabolism in many bacteria. Using electron cryotomography, we examined carboxysomes in their native states within intact cells of three chemolithoautotrophic bacteria. We found that carboxysomes generally cluster into distinct groups within the cytoplasm, often in the immediate vicinity of polyphosphate granules, and a regular lattice of density frequently connects granules to nearby carboxysomes. Small granular bodies were also seen within carboxysomes. These observations suggest a functional relationship between carboxysomes and polyphosphate granules. Carboxysomes exhibited greater size, shape, and compositional variability in cells than in purified preparations. Finally, we observed carboxysomes in various stages of assembly, as well as filamentous structures that we attribute to misassembled shell protein. Surprisingly, no more than one partial carboxysome was ever observed per cell. Based on these observations, we propose a model for carboxysome assembly in which the shell and the internal RuBisCO (ribulose-1,5-bisphosphate carboxylase/oxygenase) lattice form simultaneously, likely guided by specific interactions between shell proteins and RuBisCOs.


Proceedings of the National Academy of Sciences of the United States of America | 2013

Crystal structure of a glucose/H+ symporter and its mechanism of action.

Cristina V. Iancu; Jamillah Zamoon; Sang Bum Woo; Alexander E. Aleshin; Jun-yong Choe

Significance Glucose transporters mediate the exchange of glucose and related hexoses in living cells. In humans, these transporters (known as GLUT) are involved in several diseases, including cancer and diabetes. The glucose transporter from Staphylococcus epidermidis (GlcPSe) has high sequence homology to human GLUT, is specific for glucose, and is inhibited by human GLUT inhibitors. The crystal structure of GlcPSe, along with site-directed mutagenesis and transport-activity studies, provide insight into the mechanism of glucose transport. Glucose transporters are required to bring glucose into cells, where it is an essential energy source and precursor in protein and lipid synthesis. These transporters are involved in important common diseases such as cancer and diabetes. Here, we report the crystal structure of the Staphylococcus epidermidis glucose/H+ symporter in an inward-facing conformation at 3.2-Å resolution. The Staphylococcus epidermidis glucose/H+ symporter is homologous to human glucose transporters, is very specific and has high avidity for glucose, and is inhibited by the human glucose transport inhibitors cytochalasin B, phloretin, and forskolin. On the basis of the crystal structure in conjunction with mutagenesis and functional studies, we propose a mechanism for glucose/H+ symport and discuss the symport mechanism versus facilitated diffusion.


Journal of Structural Biology | 2008

Radiation dose reduction and image enhancement in biological imaging through equally-sloped tomography

Edwin A. Lee; B Fahimian; Cristina V. Iancu; Christian Suloway; Gavin E. Murphy; Elizabeth R. Wright; Daniel Castaño-Díez; Grant J. Jensen; Jianwei Miao

Electron tomography is currently the highest resolution imaging modality available to study the 3D structures of pleomorphic macromolecular assemblies, viruses, organelles and cells. Unfortunately, the resolution is currently limited to 3-5nm by several factors including the dose tolerance of biological specimens and the inaccessibility of certain tilt angles. Here we report the first experimental demonstration of equally-sloped tomography (EST) to alleviate these problems. As a proof of principle, we applied EST to reconstructing frozen-hydrated keyhole limpet hemocyanin molecules from a tilt-series taken with constant slope increments. In comparison with weighted back-projection (WBP), the algebraic reconstruction technique (ART) and the simultaneous algebraic reconstruction technique (SART), EST reconstructions exhibited higher contrast, less peripheral noise, more easily detectable molecular boundaries and reduced missing wedge effects. More importantly, EST reconstructions including only two-thirds the original images appeared to have the same resolution as full WBP reconstructions, suggesting that EST can either reduce the dose required to reach a given resolution or allow higher resolutions to be achieved with a given dose. EST was also applied to reconstructing a frozen-hydrated bacterial cell from a tilt-series taken with constant angular increments. The results confirmed similar benefits when standard tilts are utilized.


The EMBO Journal | 2017

Short FtsZ filaments can drive asymmetric cell envelope constriction at the onset of bacterial cytokinesis

Qing Yao; Andrew I. Jewett; Yi-Wei Chang; Catherine M. Oikonomou; Morgan Beeby; Cristina V. Iancu; Ariane Briegel; Debnath Ghosal; Grant J. Jensen

FtsZ, the bacterial homologue of eukaryotic tubulin, plays a central role in cell division in nearly all bacteria and many archaea. It forms filaments under the cytoplasmic membrane at the division site where, together with other proteins it recruits, it drives peptidoglycan synthesis and constricts the cell. Despite extensive study, the arrangement of FtsZ filaments and their role in division continue to be debated. Here, we apply electron cryotomography to image the native structure of intact dividing cells and show that constriction in a variety of Gram‐negative bacterial cells, including Proteus mirabilis and Caulobacter crescentus, initiates asymmetrically, accompanied by asymmetric peptidoglycan incorporation and short FtsZ‐like filament formation. These results show that a complete ring of FtsZ is not required for constriction and lead us to propose a model for FtsZ‐driven division in which short dynamic FtsZ filaments can drive initial peptidoglycan synthesis and envelope constriction at the onset of cytokinesis, later increasing in length and number to encircle the division plane and complete constriction.


Scientific Reports | 2017

Differences in salicylic acid glucose conjugations by UGT74F1 and UGT74F2 from Arabidopsis thaliana

A.M George Thompson; Cristina V. Iancu; K.E Neet; June Dean; Jun-yong Choe

Salicylic acid (SA) is a signaling molecule utilized by plants in response to various stresses. Through conjugation with small organic molecules such as glucose, an inactive form of SA is generated which can be transported into and stored in plant vacuoles. In the model organism Arabidopsis thaliana, SA glucose conjugates are formed by two homologous enzymes (UGT74F1 and UGT74F2) that transfer glucose from UDP-glucose to SA. Despite being 77% identical and with conserved active site residues, these enzymes catalyze the formation of different products: UGT74F1 forms salicylic acid glucoside (SAG), while UGT74F2 forms primarily salicylic acid glucose ester (SGE). The position of the glucose on the aglycone determines how SA is stored, further metabolized, and contributes to a defense response. We determined the crystal structures of the UGT74F2 wild-type and T15S mutant enzymes, in different substrate/product complexes. On the basis of the crystal structures and the effect on enzyme activity of mutations in the SA binding site, we propose the catalytic mechanism of SGE and SAG formation and that SA binds to the active site in two conformations, with each enzyme selecting a certain binding mode of SA. Additionally, we show that two threonines are key determinants of product specificity.


FEBS Open Bio | 2015

Antipsychotics inhibit glucose transport: Determination of olanzapine binding site in Staphylococcus epidermidis glucose/H(+) symporter.

Petr Babkin; Alayna M. George Thompson; Cristina V. Iancu; D. Eric Walters; Jun-yong Choe

The antipsychotic drug olanzapine is widely prescribed to treat schizophrenia and other psychotic disorders. However, it often causes unwanted side effects, including diabetes, due to disruption of insulin‐dependant glucose metabolism through a mechanism yet to be elucidated. To determine if olanzapine can affect the first step in glucose metabolism – glucose transport inside cells – we investigated the effect of this drug on the transport activity of a model glucose transporter. The glucose transporter fromStaphylococcus epidermidis (GlcPSe) is specific for glucose, inhibited by various human glucose transporter (GLUT) inhibitors, has high sequence and structure homology to GLUTs, and is readily amenable to transport assay, mutagenesis, and computational modeling. We found that olanzapine inhibits glucose transport of GlcPSe with an IC50 0.9 ± 0.1 mM. Computational docking of olanzapine to the GlcPSe structure revealed potential binding sites that were further examined through mutagenesis and transport assay to identify residues important for olanzapine inhibition. These investigations suggest that olanzapine binds in a polar region of the cytosolic part of the transporter, and interacts with residues R129, strictly conserved in all GLUTs, and N136, conserved in only a few GLUTs, including the insulin‐responsive GLUT4. We propose that olanzapine inhibits GlcPSe by impeding the alternating opening and closing of the substrate cavity necessary for glucose transport. It accomplishes this by disrupting a key salt bridge formed by conserved residues R129 and E362, that stabilizes the outward‐facing conformation of the transporter.


Scientific Reports | 2017

Establishing a yeast-based screening system for discovery of human GLUT5 inhibitors and activators

Joanna Tripp; Christine Essl; Cristina V. Iancu; Eckhard Boles; Jun-yong Choe; Mislav Oreb

Human GLUT5 is a fructose-specific transporter in the glucose transporter family (GLUT, SLC2 gene family). Its substrate-specificity and tissue-specific expression make it a promising target for treatment of diabetes, metabolic syndrome and cancer, but few GLUT5 inhibitors are known. To identify and characterize potential GLUT5 ligands, we developed a whole-cell system based on a yeast strain deficient in fructose uptake, in which GLUT5 transport activity is associated with cell growth in fructose-based media or assayed by fructose uptake in whole cells. The former method is convenient for high-throughput screening of potential GLUT5 inhibitors and activators, while the latter enables detailed kinetic characterization of identified GLUT5 ligands. We show that functional expression of GLUT5 in yeast requires mutations at specific positions of the transporter sequence. The mutated proteins exhibit kinetic properties similar to the wild-type transporter and are inhibited by established GLUT5 inhibitors N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA) and (−)-epicatechin-gallate (ECG). Thus, this system has the potential to greatly accelerate the discovery of compounds that modulate the fructose transport activity of GLUT5.


Frontiers in chemistry | 2018

Ligand screening systems for human glucose transporters as tools in drug discovery

Sina Schmidl; Cristina V. Iancu; Jun-yong Choe; Mislav Oreb

Hexoses are the major source of energy and carbon skeletons for biosynthetic processes in all kingdoms of life. Their cellular uptake is mediated by specialized transporters, including glucose transporters (GLUT, SLC2 gene family). Malfunction or altered expression pattern of GLUTs in humans is associated with several widespread diseases including cancer, diabetes and severe metabolic disorders. Their high relevance in the medical area makes these transporters valuable drug targets and potential biomarkers. Nevertheless, the lack of a suitable high-throughput screening system has impeded the determination of compounds that would enable specific manipulation of GLUTs so far. Availability of structural data on several GLUTs enabled in silico ligand screening, though limited by the fact that only two major conformations of the transporters can be tested. Recently, convenient high-throughput microbial and cell-free screening systems have been developed. These remarkable achievements set the foundation for further and detailed elucidation of the molecular mechanisms of glucose transport and will also lead to great progress in the discovery of GLUT effectors as therapeutic agents. In this mini-review, we focus on recent efforts to identify potential GLUT-targeting drugs, based on a combination of structural biology and different assay systems.


Journal of Molecular Biology | 2007

The structure of isolated Synechococcus strain WH8102 carboxysomes as revealed by electron cryotomography.

Cristina V. Iancu; H. Jane Ding; Dylan M. Morris; D. Prabha Dias; Arlene D. Gonzales; Anthony Martino; Grant J. Jensen

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Grant J. Jensen

California Institute of Technology

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Gavin E. Murphy

California Institute of Technology

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Jun-yong Choe

Rosalind Franklin University of Medicine and Science

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D. Prabha Dias

California Institute of Technology

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William F. Tivol

California Institute of Technology

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J. Bernard Heymann

National Institutes of Health

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Zhuo Li

California Institute of Technology

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Andrew I. Jewett

California Institute of Technology

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