Dissertations / Theses on the topic 'Glycoproteins Receptors'
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Hyland, Robert H. "Heterodimer formation and activation of the leukocyte integrins." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365411.
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Tiu, Hiu-kwan. "Vitellogenesis and vitellogenin receptor in shrimp : from the sites of synthesis to the final storage in the ovary /." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38481030.
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Thomas, Elaine Rhiannon. "Neutralisation of HIV-2 interactions between viral glycoproteins and cell surface receptors." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397817.
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Lau, Suk-ling Joanna, and 劉淑玲. "Molecular characterization of the chicken growth hormone receptorgene." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2005. http://hub.hku.hk/bib/B45015430.
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Mirza, Deeman. "Probing the interaction of hepatitis C virus glycoproteins with putative receptors and neutralising antibodies." Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/12685/.
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Hepatitis C virus (HCV) is a hepatotropic blood-borne virus which causes chronic hepatitis in the majority of cases and represents a global health burden. In order for HCV to enter cells, proteins on the surface of the virus must interact and bind to receptors on target cells. HCV surface molecules involved with receptor binding, and cellular entry, as well as immune escape, are the glycoproteins E1 and E2. The cellular receptors SRBI, CD81, CLDNs and most recently occludin have been shown to facilitate HCV entry into hepatocytes. Several conservative regions on E1E2 have, through substitution mutagenesis, proven to be important for receptor binding and antibody neutralisation. We aimed to characterise one discontinuous region, amino acid residues 611, 613-619 and 621, and its role in the interaction with CD81 by single alanine substitution mutagenesis. Mutant plasmids were transfected into HEK 293FT cells and assessed for protein expression and binding by conformation-sensitive, CD81-inhibiting antibodies. Also, to investigate whether a conformational change of the E1E2 occurs upon SRB1 binding, rendering the CD81 binding domains accessible, two assays have been compared. A plate based experiment, exclusive of SRBI and a cell based assay, including SRBI was designed to examine the antigenic exposure of the CD81 binding regions to targeting monoclonal antibodies. Additionally, Huh-7 cells expressing different levels of SRBI were used to investigate whether some HCVpp isolates rely on high SRB1 levels for infectivity and sensitivity to neutralising antibodies. These studies were performed to help elucidate the regions and residues important in HCV E1E2: receptor interaction and their interplay with each other and with neutralising antibodies.
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Gantner, Benjamin N. "Dectin-1 and toll-like receptor 2 : recognition of pathogens through multiple receptors shapes the innate immune response /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/8346.
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Lau, Suk-ling Joanna. "Molecular characterization of the chicken growth hormone receptor gene /." View the Table of Contents & Abstract, 2005. http://sunzi.lib.hku.hk/hkuto/record/B32037211.
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Tiu, Hiu-kwan, and 刁曉君. "Vitellogenesis and vitellogenin receptor in shrimp: from the sites of synthesis to the final storage in theovary." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39360623.
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Lam, Pui-yi, and 林佩儀. "Characterization of neutralizing and receptor binding activities in human coronavirus NL63 spike protein." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B41896865.
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Lam, Pui-yi. "Characterization of neutralizing and receptor binding activities in human coronavirus NL63 spike protein." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B41896865.
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Löfgren, Lars. "Hormones and breast cancer : aspects on receptor expression and metabolism /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-635-2/.
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Smith, Mary Kathryn. "Human coronavirus-receptor interactions /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2008.
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Thesis (Ph.D. in Microbiology) -- University of Colorado Denver, 2008.Typescript. Includes bibliographical references (leaves 168-210). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;
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Lopez, Sanchez Uriel. "Dual functions of the XPR1/SLC53A1 phosphate exporter and other transporters as nutrient transporters and receptors of gammaretrovirus envelope-like glycoproteins." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT042.
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Le phosphate inorganique (Pi) est un minéral essentiel de notre organisme, qui intervient dans la composition des acides nucléiques et des phospholipides, dans la minéralisation des os et des dents, dans la production d’énergie, et dans la régulation des voies de signalisation. L’homéostasie du Pi est étroitement régulée par différents transporteurs, et des anomalies du transport de Pi peuvent avoir des conséquences cliniques sévères. Chez l’homme, ils existent 3 transporteurs de Pi distincts de type SLC (solute carrier) avec une distribution tissulaire large et initialement identifiés en tant que récepteurs de rétrovirus : PiT1/SLC20A1, PiT2/SLC20A2, et XPR1/SLC53A1.Des mutations dans PiT2 sont associées à une maladie rare, la calcification cérébrale primaire familiale (PFBC), caractérisée par des dépôts de phosphate de calcium dans les noyaux gris centraux et par l’expression de troubles neuropsychiatriques. Alors que PiT1 ne semble pas être impliqué dans cette maladie, nous avons découvert que des mutations dans XPR1 étaient présentes chez des patients PFBC, renforçant le lien entre la maladie PFBC et les désordres de l’homéostasie du phosphate.Dans ce travail, nous avons cherché à comprendre comment PiT2 et XPR1, deux transporteurs de Pi mais de flux opposés peuvent conduire à une même maladie. Pour cela, nous avons étudié le lien entre PiT2 et XPR1 dans la régulation du Pi ainsi que les domaines de XPR1 impliqués dans le transport. Nous avons d’abord identifié de nouveaux variants PFBC dans PiT2 et XPR1 et confirmé l'effet délétère de ces mutations sur l’import et l’export. Nous avons pu distinguer des mutations qui abolissaient l’expression en surface de XPR1, et donc indirectement l’export de Pi, alors que d’autres avaient un impact fonctionnel direct sur les transporteurs pourtant présents à la membrane plasmique.L’inactivation de XPR1 dans des cellules haploïdes humaines induit une altération profonde de l’export de Pi sans effet notable sur l’import. De manière surprenante, l’inactivation de PiT2 entraine un effet modéré sur l’import, probablement dû à l'activité complémentaire de PiT1, avec une chute de l’export dépendant de XPR1. Cet effet identifie une boucle de régulation que nous avons montrée être essentielle au maintien des niveaux de phosphate et d’ATP. Ces résultats révèlent que le défaut d’export de phosphate par inactivation de PiT2 et XPR1 est susceptible d’être l’étape-clé qui conduit à une maladie commune, la PFBC.Nous nous sommes concentrés sur cette étape d‘export régulée en étudiant le domaine SPX de XPR1 dans lequel la plupart des mutations PFBC ont été retrouvées. Nous avons identifié la tankyrase (TNK) comme interactant cellulaire, et localisé son site d’interaction à la bordure carboxyle de SPX. Nous avons observé que la délétion de SPX entrainait un défaut d’export de Pi, et que la perte d’interaction de TNK à XPR1 par mutagenèse ponctuelle avait le même effet, suggérant que TNK et SPX sont 2 composants essentiels à l’export de phosphate. Enfin, nous avons identifié de nouvelles mutations de XPR1 à l'extrémité C-terminale qui abolissaient l’export de Pi, et montré que la délétion de ce domaine entrainait un défaut d’expression de XPR1 à la membrane plasmique. Nos résultats indiquent donc que les domaines N- et C-terminaux jouent un rôle clé dans l’export, et donc dans l’homéostasie du phosphate, avec le domaine C-terminal jouant plutôt un rôle dans le trafic en surface de XPR1.L’ensemble de ce travail a permis de documenter de nouvelles mutations PFBC dans les gènes PiT2 et XPR1, de démontrer que ces transporteurs étaient impliqués dans l’homéostasie intracellulaire du phosphate, en dévoilant que l’export de phosphate est vraisemblablement l’étape clé de la PFBC, ouvrant ainsi de nouvelles pistes dans la compréhension de cette maladie. Nous avons également identifié des domaines de XPR1 et un partenaire cellulaire, essentiels à l’export de Pi et/ou au trafic membranairePhosphate (Pi) is a key mineral that participates directly in the synthesis of nucleic acids and membranes, bone and tooth mineralization, energy production, and signal transduction. Pi homeostasis is tightly regulated by transporter-mediated fluxes that adjust Pi concentration in real time, and defect in Pi transport has been associated with several pathologies. In humans, three Pi transporters, which belong to the solute carrier (SLC) superfamily, are widely expressed: PiT1/SLC20A1, PiT2/SLC20A2, and XPR1/SLC53A1. Interestingly, all three were initially identified as receptors for mammalian gammaretroviruses.Mutations in PiT2/SLC20A2 are responsible for a rare neurodegenerative disorder, the primary familial brain calcification (PFBC), characterized by deposits of calcium Pi in the basal ganglia and other regions of the brain, and associated with diverse neuropsychiatric clinical manifestations. While PiT1/SLC20A1 has not been involved in PFBC, we recently identified mutations in XPR1/SLC53A1 as causative for PFBC, thus linking further the disease with cellular Pi homeostasis dysfunction.In this work, we aimed to understand how defects of opposite Pi transport functions lead to PFBC, investigated the relationship between PiT2 and XPR1 in cellular Pi regulation, and studied XPR1 domains in Pi transport. We first identified several PFBC mutations in PiT2/SLC20A2 and XPR1/SLC53A1, and confirmed their impact on Pi import or export, respectively. Some of the mutations altered transporter cell surface expression, resulting in Pi transport impairment, while others did neither alter cell surface expression, nor retroviral receptor functions, confirming that Pi transport function and viral envelope glycoprotein binding can be structurally distinguished.Using single gene knock-out human haploid cells, we showed that depletion of XPR1/SLC53A1 resulted in a dramatic Pi export alteration, with no detectable effect on Pi import, in agreement with Pi exporter function of XPR1. Interestingly, depletion of PiT2/SLC20A2 had little impact on Pi uptake, most likely due to compensatory function of PiT1/SLC20A1, with, however, a surprising impact on Pi export mediated by XPR1. This effect is reminiscent to a regulation loop that we found to maintain both Pi and ATP constant. This results unveil for the first time that Pi export alteration, and not Pi import, is likely to be the common pathophysiological impact of mutations in both PiT2 and XPR1. This would explain the synonymous pathological effects of two transporters that have opposite transport activity.We further explored this regulated phosphate export by characterizing the SPX N-terminal cytoplasmic domain of XPR1, which harbors most of the PFBC mutations. We identified a cellular tankyrase (TNK) as a binding partner and mapped the TNK-binding site to the carboxyl border of SPX; furthermore, we found that mutations that abolished TNK binding resulted in loss of Pi export. Full deletion of SPX domain maintained cell surface expression but altered export, suggesting that both TNK and SPX are essential components for Pi export. Finally, during this work, we identified mutations in the XPR1 C-terminal domain as responsible for PFBC that also impaired Pi export, and showed that deletion of this domain prevented XPR1 cell surface expression. Our results therefore indicate that N- and C-terminal domains of XPR1 play a key role in phosphate homeostasis, the latter domain appearing to exert a more prominent role in XPR1 membrane trafficking and/or folding
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Bowden, Christine Ann 1957. "CHARACTERIZATION OF THE ATTACHMENT OF TREPONEMA HYODYSENTERIAE TO HENLE INTESTINAL EPITHELIAL CELLS IN VITRO (RECEPTORS, SIALIC ACID, GLYCOPROTEINS, SPIROCHETES, SWINE DYSENTERY)." Thesis, The University of Arizona, 1986. http://hdl.handle.net/10150/275570.
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Melanson, Vanessa R. "Characterization of the Interaction Between the Attachment and Fusion Glycoproteins Required for Paramyxovirus Fusion: a Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/24.
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The first step of viral infection requires the binding of the viral attachment protein to cell surface receptors. Following binding, viruses penetrate the cellular membrane to deliver their genome into the host cell. For enveloped viruses, which have a lipid bilayer that surrounds their nucleocapsids, entry into the host cell requires the fusion of viral and cellular membranes. This process is mediated by viral glycoproteins located on the surface of the virus. For many enveloped viruses, such as influenza, Ebola, and human immunodeficiency virus, the fusion protein is responsible for mediating both attachment to cellular receptors and membrane fusion.
However, paramyxoviruses are unique among fusion promoting viruses because their receptor binding and fusion activities reside on two separate proteins. This unique distribution of functions necessitates a mechanism by which the two proteins can transmit the juxtaposition of the viral and host cell membranes, mediated by the attachment protein (HN/H), into membrane fusion, mediated by the fusion (F) protein. This mechanism allows for paramyxoviruses to gain entry into and spread between cells, and therefore, is an important aspect of virus infection and disease progression.
Despite the conservation of receptor binding activity among members of the Paramyxovirinaesubfamily, for most of these viruses, including Newcastle disease virus (NDV), heterologous HN proteins cannot complement F in the promotion of fusion; both the HN and F proteins must originate from the same virus. This is consistent with the existence of a virus-specific interaction between the two glycoproteins. Thus, one or more domains on the HN and F proteins is thought to mediate a specific interaction between them that is an integral part of the fusion process.
Therefore, the primary focus of this thesis is the identification of the site(s) on HN that directly contacts F in the HN-F interaction. The ectodomain of the HN protein consists of a stalk and a terminal globular head. Analysis of the fusion activity of chimeric paramyxovirus HN proteins indicates that the stalk region of HN determines its F protein specificity. The first goal of this research was to address the question of whether the stalk not only determines F-specificity, but does so by directly mediating the interaction with F. To establish a correlation between the amount of fusion and the extent of the HN-F interaction, a specific and quantitative co-immunoprecipitation assay was used that detects the HN-F complex at the cell surface.
As an initial probe of the role of the HN stalk in mediating the interaction with F, N-glycans were individually added at several positions in the region. N-glycan addition at positions 69 and 77 in the stalk specifically and completely block both fusion and the HN-F interaction without affecting either HN structure or its other activities. However, though they also prevent fusion, N-glycans added at other positions in the stalk also modulate activities that reside in the globular head of HN. This correlates with an alteration of the tetrameric structure of the protein as indicated by sucrose gradient sedimentation analyses. These additional N-glycans likely indirectly affect fusion, perhaps by interfering with changes in the conformation of HN that link receptor binding to the fusion activation of F.
To address the issue of whether N-glycan addition at any position in HN would abolish fusion, an N-glycan was added in another region at the base of the globular head of HN (residues 124-152), which was previously predicted by a peptide-based analysis to mediate the interaction with F. HN carrying this additional N-glycan exhibits significant fusion promoting activity, arguing against this site being part of the F-interactive domain in HN. These data support the idea that the F-interactive site on HN is defined by the stalk region of the protein.
Site-directed mutagenesis was used to begin to explore the role of individual residues in the stalk in the interaction with F. The characteristics of the F-interactive domain in the stalk of HN are that it is a conserved motif with enough sequence heterogeneity to account for the specificity of the interaction. One such region that meets these requirements is the intervening region (IR) (residues 89-95); a non-helical domain situated between two conserved heptad repeats. Several amino acid substitutions for a completely conserved proline residue in this region impair not only fusion and the HN-F interaction, but also decrease neuraminidase activity in the globular domain and alter the structure of the protein, suggesting that the substitutions indirectly affect the HN-F interaction. Substitutions for L94 also interfere with fusion, but have no significant effect on any other HN function or its structure. Amino acid substitutions at two other positions in the IR (A89 and L90) also modulate only fusion. In all cases, diminished fusion correlates with a decreased ability of the mutated HN protein to interact with F at the cell surface. These findings indicate that the IR is critical to the role of HN in the promotion of fusion and are consistent with its direct involvement in the interaction with the homologous F protein. These are the first point mutations in the HN protein for which a correlation has been demonstrated between the extent of the HN-F interaction and the amount of fusion. This argues strongly that the co-IP assay is an accurate reflection of the HN-F interaction.
The second goal of this research was to address the HN-F interaction from the perspective of the F protein by investigating the relationship between receptor binding, the HN-F interaction, and fusion using a highly fusogenic form of the F protein. It has previously been shown that an L289A substitution in NDV F eliminates the requirement for HN in the promotion of fusion and enhances HN-dependent fusion above wild-type (wt) levels. Here, it was shown that the HN-independent fusion exhibited by L289A-F in Cos-7 cells cannot be duplicated in BHK cells. However, when L289A-F is co-expressed with wt HN, enhanced fusion above wt levels is observed in BHK cells. Additionally, when L289A-F is co-expressed with IR-mutated HN proteins previously shown to promote low levels of fusion with wt F, a 2.5-fold increase in fusion was observed. However, similar to wt F, an interaction between L289A-F and the IR-mutated HN proteins was not detected. These results imply that the attachment function of HN, as well as the conformational change in L289A-F, are necessary for the enhanced level of fusion exhibited by HN proteins co-expressed with L289A-F. Indeed, two MAbs detected a conformational difference between L289A-F and the wt F protein. These findings support the idea that the L289A substitution converts F to a form that is less dependent on an interaction with HN for conversion to the fusion-active form.
The last goal of this research was to address the cellular site of the HN-F interaction, still a controversial issue based on conflicting data from studies of different paramyxoviruses, using various approaches. This is a particular point of interest, as it speaks to the mechanism by which the HN-F interaction regulates fusion. Thus, NDV HN and F were successfully retained intracellularly with a multiple arginine or KK motif, respectively. The results of Endoglycosidase H resistance and F cleavage studies indicate that the mutated proteins, HN-ER and F-ER, are retained in a compartment prior to the medial-Golgi apparatus and that they are unable to interact with a high enough affinity to co-retain or even cause reduced transport of their wt partner glycoproteins. This is consistent with the HN-F interaction occurring at the cell surface, possibly triggered by receptor binding.
In conclusion, this thesis presents evidence to argue that the IR in the stalk of the NDV HN protein directly mediates the interaction with the F protein that is necessary for fusion. Overall, the data presented in this thesis extend the current knowledge of the mechanism by which the paramyxovirus attachment protein can trigger the F protein to initiate membrane fusion. A clear understanding of this process has the potential to identify new anti-viral strategies, such as small molecule inhibitors, aimed at controlling paramyxovirus infection by interfering with early steps in the virus infection cycle.
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Louie, Sarah. "Wnt signaling regulated by Frizzled and HIPK1 /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/6267.
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Guo, Beichu. "Interaction of PKCbeta with CARMA1 mediates B cell receptor-induced NF-kappaB activation /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/8348.
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Nagpal, Kamalpreet. "A Tale of Two SNPS: Polymorphism Analysis of Toll-like Receptor (TLR) Adapter Proteins: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/540.
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The innate immune system is the first line of defense against invading pathogens. Recognition of microbial ligands by the innate immune system relies on germ-line encoded, evolutionarily conserved receptors called pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are one such family of PRRs and are involved in innate defenses to a variety of microbes. At the core of TLR signaling pathways are Toll interleukin-1 receptor (TIR) domain containing adapter proteins. Much of the specificity of TLR pathways arise from the differential use of these adapter proteins.
The TLR signaling cascade that ensues upon ligand recognition is marked by finely orchestrated molecular interactions between the receptor and the TIR domain containing adapter proteins, as well as various downstream kinases and effector molecules. Conserving the structural integrity of the TLR components is thus essential for maintaining a robust host defense system. Sometimes, changes in a protein can be brought about by single nucleotide polymorphisms (SNPs). Studies carried out in this thesis focus on polymorphisms in MyD88 adapter-like (Mal) and myeloid differentiation protein 88 (MyD88), two TIR domain-containing adapter proteins, which incidentally are also highly polymorphic.
Mal is a 235 amino acid protein that is involved in TLR2 and TLR4 signaling. The known polymorphisms in the coding region of Mal were screened with an aim to identify SNPs with altered signaling potential. A TIR domain polymorphism, D96N, was found to be completely defective in TLR2 and TLR4 signaling. Immortalized macrophage-like cell lines expressing D96N have impaired cytokine production as well as NF-κB activation. The reason for this loss-of-function phenotype is the inability of Mal D96N to bind the downstream adapter MyD88, an event necessary for signaling to occur. Genotyping studies reveal a very low frequency of this polymorphism in the population.
Similar SNP analysis was carried out in myeloid differentiation protein 88 (MyD88). MyD88 is a key signaling adapter in TLR signaling; critical for all TLR pathways except TLR3. In reporter assays, a death domain variant, S34Y, was found to be inactive. Importantly, in reconstituted macrophage-like cell lines derived from knockout mice, MyD88 S34Y was severely compromised in its ability to respond to all MyD88-dependent TLR ligands. S34Y mutant has a dramatically different localization pattern as compared to wild type MyD88. Unlike wild type MyD88, S34Y is unable to form distinct foci in the cells but is present diffused in the cytoplasm. IRAK4, a downstream kinase, colocalizes with MyD88 in these aggregates or “Myddosomes”. S34Y MyD88, however, is unable to assemble into Myddosomes, thus demonstrating that proper cellular localization of MyD88 is a feature required for MyD88 function.
This thesis thus describes two loss‐of‐function polymorphisms in TLR adapter proteins Mal and MyD88. It sheds light not only on the structural aspects of signaling by these two proteins, but also has implications for the development of novel pharmaceutical agents.
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Nambulli, Shamkumar. "Interaction of paramyxovirus glycoproteins with their cellular receptor." Thesis, Queen's University Belfast, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.557394.
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Morbilliviruses can cause severe disease in a wide range of terrestrial and marine mammals with measles still responsible for large numbers of fatalities in developing countries despite the availability of an efficacious vaccine. Identification of morbillivirus receptors, the major determinant of host range and tissue tropism, is of paramount importance in understanding the disease induced by these viruses. Identification and characterisation of receptors also facilitates the development of novel antiviral drugs which block viral attachment and entry. SLAM, also known as CD 150, is the entry receptor for wild-type strains of measles virus (MY). Whereas laboratory-adapted MY can use both SLAM and CD46. The susceptibility of SLAM negative oligodendroglioma, astrocytoma and microglioma derived cell-lines to infection with recombinant (r) CD46 "receptor blind" rM suggests the expression of an unknown virus entry receptor. While it is currently unknown whether wild-type MY uses the same receptor molecule to infect glial and epithelial cells, the absence of infected glial cells following infection with an epithelial "receptor blind" rMY suggests that MY may use the same cellular receptor to infect both cell types. This unknown receptor could be identified through the construction of a cDNA library from these cell lines and subsequent analysis using the novel bimolecular fluorescent complementation (BiFC) fusion assay developed in this study. This assay, which was developed to identify unknown viral fusion receptors, has been validated using expression plasmids encoding MY glycoproteins and known cellular receptors. A BiFC based MY receptor screen using a human spleen cDNA library produced fluorescent fusion events. These were isolated and PCR amplification was used to attempt to identify the unknown receptor Fusion assays using expression plasmids encoding canine distemper virus (CDY) heamagglutinin (H) and fusion (F) glycoproteins and BiFC fusion assay demonstrated that the H glycoprotein is the key determinant of cell tropism.
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Calaminus, Simon. "Glycoprotein receptor mediated regulation of platelet morphology." Thesis, University of Birmingham, 2007. http://etheses.bham.ac.uk//id/eprint/7203/.
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Spreading platelets sequentially form filopodia, lamellipodia, and stress fibres. This thesis demonstrates the formation of each actin structure in spread platelets, and in addition the formation of a novel actin structure, which I have termed an actin nodule. Actin nodules require Src kinase activation, and actin polymerisation, but are negatively correlated to ROCK and myosin-II activation. This thesis has investigated the role of WAVE-l, Rho kinase (ROCK) and myosin-II in spreading and aggregate stability in vitro and in vivo. ROCK or myosin-II inhibition, prevents stress fibre formation leading to appearance of splits and holes (termed fenestrations) in spread platelets on collagen. In addition, ROCK or myosin-II inhibition compromises aggregate stability on collagen at arterial rates of flow. Lamellipodia formation is inhibited in WAVE-rl - platelets spread on CRP, whilst shape change and aggregation downstream of GPVI is severely disrupted. However, GPCR agonists induce full lamellipodia formation on fibrinogen in WAVE-I-I. Aggregate formation on collagen under arterial rates of flow is unaffected further indicating . WAVE-2 can compensate for WAVE-I. Thus, WAVE-l maybe differentially regulated downstream of GPCR and glycoprotein signalling. The actin regulatory proteins, Spin-90, Β-Pix and Nck are tyrosine phosphorylated by multiple platelet agonists, but do not form a complex upon platelet adhesion. However, B-Pix is heavily phosphorylated downstream of the collagen receptor integrin, a2BI. I speculate B-Pix may play an important role in connecting PLCyl to Rac activation.
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Berlanga, Oscar. "Expression and functional characterisation of the collagen receptor glycoprotein VI." Thesis, University of Oxford, 2001. http://ora.ox.ac.uk/objects/uuid:090383e9-5213-40b5-9157-df67310dfc03.
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This thesis is concerned with the study of the collagen receptor glycoprotein VI (GPVI). GPVI has been studied in a number of human haematopoietic cell lines and found to be expressed only in those showing mekaryocytic features. Moreover, differentiation of the human cell lines HEL and CMK to a megakaryocytic lineage using the phorbol ester PMA revealed upregulation of GPVI together with the associated FcR γ-chain. Further, primary cultures of mouse marrow cells demonstrated up-regulation of GPVI towards the end of differentiation, therefore confirming data obtained with cell lines and pointing to GPVI as a possible marker of megakaryocytic differentiation. Structure/function studies of GPVI were carried out by means of transient and stable transfection of the receptor into COS-7 or K562 cells. These studies demonstrated the necessity of the transmembrane argine and the cytoplasmic tail of GPVI for association to the FcR γ-chain. Lack of association or absence of FcR γ-chain rendered GPVI unable to signal, despite binding to convulxin, a GPVI-specific ligand which causes activation of the receptor. K562 cells expressing GPVI and the FcR γ-chain were able to reconstitute the proximal but not distal events in GPVI signaling. A detailed analysis demonstrated impairment in phosphorylation and translocation of SLP-76 to the membrane, despite the presence and activation of others proteins known to be necessary for this phosphorylation/translocation to occur. Stable expression of GPVI in K562 cells, which display low levels of expression of the collagen receptors α2βl and CD36, does not confer signaling properties in response to collagen. However, the cells respond to a collagen related peptide (CRP) which is specific for GPVI and to the snake venoms convulxin, alborhagin and alboaggregin-A, demonstrating that GPVI is one important component through which these venoms are acting.
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Gough, Peter Joseph. "The molecular pathology of the macrophage scavenger receptor." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301397.
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Coombs, Peter J. "Recognition of natural and engineered ligands by glycoprotein receptors." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444900.
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Lackman, J. (Jarkko). "Glycosylation and dimerization of the human δ-opioid receptor polymorphic variants." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526221342.
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Abstract Cellular signaling by G protein-coupled receptors (GPCRs) governs a wide array of physiological functions throughout the body. The human δ-opioid receptor (hδOR) is a GPCR that modulates the sensation of pain and mood and has great potential for the treatment of pain and a variety of neurological disorders. A common single-nucleotide polymorphism (SNP) in the extracellular N-terminal tail of hδOR changes Phe to Cys at position 27. Using various biochemical and cell biological methods, the study demonstrates that several events during receptor biosynthesis and cell surface delivery are affected by the SNP. These events participate in the multifaceted regulation of the receptor and modulate receptor behavior at the cell surface. Two distinct pathways were shown to scrutinize the quality of the synthesized hδOR in the endoplasmic reticulum (ER) and target some for degradation in N-glycan-dependent and -independent ways. The hδORCys27 that matures inefficiently required N-glycan-mediated interactions with the lectin-chaperone calnexin to be expressed in a fully functional form at the cell surface, whereas the N-glycan-independent pathway was sufficient for hδORPhe27. For both variants, the N-glycan-independent quality control, which is likely to operate as a back-up pathway, led to a more rapid export from the ER and receptors at the cell surface that were less stable. Receptor dimerization emerged as an important regulatory step for receptor cell surface delivery. In co-transfected cells, interactions between the newly-synthesized variants led to the retention and subsequent ER-associated degradation of hδORPhe27. This dominant-negative attenuation of hδORPhe27 cell surface expression by hδORCys27 may have unpredictable consequences for opioid signaling in heterozygous individuals. Finally, the study shows that N-acetylgalactosamine (GalNAc)-type O-glycosylation catalyzed in the Golgi modulates hδOR expression at the cell surface by enhancing receptor stability and inhibiting constitutive downregulation. The modification of Ser residues in the receptor N-terminus by GalNAc-transferase 2 was affected by the SNP, which presents another distinction in the cellular processing of the two variants. The findings highlight the importance of the biosynthetic pathway in the regulation of GPCR behavior and pave way for strategies for treatments targeting GPCRs at this levelTiivistelmä Solujenvälisellä viestinnällä on keskeinen tehtävä kehon kaikissa toiminnoissa. δ-opioidireseptori (δOR) on solusignalointiin erikoistuneen kalvoproteiiniperheen (G-proteiiniin kytketyt reseptorit) jäsen, joka ohjaa kivuntuntemusta ja mielialoja. Sitä pidetään mahdollisena lääkekehityksen kohteena paitsi kivunlievityksen, myös useiden neurologisten häiriöiden hoidossa. δOR ilmenee kahtena polymorfisena muotona sen solunulkoisessa osassa tapahtuneen aminohappomuutoksen vuoksi (Phe27Cys). Työssä tutkittiin reseptorin glykosylaatiota ja dimerisaatiota, jotka säätelevät sen prosessointia, käyttäytymistä ja toimintaa. Käyttäen useita biokemiallisia ja solubiologisia menetelmiä työssä osoitettiin polymorfian vaikuttavan useisiin prosessointivaiheisiin ja muokkaavan siten reseptorin viestintää. Proteiinien laadunvalvontakoneiston havaittiin säätelevän reseptorin siirtymistä endoplasmakalvostolta solun pinnalle kahdella eri mekanismilla ohjaten osan reseptoreista hajotukseen. Toisin kuin Phe27-variantin, tehottomasti kypsyvän Cys27-variantin laadunvalvonta on riippuvainen reseptoriin liittyvistä N-glykaaneista ja näihin sitoutuvasta kaitsijaproteiinista, kalneksiinista. Reseptorivariantit, joista N-glykaanit puuttuvat, siirtyvät nopeammin solukalvolle, mutta ne ovat epästabiileja ja häviävät nopeasti solun pinnalta. Vaihtoehtoinen N-glykaaneista riippumaton laadunvalvontamekanismi sallii myös inaktiivisen Cys27-variantin pääsyn solun pinnalle. Varianttien dimerisoitumisen osoitettiin säätelevän niiden kuljetusta soluissa. Cys27-variantin havaittiin sitoutuvan Phe27-varianttiin aikaisessa biosynteesivaiheessa ja ohjaavan osan siitä hajotukseen. Tällä voi olla suuri merkitys opioidiviestinnässä molempia alleeleja kantavilla henkilöillä. Työssä havaittiin myös GalNAc-transferaasi-2-entsyymin ohjaavan Golgin laitteessa tapahtuvaa reseptorin O-glykosylaatiota. Se glykosyloi reseptorin solunulkoisen osan seriinitähteitä (Ser6, Ser25, Ser29), stabiloiden siten solun pinnan reseptoreita ja tehostaen niiden viestintää. Lisäksi havaittiin eroja varianttien O-glykosylaatiossa, mikä voi osaltaan selittää varianttien ilmentymisessä todettuja eroja. Tutkimus luo uutta tietoa biosynteesireitin merkityksestä G-proteiiniin kytkettyjen reseptorien säätelyssä sekä antaa pohjaa keinoille, joilla tätä voitaisiin hyödyntää farmakologisesti
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Harfouche, Rania. "Modulation of endothelial cell survival by the angiopoietin-1Tie-2 receptor pathway." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33771.
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The mechanisms by which Angiopoietin-1 (Ang-1) modulates the survival of human endothelial cells were investigated. Ang-1 inhibited both TNFalpha-induced and serum deprivation-evoked apoptosis, an effect which was associated with attenuation of caspase activation, inhibition of Smac release from the mitochondria, up-regulation of Survivin-1 expression (IAPs member) and a significant activation of the pro-survival PI-3 kinase/AKT pathway. In addition, Ang-1 activated, in a time-dependent fashion, both the anti-apoptotic ERK1/2 and pro-apoptotic p38 MAP kinases. Ang-1-evoked ERK1/2 activation was mediated in part through the PI-3 kinase pathway, whereas both, the PI-3 kinase and ERK1/2 attenuated p38 MAP kinase activation.We conclude that Ang-1 promotes endothelial cell survival through several pathways including the PI-3 kinase/AKT and ERK1/2 pathways, up-regulation of Survivin-1 as well as inhibition of Smac release and caspase activity. The preferential activation of these anti-apoptotic effects, as opposed to the activation of pro-apoptotic p38 MAP kinase, results in a net survival response.
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Mullin, Nicholas Paul. "Characterisation of ligand-binding to a carbohydrate-recognition domain of the macrophage mannose receptor." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320620.
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Murphy, Anthea Louise. "Antigenicity and receptor-binding of primary HIV-1 envelope glycoproteins." Thesis, University of Reading, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265666.
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Peiser, Leanne. "The role of the macrophage scavenger receptor in host defence." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393470.
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McKay, Paul Francis. "Cloning of the cDNA for gp200-MR6 : a novel member of the human macrophage mannose receptor family." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369208.
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Maidens, Catherine. "Characterisation of hepatitis C virus envelope glycoprotein interactions with cellular receptors." Thesis, University of Reading, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340047.
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Levander, Louise. "Effects of α1‐acid glycoprotein onpolymorphonuclear leukocytes ‐involvement of cell surface receptors." Doctoral thesis, Linköpings universitet, Cellbiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-20271.
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Alpha1‐acid glycoprotein (AGP) is a highly glycosylated lipid‐binding acute‐phaseprotein. Although the exact mechanisms are unknown, several studies havesuggested that AGP may regulate the function of neutrophils and hence modulateinflammatory responses. The general aim of this thesis was to investigate if AGP isable to mediate intracellular signalling in neutrophils through binding to specificreceptors. Measurements of intracellular calcium concentration showed that AGP elicited asmall rise in [Ca2+]i in neutrophils that was markedly enhanced by pre‐treatmentwith anti‐L‐selectin antibodies. In contrast, desialylation of AGP reduced the Ca2+mobilizing capacity significantly. The AGP‐induced Ca2+ signal was mediatedthrough Src tyrosine kinases, PLC and PI3K which suggests involvement of cellsurface receptors. Indeed, AGP was shown to bind to, and mediate Ca2+ signallingthrough, sialic acid binding immunoglobulin‐like lectin (Siglec)‐5 and/or ‐14.Increased fucosylation of AGP is common during acute‐phase reactions. We showthat hyperfucosylated AGP has a diminished Ca2+ signalling capacity compared tonormally fucosylated AGP. This could be due to a reduced capacity of AGP tointeract with Siglec‐5/‐14 since it is known that the presence of fucose residues onsialylated glycans has a negative effect on Siglec‐5/‐14 affinity. AGP was alsodemonstrated to bind to the neutrophil proteins S100A8 and S100A9. In additionwe show that AGP‐bound hydroxyeicasotetraenoic acids (HETEs) induce increasesin [Ca2+]i in neutrophils through binding to the leukotriene B4 receptor BLT2. Wepropose a two‐step binding model where AGP binds to Siglec‐5/‐14 on L‐selectinactivated neutrophils. This may orient AGP in a way that assists an interactionbetween AGP and the neutrophil membrane which favours transfer of AGP‐boundHETEs to the BLT2 receptor. In conclusion, these data gives new insights regarding how AGP interacts with andmediates signalling in human neutrophils and supports the view of AGP as beingan acute phase reactant with immunomodulatory properties.
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Davies, Suzy. "Ectopic expression of glycoprotein hormone genes and their receptors by urogenital cancers." Thesis, Queen Mary, University of London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.397701.
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Nield, Heather S. "Control by cyclic AMP of the activity and gene expression of the low density lipoprotein receptor." Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240540.
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Moodie, Fiona M. "Regulation of P-glycoprotein and glucocorticoid receptor expression in the rat intestine." Thesis, University of Edinburgh, 2005. http://hdl.handle.net/1842/24992.
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We studied the expression of genes regulating steroid sensitivity in the healthy Wistar rat and found genes were differentially expressed along the length of the colon. Notably, P-gp expression was increased in proximal compared to distal colon. A reverse gradient was noted for GR. Systemic dexamethasone treatment as well as endogenous corticosterone were shown to regulate these genes, and thereby these data support a role for steroids regulating tissue sensitivity to steroids. To further clarify the role of bacteria and disease on expression of P-gp and GR, HLA-B27 transgenic and non-transgenic rats were studied. Colonic inflammation in HLA-B27 transgenic rats decreased P-gp and GR. Bacteria were also shown to regulate expression of these genes in a site-specific manner along the colon. These data emphasise the complex gene-bacterial interactions within the colon in health and disease. Dexamethasone administered to rats with/out inflammation differentially regulated GR expression in a site-specific manner along the colon. Steroid treatment did not alter P-gp expression in the inflamed colons. These data show the complexity of the intestinal regulation of these genes in the inflamed and non-inflamed colon; corticosteroid treatment may have selected efficacy in different regions of the colon. Collectively these data suggest a role for dexamethasone treatment as well as bacteria in the regulation of genes determining steroid sensitivity in the healthy and diseased rodent intestinal epithelium. The complex interaction between P-gp and GR expression in response to bacteria has implications for potential mechanisms by which inflammation is induced in the colon.
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Mooney, Robert Francis. "The regulation of platelet aggregation by glycoprotein IIb-IIIa receptor and fibrinogen /." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60500.
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We compared both the rate and extent of platelet aggregation with the extent of fibrinogen receptor expression and specific Fg binding to activated platelets, as a function of ADP concentration. Human citrated platelet-rich plasma (diluted ten-fold) was maximally pre-activated by incubating with adenosine diphosphate (ADP) at room temperature and then stirred. Platelet aggregation was determined from the decrease in the total number of particles. The number of fibrinogen receptors or bound Fg was measured from mean fluorescence values obtained with FITC-labelled IgM monoclonal antibody PAC1, and the IgG monoclonal antibody, 9F9, respectively, using flow cytometry. The expression of fibrinogen receptors occurs within seconds of activation. The fraction of platelets with fluorescence values above one critical threshold value increased with increasing activator concentration and correlated linearly with the fraction of platelets recruited into aggregates for ADP (r $>$ 0.9). Aggregation was not rate-limited by fibrinogen receptor expression nor by Fg binding. It appears that each platelet expresses $>$90% of its maximal Fg receptors at a critical ADP concentration i.e, occupancy of ADP receptors. This, in turn, leads to rapid Fg occupancy and platelet aggregation.
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Lo, Alexandra Siu Lok, and n/a. "Paradigms of inflammation : interactions between calcium-binding proteins and the receptor for advanced glycation end products (RAGE)." University of Otago. Department of Physiology, 2005. http://adt.otago.ac.nz./public/adt-NZDU20061016.163427.
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The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily. The result of RAGE-ligand interactions augments the proinflammatory mechanisms acting in chronic inflammatory diseases. RAGE recognises a wide range of ligands that have no apparent structural similarities. It is unclear what controls this promiscuity of RAGE. The extracellular domain of RAGE has two potential glycosylation sites. It is speculated that N-linked glycosylation may have significant impact on ligand recognition, especially of S100 calcium binding protein ligands. Two objectives of this thesis were to establish whether S100A9 acts as a ligand for RAGE and to investigate whether glycosylation of RAGE has any influence on ligand recognition. These were achieved by generating two forms of RAGE. HEK 293 cells were transfected to express full-length, membrane-bound RAGE or a secreted form comprising the extracellular domain of RAGE. Site-directed mutagenesis of RAGE showed that asparagine at position 25 is the pre-dominant N-linked glycosylation site. The carbohydrate added to asparagine 25 was further modified to a non-sialylated carboxylated N-linked glycan, specifically recognised by monoclonal antibody GB 3.1. Binding studies showed that different RAGE ligands have individual requirements for glycosylation of the receptor. Binding of AGE-modified AGE-BSA or of S100B to RAGE occured independent of N-linked glycosylation of the receptor. RAGE also binds the S100 protein, MRP-14 (S100A9). In contrast to AGE-BSA or S100B, the non-sialylated carboxylated N-glycan expressed on RAGE is crucial for binding to MRP-14. However, RAGE produced in tunicamycin containing medium and thus lacking N-linked glycosylation, shows strong binding to MRP-14. It was concluded that two forms of binding are involved: the first mechanism relies on the non-sialylated carboxylated N-glycan attached to RAGE and acts in a "tethering" fashion. The second mechanism involves a conformational change of RAGE, which results in exposure of a binding site(s) and a more conventional receptor-ligand interaction.
Another objective for this thesis is to study the expression of RAGE and its alternatively spliced variants. PCR analysis has revealed several variants of RAGE that result from alternative splicing mechanisms. The variant proteins are soluble due to a lack of membrane localising sequence. PCR results confirmed the presence of transcripts encoding for spliced variants of RAGE in several tumour cell lines. Among these were transcripts that should encode a soluble form of sRAGE 2. Furthermore, it was shown that sRAGE 2 transcript can be present in forms that contain the ligand-binding V-domain of RAGE or that are N-truncated and lack the V-domain. This is the first report of a soluble, N-truncated sRAGE 2 variant.
The results in this thesis add to our knowledge of RAGE biology. MRP-14 (S100A9) is identified as a new ligand. The control of MRP-14/RAGE interaction relies on N-linked glycosylation of the receptor and further modification of the carbohydrate. "Tethering" or stronger receptor-ligand interactions are suggested as mechanisms for controlling RAGE recognition of multiple ligands. Soluble RAGE variants that lack or contain V-domain binding regions, and hence sites for glycosylation were produced. These have the capacity to compete with membrane-bound receptor for available ligand. The control of the expression of soluble RAGE variants, in concert with the control of various modification to carbohydrate expressed on the receptor, adds a level of complexity to ligand specificity. This may ultimately result in different paradigms of the inflammatory process.
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Udyavar, Akshata Ramrao. "Functional impact of CDR3ß mutation in an autoreactive myelin oligodendrocyte glycoprotein (MOG) specific T cell receptor." View the abstract Download the full-text PDF version (on campus access only), 2008. http://etd.utmem.edu/ABSTRACTS/2008-042-Udyavar-index.htm.
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Thesis (M.S.)--University of Tennessee Health Science Center, 2008.Title from title page screen (viewed on February 27, 2009). Research advisor: Terrence L. Geiger, MD, PhD. Document formatted into pages (xi, 74 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 64-74).
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Klaus, Joseph P. "Determining the role of the ERGIC-53 cargo receptor complex in arenavirus propagation." ScholarWorks @ UVM, 2014. https://scholarworks.uvm.edu/graddis/252.
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Arenaviruses and hantaviruses are human pathogens that cause significant morbidity and mortality. The current lack of vaccines and treatment options for these viruses is a global concern. Despite producing only 4 proteins, these viruses are able to maintain a persistent and asymptomatic infection in wild rodents while being continuously shed into the environment. In humans, these viruses cause a spectrum of diseases ranging from aseptic meningitis to severe hemorrhagic fever syndromes. Little is known about how arenavirus and hantavirus proteins engage and interact with the human proteome during the complex process of viral biogenesis, or how the interactions with human proteins contribute to viral propagation as well as the onset and progression of disease. This dissertation provides a road map of the protein interactions formed between a prototypic envelope glycoprotein encoded by either an arenavirus or hantavirus, and the human proteome.
The viral envelope glycoprotein (GP) decorates the surface of the virion. The primary function of the GP is to mediate attachment of the virus to specific cellular receptors, and after internalization of the virion, fuse the viral membrane with an internal endosomal membrane. In order to carry out these specific tasks, the viral GPs must first co-opt the extensive machinery found within the cellular secretory pathway to coordinate the proper glycosylation, folding, proteolytic maturation, and targeting of the GP during its biosynthesis. We identified a human protein with a conserved interaction amongst these two groups of viral GPs termed the Endoplasmic Reticulum (ER)-Golgi Intermediate Compartment Protein of 53 kiloDaltons (ERGIC-53). ERGIC-53 is an intracellular cargo receptor that normally cycles within the early secretory pathway of cells, where it is responsible for ferrying a small subset of cellular glycoproteins, most notably the coagulation factors FV and FVIII, from the ER to the Golgi apparatus.
Herein we describe a novel role for ERGIC-53 in the propagation of not only arenaviruses, but also coronaviruses and filoviruses. Following infection with an arenavirus, ERGIC-53 leaves the early secretory pathway and becomes incorporated into the virus as it pinches off from the cell surface. Newly formed viruses lacking ERGIC-53 are no longer infectious due, in part, to a defect in their ability to attach to host cells. We suggest that ERGIC-53 represents a promising broad-spectrum antiviral target because of its association with the GPs from many families of pathogenic viruses, as well as its ability to exert control over their infectivity; and finally, because ERGIC-53 itself is not required for human health. The discovery of ERGIC-53 outside of its normal location inside of cells suggests that it may have additional unknown functions. Lastly, by revealing the importance of the cellular protein in controlling viral infectivity, we provide insight into the ongoing co-evolution of virus and host.
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Brunetti, Craig R. "The role of mannose 6-phosphate receptors during herpes simplex virus replication and glycoprotein D binding." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0014/NQ30076.pdf.
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Silvestri, Michel. "Glycoprotein B of human cytomegalovirus : target for neutralising antibodies, ligand for cellular receptors, inducer of autoimmunity? /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-4082-7/.
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Haslam, lain S. "Regulation of the expression and function of P-glycoprotein by the nuclear xenobiotic receptor PXR." Thesis, University of Newcastle upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485570.
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The intestinal expression of P-glycoprotein (Pgp) has recently been recognised to impact on the disposition of a wide range of orally administered drug compounds. From an evolutionary perspective, efflux transporters such as P-glycoprotein may have developed to protect the body from ingested toxins, however the structural promiscuity displayed by Pgp in particular, has also resulted in the recognition of many modem drug compounds. The apical localisation and secretory orientation of this transporter has therefore resulted in the reduced absorption of many of these drugs, such as the cardiac glycoside digoxin, resulting in low or variable oral availability. A range of drug-drug, herb-drug and even food-drug interactions have been identified, resulting from inhibition or induction of P-glycoprotein activity, including the well characterised interactions between the antibiotic rifampin and digoxin (drug-drug) and hyperforin (an active constituent of St John's Wort) and cyclosporine A (herb-drug). The activity of a number of nuclear receptors, responsible for increasing the expression of detoxifying proteins such as Pgp and metabolic enzymes of the cytochrome P450 family, can be attributed to xenobiotic exposure. This includes 2 members of the NRlI family of nuclear receptors, the pregnane X receptor (PXR; NRII2) and constitutive androstane receptor (CAR; NR1I3), both of which have been designated the role of 'xenosensor'. Pgp expression is believed to increase along the proximal-distal axis of the mammalian intestine, although the regional inductive capacity is unknown. Here we have determined significant increases in Pgp expression and secretory activity (as determined by eH]-digoxin efflux) in the distal rat intestine, resulting from treatment with the rodent PXR activator PCN. It appears that reduced digoxin plasma concentrations result from an interplay between increased hepatic accumulation, biliary excretion and distal intestinal secretion. In order to study inductive interactions in a human system, the human intestinal adenocarcinoma cell line T84 was identified as a suitable in vitro model, expressing both MDRI and PXR, as well as displaying the epithelial characteristics (polarised expression and the formation of tight monolayers) that allow physiologically relevant bi-directional transport assays, utilising digoxin as a model Pgp substrate. T84 cells were found to respond to the PXR activator rifampin, resulting in the increased expression and function of Pgp. Digoxin ireatment also greatly increased MDRI expression and Pgp efflux activity, although this effect appears to be distinct from that of rifampin, based on the differential impact on PXR and CAR expression. Furthermore, the T84 cell line was found to lend itself to high-throughput analysis, with a range of structurally and functionally diverse drug compounds impacting on the expression and function of Pgp, as well as modulating levels of the nuclear receptors themselves.
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SOL, NATHALIE. "Etudes fonctionnelles des glycoproteines d'enveloppe des virus de l'immunodeficience humaine et de leurs recepteurs." Paris 7, 1998. http://www.theses.fr/1998PA077151.
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Au cours de l'evolution, les virus ont en general acquis une specificite qui se traduit a plusieurs niveaux : espece, tissu, cellule. Elle peut-etre determinee a plusieurs etapes du cycle de replication virale, dont la premiere est l'entree dans la cellule. Cette etape conditionne en grande partie le tropisme des virus de l'immunodeficience humaine : vih1 et vih2. Les vih peuvent infecter les cellules cd4+ de l'organisme, et la plupart des lignees humaines cd4+. Cependant certaines lignees, comme la lignee humaine astrogliale u87mgcd4 sont infectables par vih2 et pas par vih1. Notre objectif etait d'etudier les facteurs cellulaires et viraux impliques dans l'entree du vih, et plus particulierement dans le tropisme de vih-2. Le mecanisme d'entree du vih, comme celui de tous les virus enveloppes, necessite l'attachement du virus a la cellule, suivi d'une etape de fusion entre la membrane virale et la membrane plasmique, afin de permettre la penetration de la capside dans le cytoplasme. Elle implique les glycoproteines d'enveloppe du vih, comprenant la sous unite de surface gp120, et la sous unite transmembranaire gp41. L'interaction des glycoproteines d'enveloppe avec cd4 permet l'attachement du virus a la membrane cellulaire et induit des changements conformationnels necessaires a la poursuite du processus de fusion, mais ne suffit pas pour permettre l'entree du virus. Les facteurs cellulaires qui associes a cd4 permettent l'aboutissement du processus d'entree ont ete identifies en 1996. Ils appartiennent a la famille des recepteurs de chimiokines, possedant 7 domaines transmembranaires et couples aux proteines g. Le fait que certaines lignees cellulaires cd4+ soient permissives a l'infection par vih-2 et pas par vih-1, suggere que des facteurs cellulaires differents controlent l'entree de vih-1 et de vih-2. Nous avons determine le role de ces cofacteurs dans l'entree et dans le tropisme specifique de vih-2. Enfin, nous avons utilise l'homologie entre les glycoproteines d'enveloppe de vih-1 et vih-2 pour construire des proteines hybrides, et tenter de definir les domaines necessaires pour acquerir la capacite de fusionner avec les cellules u87mgcd4. Nous avons cherche egalement a definir les domaines d'interactions entre les glycoproteines d'enveloppe et les recepteurs de chimiokines.
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Néo, Thalita Athiê [UNESP]. "Clonagem e expressão da proteína E2 no vírus da hepatite C Humana: estudo da interação molecular E2-rLDL in vitro." Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/87820.
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O vírus da Hepatite C (VHC) é o principal agente etiológico das hepatites não-A e não-B, infectando aproximadamente 170 milhões de pessoas no mundo (3% da população mundial). O vírus da hepatite C (HCV; hepatitis C-virus) é envelopado tem de 50 a 70nm de diâmetro, possui uma única fita positiva de RNA e pertence ao gênero do Hepacivirus e à família Flaviridae. Seu genoma é constituído por cerca de 9.500 nucleotídeos com regiões curtas não codificadoras e hiperconservadas nas extremidades 5’ e 3’UTR, flanqueando uma única ORF. A região estrutural do vírus é constituída por 3 genes: core, E1 e E2. As proteínas do envelope, E1 e E2 do VHC, são altamente glicosiladas e apresentam 30 e 70 kDa, respectivamente. Estudos demonstram que ambas apresentam funções específicas em diferentes etapas do ciclo de replicação do vírus, atuando de forma essencial para entrada, ligação ao receptor e fusão com a membrana da célula hospedeira. A glicoproteína E2 do VHC liga-se com alta afinidade a uma alça do receptor CD81, também denominado de TAPA-1, uma tetraespanina encontrada na superfície de muitas células, incluindo hepatócitos. No entanto, o CD81 isoladamente não é suficiente para mediar a entrada celular do vírus, e vários outros co-fatores podem atuar nessa interação. Os receptores de lipoproteína de baixa densidade (LDL-r) e receptor scavenger tipo B classe I apresentam grande importância nessa relação com o VHC. Estudos sobre as glicoproteínas E1 e E2 têm mostrado que estas se associam com os LDL-r, sugerindo que o VHC use estes receptores para invadir a célula hospedeira. Além disso, estudos anteriores relatam o fato de que, as lipoproteínas poderiam proporcionar acréscimos da infectividade ao VHC. Desta forma, neste trabalho foram desenvolvidas estratégias de clonagem e expressão heteróloga da proteína E2, e avaliou-se sua imunogenicidade...
Hepatitis C is currently recognized as the primary cause of hepatitis non A - non B associated to the blood transfusion. The hepatitis C virus (HCV) is enveloped in about 50 to 70nm in diameter, presenting a positive single strand RNA and belongs to the genus Hepacivirus and the family Flaviridae. Its genome consists of 9,500 nucleotides with short non-coding regions and hiperconservadas ends 5´ and 3'UTR flanking a single ORF. The virus structural region is based on three core genes, E1 and E2. HCV E1 and E2 are highly glycosylated and have 30 and 70 kDa, respectively. Studies show that both have key role in different stages of the cycle of virus replication, acting as essential for entry, receptor binding and fusion with host cell membrane. Glycoprotein E2 of HCV binds with high affinity to a loop of CD81, a tetraspanin, also named TAPA-1, found on the surface of many cells, including hepatocytes. However, the CD81 alone is not sufficient to mediate the cellular entry of the virus, and several other co-factors may be operating in this interaction. Recipients of low density lipoprotein (LDL-r) and scavenger receptor class B type I (SR-BI) would present great importance in relation to HCV. The LDL-r plays an important role in infection for virus of the hepatitis C. Studies on the glycoproteins E1 and E2 have shown that these are associated with the LDL-r suggesting that HCV uses the LDL-r to invade the host cell. Besides, previous studies showed that lipoprotein could improve HCV infectivity. Thus, in this work the capacity of recognition of the antibodies present anti-HCV was evaluated in the positive human serum for HCV of recognizing the protein E2 recombinant produced in bacteria of the lineage Rosetta and also the capacity of connection of the protein E2 of HCV in bind LDL-r present in the surface of human cells with characteristics endoteliais (ECV 304), and such capacity was... (Complete abstract click electronic access below)
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Ljuslinder, Ingrid. "Studies of LRIG1 and the ERBB receptor family in breast and colorectal cancer." Doctoral thesis, Umeå : Umeå university, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-25678.
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Bwanali, Jessica Atupele. "Identification of hepatitis C virus E2 glycoprotein binding determinants on human scavenger receptor class B type 1." Thesis, University of Nottingham, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.537621.
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Kaur, Ishwinder. "Nuclear translocation and transferrin-transferrin receptor interaction of IPSE/[alpha}-1, a secretory glycoprotein from Schistosoma mansoni." Thesis, University of Nottingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.508222.
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Helminthic parasites have evolved with immune modulating machinery to manipulate their host's immune response and thus survive unscathed for years and in some cases even decades. However, the underlying molecular mechanisms governing the host-parasite relationship are still largely unknown. Therefore detailed investigation and evaluation of parasitic molecules is desirable. One such molecule worthy of attention is IPSE/a-1 (lnterleukin-4 inducing principle from schistosome eggs). IPSE/a-1 is a secretory glycoprotein produced exclusively by the egg stage of Schistosoma mansoni, which activates human basophils in non-antigen specific IgE dependent mechanisn;t. Sequence analyses of IPSE/a-1 using bioinformatic subcellular localisation prediction tools revealed a putative nuclear localisation signal (NLS) at the C-terminus. The present work was conducted to confirm whether this sequence ('125-PKRRRTY-131') was both necessary and sufficient for nuclear localisation of IPSE/a-1 and other heterologous GFP proteins. A plasmid encoding EGFP-IPSE/a-1, as well as a truncated mutant lacking amino acids 125-134, was transfected into Huh7 and U2-0S cell lines, and fluorescence of the fusion protein was determined by confocal laser scanning microscopy. EGFP-IPSE/a-1 was found to be exclusively nuclear, whereas the mutant displayed both nuclear and cytoplasmic staining. Furthermore, insertion of the IPSE/a-1 NLS into a tetra-EGFP construct showed nuclear localisation, and alanine scanning mutagenesis revealed a requirement for the KRRR residues. IPSE/a-l also binds to transferrin, which lead to downstream effect on cellular proliferation. Besides, fluorescence microscopy revealed that recombinant IPSE/a-l protein added exogenously to culture medium was internalized by variant Chinese hamster ovary (CRO) cells expressing the human transferrin receptor and was found in the nuclei of these cells Western blotting further confirmed this temporal relocalisation of IPSE/a-l from cytosolic to nuclear fractions. In addition, IPSE/a-l exhibited a DNA-binding activity that appeared to be dependent on the C-terminal NLS sequence. In summary, the main achievement of this work is the identification and characterization of a NLS in IPSE/a-l that is functional in mammalian cells, which will form the basis for further investigations into the biological significance of this nuclear targeting and DNA interaction e.g. IPSE/a-l may function as transcription factor in the nucleus. The properties of IPSE/a-l described here also make it an interesting potential vehicle for intracellular and nuclear drug delivery.
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Hogrefe, Kai. "Targeted platelet inhibition with a bispecific antibody fragment that binds to platelet glycoprotein IIb/IIIa receptor and tissue factor : prevention of thombosis after angioplasty with a new locally delivered bispecific antibody against tissue factor and platelet glycoprotein IIb/IIIa receptor." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/29495.
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Shore, David A. "Structural aspects of aB T-cell receptor-mediated activation of the cytotoxic T-lymphocyte by the CD3 and CD8 glycoproteins." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419548.
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Abdin, Amr [Verfasser]. "Efficacy and safety of Glycoprotein IIb/IIIa receptor antagonists in patients with infarct-related cardiogenic shock / Amr Abdin." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2019. http://d-nb.info/117616046X/34.
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May, Frauke [Verfasser], and Bernhard [Akademischer Betreuer] Nieswandt. "The role of the (hem)ITAM-coupled receptors C-type lectin-like receptor 2 (CLEC-2) and Glycoprotein (GP) VI for platelet function: in vitro and in vivo studies in mice / Frauke May. Betreuer: Bernhard Nieswandt." Würzburg : Universitätsbibliothek der Universität Würzburg, 2013. http://d-nb.info/103731140X/34.
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