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1
Taher, Mohammed Ahmed A. "Hormonal regulation of ATP binding cassette transporters." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971837139.
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Chen, Min. "Mechanistic insights into ATP hydrolysis by the ABC transporter TAP." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972577971.
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Nash, Angus A. "Characterisation of the Mycobacterium tuberculosis DrrABC ATP-binding cassette transporter." Thesis, University of Glasgow, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398529.
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Smith, Loren E. "The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282575598.
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Patel, Dipesh C. "Glycaemic influences on the ATP-binding cassette transporter A1 (ABCA1)." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6864.
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Increased glucose levels are associated with increased risk of vascular disease. The risk is elevated 2-4 fold in type 2 diabetes and there is a positive relationship between glucose (or HbA1c) levels and vascular disease in the general population. We tested the hypothesis that there is a glycaemia-mediated impairment of reverse cholesterol transport (RCT) by studying an early key step, notably the expression and activity of the ATP binding cassette transporter-A1 (ABCA1). This protein exports cellular cholesterol to apolipoprotein A1 (ApoA-I), thereby forming nascent HDL. In this thesis, it is shown that ABCA1 gene expression in leukocytes in men is reduced in Type 2 diabetes and correlates negatively with circulating HbA1c levels and fasting glucose. This confirms our earlier findings in healthy men. An independent relationship between glycaemia and leukocyte ABCG1 gene expression was not seen. ABCA1 protein concentrations in blood leukocytes were reduced in patients with diabetes. ApoA-I-mediated cholesterol efflux in cultured fibroblasts taken from subjects was studied as a measure of ABCA1 function. This negatively associated with fasting glucose at the time of sampling as well as adiposity. Cellular cholesterol removal was reduced in subjects with diabetes compared with controls. There was a positive relationship between both ABCA1 function and leukocyte protein concentration with circulating HDL cholesterol. These relationships were independent of expression of liver X receptor-α (LXRα) and peroxisome proliferator-activated receptor-γ (PPARγ). These data imply a persistent glycaemia-mediated suppression of an early step in RCT which may contribute to the excess vascular disease observed in such patients. It further proposes impaired cholesterol efflux may contribute to the low circulating HDL cholesterol which is commonly seen in patients with impaired glucose regulation.
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Fukuda, Yu. "ABCB6 Is a porphyrin transporter with a novel trafficking signal that is conserved in other ABC transporters." View the abstract Download the full-text PDF version (on campus access only), 2008. http://etd.utmem.edu/ABSTRACTS/2008-047-Fukuda-index.htm.
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Thesis (Ph.D.)--University of Tennessee Health Science Center, 2008.Title from title page screen (viewed on January 7, 2009). Research advisor: John D. Schuetz, Ph.D. Document formatted into pages (xi, 113 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 92-113).
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Bilbey, Nicolas James. "Regulation of ATP-binding cassette transporter A1 in cholesteryl ester storage disease." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/14836.
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Previous studies from the Francis laboratory have determined that regulation of ABCA1
expression is impaired in the lysosomal cholesterol storage disorder Niemann-Pick type C (NPC) disease, the presumed reason for the low plasma HDL-cholesterol (HDL-C) levels found in the majority of NPC disease patients. Cholesteryl ester storage disease (CESD) is another lysosomal cholesterol storage disorder, resulting from deficiency in lysosomal acid lipase (LAL). CESD
patients develop premature atherosclerosis, possibly related to their known low plasma HDL-C levels. We hypothesized that in CESD the reduced activity of LAL also leads to impaired ABCA1 regulation and HDL formation due to the decrease in release of unesterified cholesterol from lysosomes.
Our results show that human CESD fibroblasts exhibit a blunted increase in ABCA1 mRNA
and protein in response to addition of low density lipoprotein (LDL) to the medium when
compared to normal human fibroblasts. Efflux of LDL-derived cholesterol radiolabel and mass to apolipoprotein A-I-containing medium was markedly reduced in CESD fibroblasts compared to normal fibroblasts. Cellular radiolabeled cholesteryl ester derived from LDL and total cell cholesteryl ester mass was increased in CESD compared to normal cells. Delivery of an adenovirus expressing full length human lysosomal acid lipase (Ad-hLAL) results in correction of LAL activity and an increase ABCA1 protein expression, as well as correction of cholesterol and phospholipid release to apoA-I and normalization of cholesteryl ester levels in the CESD fibroblasts. These accumulated results suggest ABCA1 expression is dependent on lysosomal acid lipase activity, and provide additional support for a major role of the lysosomal pool of
unesterified cholesterol as a regulator of ABCA1 expression and HDL formation in humans.
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Bissonnette, Rachel. "The ATP binding cassette transporter A1 gene : expression and role in hypoalphalipoproteinemia." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=78247.
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The present study was undertaken primarily to determine the prevalence of ABCA1 gene defects in a selected population with a HDL-C < 5 th percentile. The results showed that 30% of the selected patients had a lipid efflux defect and 16% (10/64) of those patients had a mutation in the ABCA1 gene. The cholesterol and phospholipid efflux showed a high correlation with HDL-C levels. In addition, both phospholipid and cholesterol effluxes (r = 0.64 p < 0.001 and r = 0.48 p < 0.001, respectively) were significantly correlated to HDL-C levels in selected hypoalphalipoproteinemia subjects.Knowing that ABCA1 is regulated by cholesterol, oxysterols, and cAMP in peripheral cells, it was also of interest to investigate the regulation in other cells where cholesterol metabolism is an important function. Therefore the second objective was to determine the regulation of ABCA1 in hepatocytes. The results demonstrated that ABCA1 was not regulated in HepG2 cells but strongly regulated in fibroblasts.
Taken together, these studies support the two-step hypothesis proposed by Fielding et al. These studies also suggest that ABCA1 regulation in the liver is different than in peripheral cells. We believe that understanding the ABCA1 pathway will lead to a better comprehension of the reverse cholesterol transport system.
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Soumian, Soni. "The role of ATP binding cassette transporter A1 in atherosclerotic vascular disease." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501124.
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Yao, Yao. "Multidrug transport by the ABC transporter Sav1866 from Staphylococcus aureus." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609491.
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Levine, Kara B. "Identification of the Human Erythrocyte Glucose Transporter (GLUT1) ATP Binding Domain: A Dissertation." eScholarship@UMMS, 1999. https://escholarship.umassmed.edu/gsbs_diss/247.
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The human erythrocyte glucose transport protein (GLUT1) interacts with, and is regulated by, cytosolic ATP. This study asks the following questions concerning ATP modulation of GLUT1 mediated sugar transport. 1) Which region(s) of GLUT1 form the adenine nucleotide-binding domain? 2) What factors influence ATP modulation of sugar transport? 3) Is ATP interaction with GLUT1 sufficient for sugar transport regulation?
The first question was addressed through peptide mapping, n-terminal sequencing, and alanine scanning mutagenesis of GLUT1 using [32P]-azidoATP, a photoactivatable ATP analog. We then used a combination of transport measurements and photolabeling strategies to examine how glycolytic intermediates, pH, and transporter oligomeric structure affect ATP regulation of sugar transport. Finally, GLUT1 was reconstituted into proteoliposomes to determine whether ATP is sufficient for the modulation of GLUT1 function in-vitro.
This thesis presents data supporting the hypothesis that residues 332-335 contribute to the efficiency of adenine nucleotide binding to GLUT1. In addition, we show that AMP, acidification, and conversion of the transporter to its dimeric form antagonize ATP regulation of sugar transport. Finally, we present results that support the proposal that ATP interaction with GLUT1 is sufficient for transport modulation.
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Salaa, Ihsene. "Functional characterisation of the putative multidrug transporter PatAB from S. pneumoniae." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610746.
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Petry, Frauke. "Charakterisierung eines neuen ATP-binding-cassette-Transporters aus der ABCA-Subfamilie." Doctoral thesis, [S.l.] : [s.n.], 2004. http://webdoc.sub.gwdg.de/diss/2004/petry/petry.pdf.
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Pannu, Parveer Singh. "Regulation of ATP-binding cassette transporter A1 In intimal-type arterial smooth muscle cells." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44171.
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The removal of cholesterol from cells and formation of high-density lipoprotein (HDL) particles is critically dependent on the membrane lipid transporter ATP-binding cassette transporter A1 (ABCA1). Previous studies from the Francis laboratory have determined that the regulation of ATP-binding cassette transporter A1 (ABCA1) expression is impaired in model intimal-type arterial smooth muscle cells (SMCs) and human intimal SMCs in atherosclerotic coronary arteries, providing a novel explanation for cholesterol accumulation and foam cell formation in human atheroma. Growing evidence appears to emphasize the importance of the lysosomal-mitochondrial oxysterol pathway in regulating ABCA1 expression. We hypothesized that the reduced expression of ABCA1 in model intimal-type arterial SMCs is due to impaired enzyme sterol 27-hydroxylase (CYP27A1) expression, resulting in impaired oxysterol production critical for the activation of ABCA1 gene expression via the Liver X receptor (LXR) pathway.
Our results show that intimal-type arterial SMCs exhibit a reduced expression of CYP27A1 mRNA and protein. Exogenous treatment of these cells with LXR agonists increases ABCA1 expression, indicating an intact LXR-mediated activation of ABCA1 gene expression. Despite successful transfection of CYP27A1 in these SMCs, intimal-type arterial SMCs do not increase their expression of ABCA1. The expression of steroidogenic acute regulatory protein D1 (StARD1), responsible for the delivery of cholesterol to CYP27A1, is also reduced in intima-type SMCs. We also show preliminary results of reduced human arterial intimal SMC-specific CYP27A1 expression in coronary arteries with native atherosclerosis. The findings of this thesis provide a narrative highlighting the importance of the intracellular transport of cholesterol via StaRD1 to CYP27A1 for the activation of LXR-dependent ABCA1 expression in arterial SMCs, and provide further insight into the dysregulation of ABCA1 expression in human atherosclerotic arterial SMCs that may contribute to the foam cell population and subsequent plaque formation in human atherogenesis.
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BOCCHETTA, Simone. "Up-regulation of the ATP-binding cassette transporter A1 inhibits hepatitis C virus infection." Doctoral thesis, Università del Piemonte Orientale, 2014. http://hdl.handle.net/11579/45964.
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Simpson, Brent W. "Genetic investigation of how an ATP hydrolysis cycle is coupled to lipopolysaccharide transport." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523988371297363.
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Witting, Scott R. "The Role of Sphingolipids in Cholesterol Efflux Mediated by ATP-Binding Cassette Transporter AI (ABCAI)." University of Cincinnati / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1089749086.
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Paulus, Barbara [Verfasser], and Oliver [Akademischer Betreuer] Zolk. "ATP-Binding Cassette (ABC)-Transporter im humanen Myokard: Expressionsänderungen bei Herzinsuffizienz / Barbara Paulus. Betreuer: Oliver Zolk." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2012. http://d-nb.info/1025963946/34.
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Hirsch-Reinshagen, Veronica. "The role of the ATP-Binding Cassette transporter A1 in Alzheimer Disease neuropathology and brain lipoprotein metabolism." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/30889.
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The ATP-Binding Cassette transporter A1 (ABCA1) is a ubiquitously expressed protein that
mediates the efflux of cholesterol and phospholipids from the plasma membrane onto lipid poor
apolipoproteins (apos), such as apoA-l and apoE. Outside the central nervous system (CNS),
this process constitutes the rate-limiting step in the generation of high-density lipoproteins
(HDL). Low levels of HDL and cellular lipid accumulation are the hallmarks of Tangier disease,
a genetic disease caused by mutations in the ABCA1 gene. ABCA1 is also expressed in the
brain, the most cholesterol rich organ in the body. However, previous to this thesis, the role of
ABCA1 in brain cholesterol metabolism had been poorly explored. Furthermore, recent data
indicated that disturbances in cholesterol homeostasis in the CNS may play an important
pathogenic role in the development of Alzheimer Disease (AD). This, in turn, suggested that
ABCA1 may also affect the progression of AD. The overall goal of this work is to gain insights
into the role of ABCA1 in the development of AD neuropathology and brain lipoprotein
metabolism.
This thesis presents original data showing that ABCA1 deficiency results in a dramatic
reduction in brain apoE levels. Because apoE has a demonstrated role in amyloid deposition,
we also studied the effects of ABCA1 deficiency on amyloidogenesis in AD transgenic mice.
We found that the absence of ABCA1 results in increased amyloid deposition despite low levels
of apoE. The observation that ABCA1-deficiency is proamyloidogenic raised the question
whether ABCA1 overexpression may reduce amyloid formation. We thus evaluated AD
neuropathology in AD mice crossed to an ABCA1 bacterial artificial chromosome (BAC)
transgenic mouse model. We found that although ABCA1 expression and apoE levels are
elevated in the brains of ABCA1 BAC mice compared to non-transgenic controls, these effects
were abolished in the presence of AD transgenes. This suggests that overexpression ofphysiologically regulated ABCA1 may be altered in brains with amyloid deposits compared to
amyloid-free brains. These studies thus constitute original contributions to our understanding of
the role of ABCA1 in brain lipid metabolism, and highlight the mechanisms by which ABCA1
may impact the development of AD neuropathology in vivo.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Lau, Calvin Ho-Fung. "Inorganic ion transport and sensing by the bacterial multidrug ATP-binding cassette transporter LmrA of Lactococcus lactis." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608774.
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Zamora, Garcia Rafael E. "Characterisation of the Doxorubicin pump of Streptomyces peucetius : the DrrA component of the DrrAB ATP-binding cassette transporter." Thesis, University of Glasgow, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438971.
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Sasaki, Mayumi. "Cloning of ABCA17, a novel rodent sperm-specific ABC (ATP-binding cassette) transporter that regulates intracellular lipid metabolism." Kyoto University, 2007. http://hdl.handle.net/2433/135646.
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Finkenwirth, Friedrich. "Substratbindung und -freigabe während des Katalysezyklus eines biotinspezifischen ECF-Transporters." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2017. http://dx.doi.org/10.18452/17745.
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ECF (Energy-Coupling Factor)-Transporter sind prokaryotische Aufnahmesysteme für Mikronährstoffe, die eine spezielle Gruppe von Transportern mit ATP-Bindekassette (ABC) darstellen. Sie beinhalten zwei asymmetrische Membranproteine, von denen eins (S) für die spezifische Bindung und Translokation des Substrates und das andere (T) für die Kopplung mit den ATPasen (A1,A2) zuständig ist. Bei ECF-Transportern der Subklasse I bilden diese Komponenten eine Einheit, während bei Vertretern der Subklasse II ein AAT-Modul mit wechselnden S-Einheiten interagiert. In der vorliegenden Arbeit wurde der Transportmechanismus, der eine Drehung der kompletten S-Einheit in der Membran beinhaltet, anhand des Biotintransporters BioMNY erstmals experimentell validiert. Durch Rekonstitution in Lipid-Nanodiscs, chemische Quervernetzung, fluoreszenz- und ESR-spektroskopische Techniken sowie einen Bindungstest mit radioaktivem Biotin wurde gezeigt, dass (i) die ATP-Bindung an die ATPasen zu einer Aufrichtung der S-Einheit (BioY) führt, (ii) diese Bewegung die Substratbeladung ermöglicht und (iii) BioY dabei ununterbrochen mit der T-Einheit (BioN) interagiert. Dies stellt einen Gegensatz zu Systemen der Subklasse II dar, für die ein ATP-abhängiger Austausch von S-Einheiten im Transportzyklus gezeigt worden war. Darüber hinaus wurde ein Escherichia coli-Stamm konstruiert, der durch Blockierung seines hochaffinen Biotintransporters und des -synthesewegs auf Spuren von Biotin nicht wachsen kann. Dieser Stamm ermöglichte einen eindeutigen Nachweis der Transportaktivität einiger solitärer BioY-Proteine. Aufgrund der einheitlichen Topologie von S-Einheiten ist ein Kippen auch für solitäre BioY-Varianten wahrscheinlich. Auch die metallspezifischen S-Einheiten CbiM und NikM besitzen ohne AAT-Modul eine basale Co2+- bzw. Ni2+-Transportaktivität. Ein ESR-spektroskopischer Kobaltnachweises zeigte, dass die aus nur zwei Membranhelices bestehende CbiN-Einheit für die Metallbeladung von CbiM essentiell ist.ECF (Energy-Coupling Factor) transporters are a subgroup of ABC transporters that mediate uptake of micronutrients into prokaryotic cells. In contrast to canonical ABC importers, ECF transporters comprise two unrelated membrane proteins, one of which is responsible for specific and high affinity substrate binding (S) and the other one constitutes the coupling component (T) between S and the cytosolic ABC-ATPases (A1,A2). Subclass I transporters consist of four dedicated components whereas in subclass II transporters, a central AAT-module may interact with various S units. The biotin specific subclass I ECF transporter BioMNY was used to experimentally verify the hitherto hypothetic transport mechanism, which involves a rotation of the S unit within the membrane. With a series of experiments including reconstitution of BioMNY into lipid nanodiscs, site-specific cross-linking, a substrate binding assay with radioactive biotin and both fluorescence and EPR spectroscopic techniques, the ATP-dependent rotation of BioY (S) as a prerequisite for substrate binding and release was shown for the first time for an ECF transporter. Unlike subclass II transporters, for which an ATP-dependent release of the S unit was proposed, BioY interacts continuously with BioN (T) during the transport cycle. In a second focus of the work, an Escherichia coli reporter strain for biotin transporters was constructed. Due to inactivation of both biotin synthesis and the intrinsic high affinity biotin transporter, this strain was not capable of growing on trace amounts of biotin. With the use of this strain, transport activity of recombinantly produced solitary BioY proteins that naturally lack other ECF components was evidenced. Transport activity in the absence of AAT modules is also a feature of the Co2+ and Ni2+ specific S components CbiM and NikM. An EPR spectroscopic Co2+ detection assay helped underscoring the essential role of the small membrane protein CbiN for Co2+ loading of CbiM.
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Clémençon, Benjamin. "Etude conformationnelle de protéines membranaires mitochondriales modèles chez Saccharomyces cerevisiae : analyses des relations structure/fonction du transporteur d'ADP/ATP et de l'accessibilité au solvant de la porine VDAC." Grenoble, 2010. http://www.theses.fr/2010GRENV065.
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Les transporteurs d'ADP/ATP (Ancp) et de phosphate inorganique (PiC) ainsi que la porine VDAC représentent les principaux maillons d'une machinerie de transport d'ADP, d'ATP et de phosphate inorganique à travers la double membrane mitochondrial. Actuellement, les connaissances relatives aux mécanismes moléculaires mis en jeu dans cette machinerie accusent un retard. L'objectif de ce projet de Thèse a été d'amener de nouveaux éléments sur l'état conformationnel de ces protéines étudiées dans la levure Saccharomyces cerevisiae, modèle biologique où la génétique est facilitée. La majeure partie de ce projet a concerné l'Ancp de levure qui assure l'échange d'ADP cytosolique contre de l'ATP matriciel néosynthétisé suite aux processus de phosphorylation oxydative. Il peut être inhibé spécifiquement par deux poisons naturels, le carboxyatractyloside (CATR) et l'acide bongkrékique (BA) qui stabilisent la protéine dans deux états conformationnels distincts adoptés lors du mécanisme de transport. Afin de mieux comprendre cette dynamique, une étude comparative des deux conformères a été réalisée en combinant l'échange hydrogène/deutérium couplé à la spectrométrie de masse (HDX-MS) aux outils biochimiques directement liés à l'étude des Ancp. Les résultats obtenus corrèlent l'hypothèse d'une structure malléable du transporteur dans laquelle des changements conformationnels importants interviennent. D'autre part, ce projet a permis d'obtenir les premières données d'accessibilité au solvant du PiC. Enfin, l'étude en HDX-MS de VDAC, nous a permis de montrer que son accessibilité au solvant en solution de détergent était en accord avec les données structurales publiées récemmentThe ADP/ATP (Ancp) and phosphate inorganic (PiC) carriers as well as the VDAC porin catalyze import and export of ADP, ATP and Pi across the mitochondrial membranes. Characterization of this mechanism at the molecular level is not well understood. The main goal of this work concerns the study of the conformational state of these proteins in detergent solution purified from the yeast Saccharomyces cerevisiae where the genetic is easier. The major part of this project concerned the Ancp located in the inner mitochondrial membrane that catalyzes the transmembrane exchange of ADP and ATP between the cytosolic and the matrix compartments. ADP/ATP transport is achieved by interconversion of Ancp between two conformational states that are fixed by the specific transport inhibitors carboxyatractyloside (CATR) and bongkrekic acid (BA). Conformational dynamics of the Ancp was investigated by hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS). The data were compared to those obtained using molecular and biochemical approaches. Our results suggest a flexible structure of the carrier and a real synergy between each side of the carrier during the transport mechanism of nucleotides. On the other hand, these work provided the first data about the solvent accessibility of PiC. Finally, the study of VDAC in HDX-MS allowed us to show that its solvent accessibility in detergent solution corroborated the structural data published previously
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De, Angeli Alexis. "Functional characterization of the vacuolar transporter ClCa from Arabidopsis thaliana : NO3-/H+ exchange activity and regulation by nucleotides." Paris 11, 2008. http://www.theses.fr/2008PA112073.
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Le nitrate représente pour la majeure partie des plantes terrestres une importante source d’azote. Les plantes absorbent le nitrate du sol, l’assimilent dans des composés azotés et en stockent le surplus dans la vacuole centrale. Les protéines responsables du transport intracellulaire du nitrate sont encore inconnues, mais il a été suggéré que des protéines de la famille des CLC (ChLoride Channel) pouvaient être impliquées dans ces fonctions. Ces travaux de thèse démontrent que la protéine AtClCa (Arabidopsis thaliana ClC) est localisée dans la membrane vacuolaire et transporte des anions au travers du tonoplaste. Ils démontrent également que AtClCa est un antiport NO3-/H+ avec une stoechiométrie de 2 NO3- transportés pour chaque H+ transféré. Sa propriété d’antiport, ainsi que sa spécificité pour le nitrate, permettent à AtClCa d’accumuler le nitrate dans la vacuole. Son activité de transport est inhibée par l’ATP, alors que l’ADP et l’AMP n’ont pas d’effet sur le courant porté par AtClCa. Cependant, l’AMP et l’ATP entrent en compétition pour le site d’interaction avec AtClCa. Ce site d’interaction avec les nucléotides se trouve probablement dans le domaine C-terminal de la protéine. Le domaine C-terminal de AtClCa a été modélisé en utilisant la structure du C-terminal de la protéine humaine hClC-5. Les données de dynamique moléculaire obtenues via ce modèle s reproduisent les propriétés d’interaction entre AtCLCa et les nucléotides déterminées expérimentalement. L’ensemble de ces données montre que AtClCa est un élément clef de l’homéostasie du nitrate intracellulaire, et que son activité de transport est régulée en fonction de l’état métabolique de la celluleNitrate is the major nitrogen source for plants. Plants absorb nitrate from the soil, assimilate it in nitrogen compounds and stock the surplus of nitrate in the central vacuole. The proteins responsible for the intracellular transport of nitrate are unknown. It has been suggested that proteins that belong to the CLC family (ChLoride Channel) could be involved in nitrate intracellular homeostasis. In the present thesis we showed that AtClCa (Arabidopsis thaliana ClCa) is localized in the vacuolar membrane, and demonstrated its ability to mediate anions currents across the tonoplast. We could also demonstrate that AtClCa is a NO3-/H+ antiporter with a stoichiometry of 2NO3- transported for each H+ transferred. The antiporter property, together with nitrate specificity, enable AtClCa to mediate the accumulation of nitrate in the vacuole. We also showed that the current mediated by AtClCa is inhibited by ATP. ADP and AMP have no effect on AtClCa current, but AMP competes with ATP for the site of interaction with AtClCa. The interaction of nucleotides with AtClCa takes place presumably at its C-terminal. The C-terminal domain of AtClCa has been modelled by homology using the structure of the C-terminal of hClC-5. The data obtained with this model by molecular dynamics simulations can reproduce the experimental data on the interaction properties of AtClCa and the nucleotides. The set of data presented in this thesis shows that AtClCa is a key element for the homeostasis of intracellular nitrate, and that its transport activity is regulated in function of the metabolic state of the cell
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Sahrhage, Tim Oliver [Verfasser], and Marc [Akademischer Betreuer] Freichel. "Verteilung der ATP-binding-cassette Transporter ABCG1, ABCG2, ABCB9 und ABCE1 in murinem Hodengewebe / Tim Oliver Sahrhage. Betreuer: Marc Freichel." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2014. http://d-nb.info/1053725469/34.
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Stahmer, Björn [Verfasser], and Franz [Akademischer Betreuer] Rinninger. "Untersuchungen zur Funktion von ATP-Binding Cassette Transporter A1 (ABCA1) im HDL-Stoffwechsel in vivo / Björn Stahmer. Betreuer: Franz Rinninger." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2014. http://d-nb.info/1050818393/34.
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Johnson, Soraya Sarah. "Control of the protein and lipid content of the plasma membrane by ATP-binding cassette transporter proteins in S. Cerevisiae." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/825.
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Pdr5 and Yor1 are two ATP-binding cassette transporters regulated by the pleiotropic drug resistance (PDR) network in the yeast Saccharomyces cerevisiae. Recent work from another group demonstrated that a pdr5Δ yor1 strain confers remarkable resistance to a sphingolipid intermediate, phytosphingosine (PHS), which was surprising as loss of these transporters normally leads to elevated drug sensitivity.
PHS is toxic to the cell at high levels due to mislocalization of nutrient permeases, such as the high affinity tryptophan transporter, Tat2. Although the above study suggested that this resistance was due to increased expression of Rsb1, a known mediator of PHS tolerance, this was not reproducible in our hands and we sought to identify other determinants for this phenotype. The work presented here demonstrates that the pdr5Δ yor1 strain exhibits delayed turnover of Tat2 and an increase in tryptophan uptake, which we postulate is due to changes membrane asymmetry resulting in decreased endocytosis. Conversely, cells lacking Rsb1 showed a decrease in tryptophan import and increased Tat2 turnover, independent of endogenous PHS levels. Rsb1 has a predicted 7 transmembrane (7TM) topology, which argues against the idea that Rsb1 functions directly in PHS transport, as there are currently no known transporters with this topology. These data suggest that Rsb1 and Pdr5/Yor1 function in regulation of endocytosis of Tat2, and possibly other membrane proteins.
Ethyl methanesulfonate mutagenesis of the pdr5Δ yor1 strain and a candidate gene approach were alternative methods used to identify mediators of PHS tolerance in this strain. Inconsistent results from PHS selection led to the discovery that the pdr5Δ yor1 strain was also robustly resistant to the sphingolipid biosynthesis inhibitor, Aureobasidin A (AbA), which was subsequently used for analysis. These approaches revealed several genes, including Gda1, Mss4, and Ypk1 that are important for AbA tolerance in the pdr5Δ yor1 strain. Many of these determinants play a role in cell wall integrity, suggesting that loss of Pdr5 and Yor1 may lead to activated cell wall integrity pathways resulting in altered cell wall structure.
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Tangella, Lokeswari Prathyusha. "An investigation on role of the ATP-binding cassette B5 (ABCB5) transporter as potential mediator of melanoma resistance to BRAF inhibition." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2020. https://ro.ecu.edu.au/theses/2369.
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Cutaneous melanoma is a highly metastatic and drug-resistant skin cancer type, responsible for a disproportionate number of skin cancer deaths. Targeted therapies, in the form of BRAF inhibitors (BRAFis), have been effective at treating BRAFV600 mutant melanomas. However, majority of the melanoma patients fail to respond to BRAFis due to intrinsic or acquired resistance within one year of treatment commencement. Multiple mechanisms that contribute to BRAFi resistance in melanoma cells have been identified, as discussed in the review in Chapter 1. Overexpression of ATP-binding cassette (ABC) transporters has been linked to multidrug resistance in numerous cancer types. These transporters expel the anti-cancer drugs out of the cell, thereby decreasing the intracellular concentration of the drug. In melanoma, the ATP-binding cassette B5 transporter (a member of ABC superfamily) has been linked to chemoresistance by drug extrusion. Moreover, overexpression of ABCB5 has been observed in BRAFV600 melanoma cells after short-term BRAFi treatment. In this study we investigated the role of the ABCB5 transporter as potential mediators of resistance to BRAFis by drug expulsion.
In Chapter 2, we showed increased ABCB5 expression in melanoma cell lines after short-term treatment with the BRAFis accompanied by an increased expression of melanocytic signature. Gene expression of fluorescent activated cell sorted melanoma cells into ABCB5high and ABCB5low populations, revealed an increased melanocytic signature in the ABCB5high population. Moreover, analysis of single-cell RNA sequencing (scRNAseq) data of two BRAFV600 melanoma cell lines, A2058 and 451Lu, revealed a strong association between ABCB5 expression and melanocytic signature. Based on these initial observations, the capacity of the ABCB5 transporter to efflux BRAFis was evaluated indirectly through an in-silico approach using molecular docking simulations (Chapter 3 and 4), and directly through in vitro experiments using an ABCB5 overexpressing melanoma BRAFV600 cell line (Chapter 5).
In Chapter 3, a full-length ABCB5 model was generated, based on mouse ATP-binding cassette B1 transporter (ABCB1; Pgp1), a close homologue of ABCB5. Molecular dynamics simulations were performed in 2 model cell membranes and the dominant conformation was identified. Docking simulations of known ABCB5 substrates such as taxanes, anthracyclines, camptothecin and etoposide enabled the identification of at least three putative substrate binding sites in ABCB5. The overlap of these three binding sites with validated binding sites for these chemotherapeutic drugs in Pgp1 corroborate our findings. In Chapter 4, docking simulations revealed at least one overlapping binding site for BRAFis and chemotherapeutic drugs on ABCB5, suggesting that BRAFis could potentially act as a substrate for ABCB5. In Chapter 5, we generated an ABCB5 overexpressing BRAFV600E melanoma cell line. However, no differences in sensitivity to BRAF inhibition was observed as a result of ABCB5 overexpression. Intracellular drug accumulation analyses revealed no reduction in vemurafenib or dabrafenib concentrations, indicating that BRAFis do not act as substrates for ABCB5.
Altogether, our studies suggest that ABCB5 expression is linked to the melanocytic program. However, despite the molecular docking evidence that BRAFis may be substrates of ABCB5, in vitro studies failed to demonstrate direct efflux of BRAFis by ABCB5.
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Leitch, Jeffry M. "How Does ATP Regulate Erythrocyte Glucose Transport?: a Dissertation." eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/335.
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Human erythrocyte glucose sugar transport displays a complexity that is not explained by available models. Sugar transport was examined in resealed red cell ghosts under equilibrium exchange conditions (intracellular [sugar] = extracellular [sugar]). Exchange 3-O-methylglucose (3MG) import and export are monophasic in the absence of cytoplasmic ATP but are biphasic when ATP is present. Biphasic exchange is observed as the rapid filling of a large compartment (66% cell volume) followed by the slow filling of the remaining cytoplasmic space. Two models for biphasic sugar transport are presented in which 3MG must overcome a sugar-specific, physical (diffusional) or chemical (anomerization) barrier to equilibrate with cell water. The anomerization model was rejected through several lines of direct experimental investigation. 1) The sizes of the fast and slow phases of sugar transport do not correlate with the equilibrium anomer distributions of all GLUT1 sugar substrates. 2) Increasing the rate of anomerization by addition of exogenous intracellular mutarotase has no effect on biphasic transport kinetics. 3) Direct measurement of initial rates of sugar uptake or exchange demonstrates that GLUT1 shows no anomer preference. The physical barrier model was further refined by the use of the counterflow condition (intracellular [sugar] >> extracellular [sugar]). The presence of a physical barrier alone was unable to explain the complex counterflow time courses observed. As a result, the model was modified to include the action of a specific sugar export that is compartmentalized from rapidly equilibrating, GLUT1-mediated uptake and exit.
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Wang, Fen. "In silico and in vitro determination of substrate specificity for Breast Cancer Resistance Protein (BCRP) transporter at the blood-brain barrier." Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-444527.
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Background The Breast Cancer Resistance Protein (BCRP) drug transporter is important for drug disposition and plays a critical role in regulating drug entry into the brain. Its substrate spectrum overlaps with substrates of Multi Drug Resistance Protein 1 (MDR1, P-gp), which influences and complicates the interpretation of data on drug distribution into tissues (e.g. brain). Distinguishing BCRP mediated transport from the transport by the MDR1 is often problematic. However, with new in vitro tools, this is now possible. In this project, two drug compounds, i.e. Dantrolene and Ritonavir, were investigated using these new in vitro models. The results from the experimental in vitro assay were matched with molecular dynamics (MD) simulations. Using coarse-grained (CG) simulations, a model of the BCRP transporter in a lipid bilayer was built, this model is based on the human BCRP structure revealed by Taylor et al (2017). Simulations were run for Dantrolene (a known substrate of BCRP) independently three times, and another with Ritonavir (a non-substrate) three times. Aim To determine substrate specificity for the BCRP transporter for two compounds, and to construct a CG model of BCRP transporter to see whether in silico methods can be used as an alternative for assessing substrate specificity. Methods Madin-Darby canine kidney (MDCK) II cell line with no endogenous canine MDR1 (cMDR1) expression (MDCKcMDR1-KO), overexpressing human MDR1 (hMDR1) (MDCK-hMDR1cMDR1-KO) and stable expression of human BCRP (hBCRP) (MDCK-hBCRPcMDR1-KO) cells were cultured and used in Transwell experiments. Samples were analyzed using LC-MS/MS to determine the substrate concentrations. Apparent permeability and efflux ratio was calculated and evaluated. MD simulations used the Martini 3 CG force field, and were run with Gromacs (version 2020.4). Tools including MODELLER, INSANE and others were used to construct the initial model (Webster, 2000; Wassenaar et al., 2015), for parameterization of substrate and non-substrate molecules. And visual inspection was done with the visual molecular dynamics (VMD) program and PyMOL. Results In vitro transport experiment confirmed that Dantrolene is a BCRP specific substrate, and Ritonavir is MDR1 specific substrate. Following simulations of these two compounds, Dantrolene is observed to stay in the transmembrane domains (TMD) for a certain period (on average several hundreds of nanoseconds), while Ritonavir is not found to bind in the TMD, which provides a proof of concept for future studies.
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Matsson, Pär. "ATP-Binding Cassette Efflux Transporters and Passive Membrane Permeability in Drug Absorption and Disposition." Doctoral thesis, Uppsala University, Department of Pharmacy, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8371.
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Transport into and across the cells of the human body is a prerequisite for the pharmacological action of drugs. Passive membrane permeability and active transport mechanisms are major determinants of the intestinal absorption of drugs, as well as of the distribution to target tissues and the subsequent metabolism and excretion from the body. In this thesis, the role of ATP-binding cassette (ABC) transporters and passive permeability on drug absorption and disposition was investigated. Particular emphasis was placed on defining the molecular properties important for these transport mechanisms.
The influence of different transport pathways on predictions of intestinal drug absorption was investigated using experimental models of different complexity. Experimental models that include the paracellular pathway gave improved predictions of intestinal drug absorption, especially for incompletely absorbed drugs. Further, the inhibition of the ABC transporters breast cancer resistance protein (BCRP/ABCG2) and multidrug-resistance associated protein 2 (MRP2/ABCC2) was experimentally investigated using structurally diverse datasets that were representative of orally administered drugs. A large number of previously unknown inhibitors were identified among registered drugs, but their clinical relevance for drug-drug interactions and drug-induced toxicity remains to be determined. The majority of the inhibitors affected all three major ABC transporters BCRP, MRP2 and P-glycoprotein (P gp/ABCB1), and these multi-specific inhibitors were found to be enriched in highly lipophilic weak bases.
To summarize, the present work has led to an increased knowledge of the molecular features of importance for ABC transporter inhibition and passive membrane permeability. Previously unknown ABC transporter inhibitors were identified and predictive computational models were developed for the different drug transport mechanisms. These could be valuable tools to assist in the prioritization of experimental efforts in early drug discovery.
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Bowden, Kristin Louise. "The role of lysosomal acid lipase in regulation of the ATP-binding cassette transporter A1, high density lipoprotein and reverse cholesterol transport." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/45369.
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The key regulator of initial HDL particle formation by cells is the ATP-binding cassette transporter A1 (ABCA1). ABCA1 expression is regulated primarily by oxysterol dependent activation of the liver X receptor (LXR). We investigated the role of lysosomal cholesterol on ABCA1 regulation by studying the lysosomal disorder Cholesteryl Ester Storage Disease (CESD). CESD is caused by genetic mutations in the LIP-A gene that result in only 5% of normal activity of lysosomal acid lipase (LAL), an enzyme that hydrolyzes cholesteryl esters (CE) and triglycerides on internalized lipoproteins specifically within the lysosome. We hypothesized that the flux of unesterified cholesterol out of the lysosomes from LAL-mediated hydrolysis of LDL cholesteryl esters is a key regulator of cellular ABCA1 expression, HDL formation and reverse cholesterol transport (RCT). We found that primary skin fibroblasts derived from individuals with CESD had impaired upregulation of ABCA1 in response to LDL loading, reduced phospholipid and cholesterol efflux to apoA-I, lower production of 27-hydroxycholesterol (27-OH) production in response to LDL loading and reduced α-HDL particle formation. This defect was recapitulated in normal fibroblasts following treatment with LAL inhibitors, whereas, treatment with conditioned medium from normal fibroblasts containing secreted LAL rescued ABCA1 expression, apoA-I-mediated cholesterol efflux, HDL particle formation and production of 27-OH by CESD cells. We further investigated the role of LAL in RCT from macrophages specifically using an immortalized macrophage cell line created from LAL-deficient mouse peritoneal macrophages (LAL-/-). LAL-/- macrophages exhibited reduced basal and cholesterol-stimulated ABCA1 expression in culture, and reduced ability to support RCT in LAL-/- mice compared to wild-type (LAL⁺/⁺) macrophages injected into LAL⁺/⁺ mice. ABCA1 protein expression was reduced in LAL-/- mouse liver and mRNA expression of several LXR-dependent genes involved in reverse cholesterol transport (ABCG1, ABCG5, ABCG8, CYP7A1, SR-B1) were differentially modulated compared to LAL⁺/⁺ controls. These results indicate a critical role of LAL in promoting lysosomal flux of cholesterol for ABCA1 expression, cellular cholesterol efflux and RCT in vivo.
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Wang, Xuan. "Internalization of Extracellular ATP by Cancer Cells and its Functional Roles in Cancer Drug Resistance." Ohio University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1505834714683835.
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Zein, Aiman. "Structure-Function Relationship of the Sterol Transporter ABCG5/G8: Expression, Purification and Enzymatic Characterization of ABCG5/G8 Missense Loss of Function Mutations." Thesis, Université d'Ottawa / University of Ottawa, 2020. http://hdl.handle.net/10393/40742.
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The heterodimeric ATP-binding cassette (ABC) transporter, ABCG5/G8, is responsible for direct secretion of cholesterol and dietary sterols into the gut lumen and the bile. Inactivating mutations of ABCG5/G8 cause sitosterolemia, a rare autosomal recessive disease characterized by the accumulation of plant sterols in plasma, hypercholesterolemia and development of premature coronary heart disease. Functional and structural characterization of ABCG5/G8 is necessary to understand its mechanism and how the genetic defects impact its function. In this thesis, I expressed seventeen constructs of various disease-causing or catalytically deficient missense mutations in Pichia pastoris yeast. This establishes reagents for in vitro functional and structural studies. Secondly, I focused on two disease mutants (ABCG5-E146Q and ABCG8-R543S) and a sterol binding mutation (ABCG5-A540F) and established large-scale purification of these mutants. Using a cholesterol hemisuccinate (CHS)-dependent ATPase assay, I determined ATP hydrolysis by these three mutants and analyze their kinetic parameters. All missense mutants showed a significantly impaired ATPase activity, but the ability of ATP binding appeared unchanged between the WT and the mutants. This work demonstrates an intimate structure-function relationship in ABCG5/G8 and sheds some light on the mechanistic details of this important cholesterol-regulating ABC transporter.
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Al-Khfajy, Wrood Salim Dawood. "Role Of Transmembrane 141 in Cholesterol Metabolism." Kent State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=kent1416142859.
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Layeghkhavidaki, Hamed. "Effet des polluants de type hydrocarbures aromatiques polycycliques sur l'homéostasie lipidique et les récepteurs des lipoprotéines hépatiques." Thesis, Université de Lorraine, 2014. http://www.theses.fr/2014LORR0120/document.
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L'obésité est une maladie multifactorielle qui constitue un facteur de risque de nombreuses pathologies, notamment les maladies cardiovasculaires, le diabète et les maladies neurodégénératives. Des études épidémiologiques récentes suggèrent un effet obésogène des contaminants environnementaux, mais peu d'informations sont disponibles sur leur effet potentiel sur le métabolisme des lipoprotéines hépatiques. L'objectif de cette étude était de déterminer l'effet de polluants environnementaux de la famille des hydrocarbures aromatiques polycycliques (HAP) sur trois récepteurs des lipoprotéines, le récepteur des LDL (LDL-R), le lipolysis-stimulated lipoprotein receptor (LSR) et le scavenger receptor B1 (SR-B1) ainsi que sur les ATP binding cassette transporter A1 (ABCA1) et G1 (ABCG1) en utilisant des modèles cellulaires et/ou animaux. Les études par immunoblots et immunofluorescence in vitro ont révélé que l'exposition de cellules Hepa1-6 au B[a]P diminue de manière significative les taux de protéine LSR, LDL-R et ABCA1, alors qu’aucune modification significative du taux et de l’activité du LSR n’a été observée lors d’une exposition au pyrène ou au phénanthrène. L’analyse en temps réel par PCR et les études avec la lactacystine ont révélé que cet effet était dû principalement à une augmentation de la dégradation par le protéasome plutôt qu’à une diminution de la transcription ou à une augmentation de la dégradation lysosomale. En outre, les ligand-blots ont révélé que les lipoprotéines exposées au B[a]P avaient une affinité réduite pour le LSR ou le LDL-R. Des souris C57Bl/6RJ ont été traitées par le B[a]P (0,5 mg / kg, i.p) toutes les 48 h pendant 15 jours. Le gain de poids observé est accompagné d’une augmentation des taux de triglycérides et de cholestérol plasmatiques, du taux de cholestérol hépatique, et d’une diminution du taux de LDL-R et ABCA1 chez animaux traités au B[a]P par rapport aux témoins. Les corrélations observées entre les taux de LSR et de LDL-R hépatiques chez les souris contrôle ne sont plus observées chez les souris traitées au B[a]P, ce qui suggère un dérèglement du métabolisme des lipoprotéines hépatiques. Ces résultats suggèrent que la prise de poids induite par le B[a]P est peut-être liée à son action inhibitrice sur le LSR et le LDL-R, ainsi que sur l’ABCA1 et le métabolisme des lipoprotéines hépatiques, ce qui conduit à un statut lipidique modifié chez les souris traitées au B[a]P, donnant ainsi un nouvel éclairage sur les mécanismes sous-jacents de la contribution des polluants tels que le B[a]P à la perturbation de l'homéostasie lipidique, susceptible de contribuer à la dyslipidémie associée à l'obésitéObesity is a multifactorial disorder that represents a significant risk factor for many pathologies including cardiovascular diseases, diabetes and neurodegenerative diseases. Recent epidemiological studies suggest potential obesogenic effects of environmental contaminants, but little information is available on their potential effect on hepatic lipoprotein metabolism. The objective of this study was to determine the effect of the common environmental pollutants, belonging to polycyclic aromatic hydrocarbon (HAP) on three lipoprotein receptors, the LDL-receptor (LDL-R), the scavenger receptor B1 (SRB1) and the lipolysis-stimulated lipoprotein receptor (LSR) as well as the ATP binding cassette transporters A1 (ABCA1) and G1 (ABCG1) using cell and/or animal models. Immunoblot and immunofluorescence in vitro studies revealed that exposure of Hepa1-6 to benzo[a]pyrene (B[a]P) significantly decreased LSR, LDL-R and ABCA1 protein levels, whereas no significant changes in protein levels and LSR activity where observed upon cell treatment with pyrene or phenanthrene. Real-time PCR analysis, lactacystin and chloroquine studies revealed that this effect was due primarily to increased proteasome-mediated degradation rather than to decreased transcription or to increased lysosomal degradation. Furthermore, ligand blots revealed that lipoproteins exposed to B[a]P displayed markedly decreased binding to LSR or LDL-R. C57Bl/6RJ mice were treated with B[a]P (0.5 mg/kg, i.p) every 48 h for 15 days. The increased weight gain observed was accompanied by increased plasma triglycerides and cholesterol levels, increased liver cholesterol content, and decreased LDL-R, ABCA1, ABCG1 and SR-B1 protein levels in B[a]P-treated animals as compared to controls. Correlations observed between hepatic LSR and LDL-R levels in control mice were no longer observed in B[a]P treated mice, suggesting a potential dysregulation of hepatic lipoprotein metabolism.Taken together, these results suggest that B[a]P-induced weight gain may be due its inhibitory action on LSR and LDL-R, as well as ABCA1 and lipoprotein metabolism in the liver, which leads to the modified lipid status in B[a]P-treated mice, thus providing new insight into mechanisms underlying the involvement of pollutants such as B[a]P in the disruption of lipid homeostasis, potentially contributing to dyslipidemia associated with obesity
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Clee, Susanne M. "Lipoprotein lipase and the ATP binding cassette transporter ABCA1 : two genes regulating plasma high density lipoprotein cholesterol and triglyceride levels and risk of coronary artery disease." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/NQ61073.pdf.
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Marion, Carolyn. "Modification and Utilization of Carbohydrates by Streptococcus pneumoniae." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338303033.
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Ahmed, Romel [Verfasser], Steffen [Akademischer Betreuer] Abel, Edgar [Akademischer Betreuer] Peiter, and Tamara [Akademischer Betreuer] Gigolashvili. "Molecular identification and characterization of the phosphate deficiency response related genes, PRT1 (ATP-Phosphoribosyl Transferase 1) and ALMT1 (Aluminium-activated Malate Transporter 1) / Romel Ahmed. Betreuer: Steffen Abel ; Edgar Peiter ; Tamara Gigolashvili." Halle, Saale : Universitäts- und Landesbibliothek Sachsen-Anhalt, 2015. http://d-nb.info/1090787162/34.
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HATIN, ISABELLE. "L'adenylate translocase : un adp/atp transporteur chez plasmodium falciparum." Paris 7, 1994. http://www.theses.fr/1994PA077245.
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L'adp/atp transporteur catalyse l'echange adp/atp a travers la membrane interne des mitochondries. La proteine fonctionnelle est un dimere de deux sous unites identiques de 30 a 34 kda chaque, codee par le genome nucleaire. Cette proteine appartient a une superfamille de transporteurs mitochondriaux. L'objectif de ce travail etait de montrer la presence d'un gene codant pour un adp atp transporteur chez p. Falciparum. L'utilisation repetee de la pcr, nous a permis d'etablir qu'une sequence nucleotidique chez p. Falciparum code pour un polypeptide de 301 acides amines, homologue aux adt mitochondriales. L'alignement de cette sequence avec les sequences deja publiees pour d'autres organismes eucaryotes montre que l'adp/atp transporteur de p. Falciparum comporte toutes les sequences considerees comme importantes pour sa localisation intramembranaire ainsi que pour sa fonctionalite. Le profil d'hydrophilie revele six domaines hydrophobes, potentiellement transmembranaires. Le northern blot des arn a partir de cultures synchrones, montre un faible taux de transcription du messager specifique de l'adp/atp transporteur chez p. Falciparum. La quantification de ces arnm par hybridation in situ a revele une expression plus faible au stade trophozoite qu'au stade anneau et schizonte. Le gene codant pour ce transporteur chez p. Falciparum est localise sur le chromosome 10. L'immuno-electromicroscopie avec un anticorps polyclonal heterologue montre un marquage uniquement dans le membrane interne de la mitochondrie de p. Falciparum
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Heumann, Jan H. "The potential role of ABC transporters as factors influencing drug susceptibility in the salmon louse, Lepeophtheirus salmonis (Kroyer, 1837)." Thesis, University of Stirling, 2014. http://hdl.handle.net/1893/21812.
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Efficient control of sea lice is a major challenge for the sustainable production of farmed Atlantic salmon (Salmo salar (Linnaeus, 1758)). These marine ectoparasites feed on mucus, skin and blood of their hosts, thereby reducing the salmon’s growth rate and overall health. In the northern hemisphere, the most prevalent species is Lepeophtheirus salmonis (Krøyer, 1837). In 2006, global costs of sea lice infections are estimated to have exceeded €300 million, with the majority spent on a limited number of chemical delousing agents. Emamectin benzoate (EMB; SLICE®), an avermectin, has been widely used since its introduction in 2000, due to its convenient administration as an in-feed medication and its high efficacy against all parasitic stages of L. salmonis. However, over-reliance on a single or limited range of medicines favours the emergence of drug resistance and, as a result, the efficacy of this compound in treating L. salmonis has decreased in recent years, as reported from e.g. Chile, Norway, Scotland and Canada. Declining efficacy underlines the need for an improved understanding of the molecular mechanisms underlying EMB drug resistance in L. salmonis. Elucidation of these mechanisms would allow for improved monitoring tools, earlier detection of developing resistance, extended usability of current delousing agents and development of new parasiticides. The work described in this thesis sets out to examine the molecular mechanisms underlying EMB resistance in L. salmonis. In earlier studies, research in nematodes and arthropods has linked drug efflux transporters belonging to the family of ATP-binding cassette (ABC) transporters to ivermectin (IVM) resistance, a parasiticide with high chemical similarity to EMB. ABC transporters such as permeability glycoprotein (P-gp), transport a wide range of substrates, including drugs, and have been suggested to provide a potential molecular mechanism through which EMB resistance might be mediated in sea lice. As an example of such mechanisms, increased expression of P-gp is one of the causative factors for drug resistance in human cancer cells and avermectin resistance in nematode parasites such as Caenorhabditis elegans or Haemonchus contortus. Initial research involved screening for novel salmon lice P-gps that might contribute to EMB resistance. A novel P-gp, SL-PGY1, was discovered using a combined bioinformatic and molecular biological approach. The expression was compared in two well-characterised L. salmonis strains differing in their susceptibility to EMB (S = susceptible, R = resistant). Prior to EMB exposure, mRNA levels did not differ from each other, while, after 24 h exposure, a 2.9-fold increase in SL-PGY1 mRNA expression was observed in the R strain. SL-PGY1 appears not to be a major factor contributing to reduced EMB susceptibility, although it could play a role, as expression levels increased upon exposure to EMB. A further four additional drug transporters (ABC C subfamily) were also discovered showing high homology to multidrug-resistance proteins (MRP). The relative expression levels of each MRP was compared in the strains S and R, before and after exposure to EMB. No significant changes were found in their expression patterns. If ABC drug transporters mediate the efflux of EMB and thereby reduce the intracellular concentrations of the drug in exposed animals, the inhibition of those ABC drug transporters was expected to lead to higher intracellular levels of EMB. This could result in an enhanced toxic effect when EMB is co-administered with an inhibitor. Two known inhibitors of human P-gps and MRPs, cyclosporin A (CSA) and verapamil (VER), were co-administered with EMB. CSA increased the toxic effect of EMB in both tested strains, implying that the targets of CSA are expressed at comparable levels and that they may be part of the mechanism conferring EMB resistance. VER increased the toxic effect of EMB in the R strain, but had no significant effects on the S strain. This implies that the expression of factors inhibited by VER differs between the two L. salmonis strains. It is hypothesised that a number of ABC transporters with distinct, yet overlapping patterns of inhibitor specificity are affected by those inhibitors. The search for drug-resistance conferring genes was complemented with a systematic, genome-wide survey of ABC transporters in L. salmonis to find additional members of this important gene family. Next-generation high-throughput RNA sequencing (RNA-seq) was employed to assemble a reference transcriptome from pooled total RNA of salmon lice at different development stages. The transcriptome was assembled against the L. salmonis genome and annotated. Thirty-nine putative ABC transporters were found. Of further interest were transcripts of the subfamily B, C and G, as they contain drug-transporting ABC proteins. For the ABC B subfamily, one full (SL-PGY1) and three half transporter transcripts were found. Only full transporters are known to transport drugs and SL-PGY1 is apparently not a major factor contributing to EMB resistance. Fourteen ABCC sequences were found – 11 MRPs and 3 homologues to sulfonylurea receptors. Of interest are MRPs, as they contribute to drug detoxification in humans and invertebrates. Four MRPs had been identified previously and their expression ratios did not differ between S and R strain parasites. Seven sequences belonging to ABCG subfamily were found. However, none of the L. salmonis ABCG transcripts identified showed sufficient homology to known drug transporters in other species. With the currently limited understanding of the mechanisms conferring EMB resistance, monitoring the susceptibility of L. salmonis subpopulations is essential. Dose-response bioassays are currently widely used. Tests with pre-adult II or adult parasites requires relatively large numbers of parasites (~150) to conduct this type of bioassay, which may not always be available. Addressing this issue, we tested the feasibility of a single-dose bioassay (requiring fewer test animals than dose-response bioassays) to discriminate between L. salmonis strains with differing EMB susceptibility. This alternative approach uses time-course toxicity analysis, where the toxic effect of EMB is monitored over time. After clearly defining the effect criteria, we found that it is possible to discriminate between those L. salmonis strains. However, while requiring fewer test animals, time course toxicity analysis is more labour-intensive, but the alternative design can be suitable under certain circumstances. The work reported here has provided new knowledge concerning the mechanisms of EMB resistance in sea lice. Several novel putative drug transporters have been identified, an important first step toward unravelling the complex interactions of genes involved in EMB resistance in this commercially important parasite.
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BADONE, F. CERINO. "STUDY OF LOW PHYTIC ACID 1 LOCUS IN MAIZE." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/168725.
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Phytic acid (myo-inositol-1,2,3,4,5,6-hexakisphosphate; InsP6) is ubiquitous in eukaryotic cells and constitutes the major storage form of phosphate in plant seeds (from 60% to 80%). During maturation it is accumulated in the protein storage vacuole in inclusions called globoids; the phosphate groups present in phytic acid (PA) are able to form phytate salts (phytin) binding important mineral cations. In mature maize kernels, 80% of PA is localized in the scutellum and the remaining 20% in the aleurone layer. The phosphorus stored as PA is remobilized during germination by phytase enzymes: these are also found in many microorganisms.
Regarding the involvement of P in agricultural production and its sustainability, it has been estimated that nearly 50% of elemental P used yearly in global agricultural activities is accumulated in the PA.
PA forming mixed salts with mineral cations is mainly excreted by monogastric animals and humans because they do not have phytase activity in their digestive systems. Considering that seeds are an important component of animal feed and human food, the limitations of phosphorus and micronutrients bioavailability imply a decrease in their nutritional value. Furthermore the undigested phosphorous contained in excreted phytin can contribute to water pollution (eutrophication).
These negative effects have led to breeding programmes which have the aim of reducing the PA content in the seeds of several cultivated plants. The main way to reach this result by conventional breeding is the isolation of low phytic acid (lpa) mutations, capable of restraining the biosynthesis or the storage of PA in the seed; the increased P and mineral cation bioavailability in lpa seeds is confirmed by nutritional trials.
In maize three low phytic acid mutants have been isolated: lpa1 and lpa2 by chemical mutagenesis, lpa3 by transposon tagging. Compared to the other mutations in maize, lpa1 exhibited the major reduction of PA in the seed, this comes with a proportional increase of free P without changing the total P content. Taking advantage of this property, lpa mutants can be recognized by the HIP (high inorganic phosphate) phenotype of the seeds. The Lpa1 gene encodes for ZmMRP4 (accession number EF586878) a multidrug-associated-protein (MRP) belonging to the subfamily of ATP-binding cassette (ABC) transmembrane transporters. MRP proteins are implicated in different roles like the transport of organic ions and anthocyanins, detoxification of xenobiotic compounds, transpiration control, and tolerance to oxidative stress. The role of this MRP protein is not completely understood but it is fundamental for phytic acid accumulation and viability of seeds. low phytic acid mutants isolated in rice and soybean are related to defects in homologues of the maize ABC transporter.
It was observed that lpa mutations found in several crops usually bring pleiotropic effects on plant and seed performance, such as reduced germination and emergence rate, lower seed filling, weakening in stress resistance. The presence of pleiotropic effects shows that lpa mutations influence not only the seed but also the whole plant and its production. This can reflect the relevance of inositol phosphates as multifunctioning molecules, and their involvement in fundamental signaling and developmental pathways, like DNA repair, RNA editing, chromatin remodeling and control of gene expression. Furthermore phytic acid exhibits, by its ability to chelate iron, a potent antioxidant activity, avoiding the formation of reactive oxygen species.
With the aim to isolate new maize low phytic acid mutants mutagenesis treatment were performed with EMS (ethyl-methanesulfonate). Since wild type mature maize seeds contain high amount of phytic phosphate and low free phosphate content, we screened the mutagenized population looking for seeds containing high levels of free phosphate (HIP phenotype), a typical feature of lpa.
In previous studies a single recessive lpa mutation (originally named lpa241 and obtained by EMS pollen-tratment mutagenesis) was isolated and described, it was allelic to the lpa1-1 mutant, and was consequently renamed lpa1-241.
A first evidence of non-Mendelian inheritance of lpa1 trait came from the appearance of unexpected free phosphate phenotypes in Lpa1/lpa1-241. When heterozygous families were selfed, we observed an overall increase of the mutant phenotype ratio due to the appearance of weak and intermediate phenotype, not consistent with a monogenic recessive mutation. This phenomenon can be explained with a partial Lpa1 allele silencing caused by trans interaction with the paramutagenic lpa1-241 allele.
We performed genetic and molecular analyses of the lpa1-241 mutation that indicate an epigenetic origin of this trait, that is, a paramutagenic interaction that results in meiotically heritable changes in ZmMRP4 gene expression, causing a strong pleiotropic effect on the whole plant. To our knowledge, this is the first report of a paramutagenic activity not involving flavonoid biosynthesis in maize, but regarding a key enzyme of an important metabolic pathway in plants.
We isolate a new maize (Zea mays L.) low phytic acid 1 mutant allele obtained by chemical EMS seed mutagenesis. We performed the allelism test with two other lpa1 mutants: lpa1-1 and lpa1-241, our mutant failed to complement these mutants. This mutant, named lpa1-7, exhibits a monogenic recessive inheritance and lethality as homozygous. We demonstrate that in vitro cultivation can overcome lethality allowing the growth of adult plants and we report data regarding embryo and leaf abnormalities and other defects caused by negative pleiotropic effects of this mutation. We conducted two experiments to ascertain the nature of lpa1-7 and. we also performed physiological analysis, histological observations and considerations regarding the effects of the lpa1 mutations on the plant.
Pigmented maize contains anthocyanins and phenolic compounds which are phytochemicals synthesized in the plant by secondary metabolism; although these compounds are considered as non-nutritive, in these years the interest in antioxidant and bioactive properties has increased due to their health benefits. Anthocyanins are water soluble secondary metabolites belonging to the class of flavonoids and they play important roles in several aspect of plant biology. The anthocyanins are present in the vacuole in a glycosilated form and their colour is influenced in part by the pH of this compart. In maize they are synthesized by a complex pathway made up of more than 20 genes, and regulated by two classes of transcription factors: r1/b1 bHLH genes and c1/pl1/p1 MYB gene families.
Our aim is the constitution of maize inbred lines carrying low phytic acid mutations together with regulatory genes pushing the anthocyanin accumulation in the kernels and seedlings, so they can compensate the leak in antioxidant activity induced by the low phytic acid mutation.
We found that the lpa1-241 line is able to alter the accumulation of anthocyanin in kernel tissues. The anthocyanins, are present in the vacuole where their colour is dependent on the pH. In maize the anthocyanins are cytoplasmically synthesized molecules probably transported in the vacuole by ZmMRP3 gene activity.
We observed an interaction between the accumulation of anthocyanin pigments in the kernel and the lpa mutations. In fact the lpa1-241 mutant accumulates a higher level of anthocyanins as compared to wild type either in the embryo or in the aleurone layer in a genotype able to accumulate anthocyanin. Furthermore, we demonstrate that these pigments are mislocalised in the cytoplasm, conferring a blue pigmentation of the scutellum, because of the neutral/basic pH of this cellular compartment; expression analysis showed a reduction of ZmMRP3 anthocyanins’ transporter gene expression. On the whole, these data strongly suggest a possible interaction between the lpa mutation and anthocyanin accumulation and compartmentalization in the kernel.
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Williams, Stanley J. "Inhibition of Aryl Hydrocarbon Receptor (AhR) Activity Decreases ABCG2 Expression and Activity." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2018. http://digitalcommons.auctr.edu/cauetds/122.
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The androgen receptor’s (AR) resurgence following treatment leads to castration resistant prostate cancer (CRPC). Studies show that the aryl hydrocarbon receptor (AhR) regulates AR signaling, is constitutively active, and enhances AR signaling in CRPC. AhR has ligands with carcinogenic properties and interacts with phytochemicals with anti-tumorigenic properties. Curcumin inhibits AhR activity and multidrug transporter ABCG2 activity, which mediates substrates out of the cell. Elevated ABCG2 expression causes resistance to anticancer drugs. AhR transcriptionally activates ABCG2 and our hypothesis is that inhibition of AhR activity by curcumin will decrease ABCG2 expression and activity in CRPC cells. C4-2 cells were treated with increasing concentrations of curcumin (0, 10, 25, 50µM) and CH223191 (50µM). Results show that curcumin decreases AhR, CYP1B1 and ABCG2 gene expression. Higher concentrations of curcumin diminish AhR and ABCG2 protein expression, ABCG2 activity, and cell proliferation. These results will help reveal a role for AhR in drug resistance.
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Marchand, Laurène. "Etude fonctionnelle et structurale d'un transporteur d'ATP/ADP chloroplastique." Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENV020/document.
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L'hydrolyse de l'ATP en ADP constitue la principale source d'énergie de la cellule. Le transport de ce nucléotide depuis son lieu de synthèse vers le cytosol est essentiel pour la plupart des réactions métaboliques et nécessite un passage à travers les membranes. Ainsi, un grand nombre de transporteurs d'ATP/ADP sont présents dans les différents organites tels que les mitochondries, les chloroplastes, et autres types de plastides mais aussi chez les bactéries pathogènes (Rickettsia prowazekii, Protoclamydiae amoebophila) (Trentmann et al, 2007).L'équipe s'intéresse principalement à 2 types de transporteurs d'ADP et d'ATP, la famille des transporteurs mitochondriaux (MCF) et la famille des NTT (plastes et bactéries). Malgré des fonctions similaires, ces 2 familles de transporteurs possèdent des propriétés biochimiques et structurales différentes. De nos jours, il n'existe aucune information structurale disponible sur la famille des NTTs. La détermination de cette structure pourrait permettre de comprendre le mécanisme de transport de ces transporteurs mais plus généralement comprendre le transport de l'ATP et ADP dans les cellules.Une étude a été initiée sur la structure et la fonction de la famille des NTT plus particulièrement des transporteurs chloroplastiques d'Arabidopsis thaliana mais aussi des transporteurs bactériens. Toutefois, ma thèse concerne principalement les transporteurs chloroplastiques NTT1 et NTT2. Ces 2 isoformes sont localisées dans la membrane interne des chloroplastes et permettent de pourvoir le stroma en ATP lorsque la photosynthèse ne peut pas avoir lieu par manque de lumière.Nous avons déterminé et optimisé les conditions de surexpression des 2 isoformes dans un système hétérologue puis de purification en détergent). Nous avons mis au point des méthodes permettant de caractériser le transporteur en solution et de mesurer son activité dans le but d'aboutir à une étude structurale. Des pistes de cristallisation ont également étaient obtenuesATP is the main energy currency in the cell and its transport across membranes is essential for most of the metabolic reactions. A large number of ATP/ADP transporters are present in the different cell organelles such as mitochondria, chloroplasts, other types of plastids and some are also found in bacteria (Rickettsia prowazekii, Protoclamydiae amoebophila) (Trentmann et al, 2007). The team is mainly interested in two distinct transporters families, the mitochondrial carrier family (MCF) and the NTT family. Despite similar function, mitochondrial ADP/ATP transporters (Pebay-Peyroula et al, 2003) and NTT proteins exhibit different structural and biochemical properties. To date no structural information is available on the NTT family. The determination of a structure would help for understanding the transport mechanism of these carriers and more generally the different mechanisms of the transport of ADP and ATP within the cell.We initiated a structure-function study on the NTT family focusing on chloroplast transporters from Arabidopsis thaliana and also from bacteria. My thesis is focused on chloroplast NTT1 and NTT2. These isoforms are localized in the inner membrane of chloroplast. They transport ATP inside the chloroplast in order to supply the different reactions occurring in the stroma when the photosynthesis does not occur.We have determined and optimized conditions to overexpress these 2 isoforms in heterologous systems and to purify the protein in detergents. We have also set up tools to characterize the carrier in solution and to measure its transport activity opening the way to functional and structural studies. We obtained promising crystallization hits
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Moiseeva, Vera. "Caractérisation de l'état oligomérique du transporteur mitochondrial ADP/ATP dans des membranes natives." Thesis, Grenoble, 2012. http://www.theses.fr/2012GRENY018.
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Le passage sélectif de molécules à travers la membrane interne des mitochondries est essentiel aux processus métaboliques des cellules eucaryotes. Cette communication cellulaire est assurée par des protéines transmembranaires de la famille des transporteurs mitochondriaux (MCF). Le transporteur ADP/ATP (AAC) est le membre le plus connu et le mieux caractérisé de cette famille. Il est responsable de l'import d'ADP dans la matrice mitochondriale et de l'export d'ATP après synthèse vers le cytosol. La structure d'AAC est connue mais plusieurs questions restent ouvertes concernant le mécanisme du transport, la sélectivité et l'état oligomérique, controversé, de la protéine. Pendant plusieurs années des études biochimiques réalisées sur la protéine solubilisée en détergent étaient en faveur d'une organisation dimérique du transporteur, mais la structure d'AAC, monomérique a remis en cause ce dogme. Afin de caractériser l'organisation oligomérique d'AAC in vivo, nous avons combiné plusieurs approches. Nous avons réalisé des expériences de FRET (Fluorescence Resonance Energy Transfer) directement sur des cellules mammifères ou bactériennes (E. coli) surexprimant la protéine AAC fusionnée avec des sondes FRET. En parallèle, nous avons mis au point des tests fonctionnels afin de contrôler l'état des mitochondries et l'activité du transporteur dans ces cellules. Enfin nous avons étudié la stoechiométrie de liaison de l'inhibiteur carboxyatractyloside grâce à des mesures de respiration sur des mitochondries extraites de foie de rat et placées dans différents états métaboliques. L'ensemble des résultats présentés dans ce manuscrit ont permis de montrer que 1) l'unité fonctionnelle d'AAC est monomérique 2) l'organisation structurale d'AAC dans les membranes natives dépend de l'état métabolique des mitochondries et peut être associée à des phénomènes de régulationThe transport of small molecules through the inner mitochondrial membrane is essential in eukaryotic metabolism and is selectively controlled by a family of integral membrane proteins, the Mitochondrial Carrier Family (MCF). The ADP/ATP carrier (AAC), which is responsible for the import of ADP to the matrix of mitochondria and the export of newly synthesized ATP toward the cytosol, is the best-known and characterized MCF member. Although its structure sheds light on several aspects of the carrier activity, additional investigations are still required to decipher the whole transport mechanism, to understand the specificity and to characterize the controversial oligomeric state of the protein. For many years, based on studies mainly carried on detergent solubilized AAC the general consensus has been in favor of a dimeric organization of the carrier. The AAC three-dimensional structure, monomeric, broke this dogma. In order to get a precise insight into the in vivo oligomeric organization of AAC we combined several approaches. Fluorescence resonance energy transfer (FRET) measurements were performed directly on mammalian and E.coli cells expressing AAC labeled with several types of FRET probes. In parallel, different functional assays were established to control the state of the mitochondria in these cells and the transport activity of these AAC fusions. Lastly, measurements of the respiration rate coupled to the titration of the inhibitory effect of carboxyatractyloside on isolated rat liver mitochondria were used to investigate the organization of AAC in native mitochondria within two regimes of oxidative phosphorylation. Taken together the results described herein revealed that 1) AAC can function mechanistically as a monomer, 2) the organization of AAC in native membranes might be related to the state of the mitochondria and be involved in regulation
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Dahout-Gonzalez, Cécile. "Transporteur mitochondrial ADP/ATP : structure tridimensionnelle à 2,2 Å de résolution et dynamique fonctionnelle." Université Joseph Fourier (Grenoble), 2003. http://www.theses.fr/2003GRE10192.
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Hardy, Lise. "Identification de nouveaux acteurs du métabolisme des HDL : impact sur les maladies cardiovasculaires Critical role of the human ATP-binding cassette G1 transporter in cardiometabolic diseases A Genome Wide Association Study on plasma FV levels identified PLXDC2 as a new modifier of the coagulation process." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS546.
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De faibles concentrations de cholestérol associé aux HDL (HDL-C) est un facteur de risque indépendant des maladies cardiovasculaires (MCV). Les HDL sont capables de réaliser de l’efflux de lipides des tissus périphériques pour assurer son retour vers le foie, et ont des rôles athéroprotecteurs. Le travail mené ici vise à identifier de nouveaux acteurs impliqués dans la détermination des fonctions des HDL. Le transporteur ABCG1 réalise de l’efflux de cholestérol, de phospholipides (PL), ou encore de vitamines à partir des macrophages périphériques vers les HDL. Nous avons montré que la stimulation de l’expression d’ABCG1 dans l’hépatocyte favorisait un réarrangement du contenu des HDL en PL. Ce remodelage est associé à une amélioration de la capacité d’efflux de cholestérol des HDL et de leur fonction anti-inflammatoire. En parallèle, des études épidémiologiques nous ont permis d’identifier ZNF471, nouveau facteur de transcription. Il semble capable de moduler l’expression et l’activité de protéines clés du métabolisme des lipides, via une régulation épigénétique impactant la méthylation de l’ADN : ZNF471 dans les hépatocytes augmente la méthylation de l’ADN sur la région promotrice du gène codant la CETP. En conséquence, l’expression du gène et l’activité protéique de la CETP sont réduits, ce qui favorise l’accumulation de HDL-C. De plus, les capacités d’efflux de cholestérol des HDL sont également stimulées par ZNF471. Ces travaux de recherche permettent l’identification de nouveaux acteurs du métabolisme des lipoprotéines HDL. Ils ouvrent ainsi la voie à de nouvelles explorations thérapeutique et mécanistique sur les rôles des HDL dans les MCV liées à l’athéroscléroseSince low concentrations of High-Density Lipoproteins-cholesterol (HDL-C) are associated with increased cardiovascular disease (CVD) risk, HDL are recognized as protective in atherosclerotic CVD (ASCVD). Indeed, HDL promote lipid efflux from macrophages and other atheroprotective activities. Here, we aimed to identify new factors implicated in the determination of atheroprotective functions of HDL. ATP-Binding Cassette G1 (ABCG1) transporter perform cholesterol, phospholipids or vitamin efflux from peripheral macrophages to HDL. We showed that ABCG1 expression in hepatocytes promoted HDL phospholipid content rearrangement. This HDL remodeling is associated with a better cholesterol efflux capacity and an improvement of their anti-inflammatory properties. Simultaneously, epidemiological studies allow us to identify a novel transcription factor, ZNF471 (Zinc Finger Protein 471). ZNF471 seems to modulate expression and activity of key proteins implicated in lipid metabolism, through epigenetic DNA methylation regulation. We highlighted that ZNF471 expression in hepatocytes increased DNA methylation in CETP (Cholesterol Ester Transfer Protein) gene promoter region. As a consequence, CETP gene expression and protein activity were diminished, which raised HDL-C circulating concentrations. We also pointed out that ZNF471 expression stimulated HDL cholesterol efflux capacities. This work allows the identification of novels genetic and epigenetic actors in determining HDL lipoproteins activities. It paves the way for new therapeutic and mechanistic insights on the roles of HDL in ASCVD
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Gray, Christopher H. "ATP-binding cassette transporters of Paracoccidiodes brasiliensis." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342042.
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Walzel, Bernd. "Cellular creatine transporters : identification and characterization of the plasma membrane - and a novel mitochondrial creatine transporter /." [S.l.] : [s.n.], 2000. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=14028.
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