Dissertations / Theses on the topic 'Protein families'
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Abhiman, Saraswathi. "Prediction of function shift in protein families /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-869-X/.
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Biswas, Arpan Dinakarpandian Deendayal. "Complexity analysis of protein families." Diss., UMK access, 2004.
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Thesis (M.S.)--School of Computing and Engineering. University of Missouri--Kansas City, 2004."A thesis in computer science." Typescript. Advisor: Deendayal Dinakarpandian. Vita. Title from "catalog record" of the print edition Description based on contents viewed Feb. 22, 2006. Includes bibliographical references (leaves 60-62). Online version of the print edition.
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Elfving, Eric. "Automated annotation of protein families." Thesis, Linköpings universitet, Bioinformatik, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-69393.
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Introduction: The great challenge in bioinformatics is data integration. The amount of available data is always increasing and there are no common unified standards of where, or how, the data should be stored. The aim of this workis to build an automated tool to annotate the different member families within the protein superfamily of medium-chain dehydrogenases/reductases (MDR), by finding common properties among the member proteins. The goal is to increase the understanding of the MDR superfamily as well as the different member families.This will add to the amount of knowledge gained for free when a new, unannotated, protein is matched as a member to a specific MDR member family. Method: The different types of data available all needed different handling. Textual data was mainly compared as strings while numeric data needed some special handling such as statistical calculations. Ontological data was handled as tree nodes where ancestry between terms had to be considered. This was implemented as a plugin-based system to make the tool easy to extend with additional data sources of different types. Results: The biggest challenge was data incompleteness yielding little (or no) results for some families and thus decreasing the statistical significance of the results. Results show that all the human and mouse MDR members have a Pfam ADH domain (ADH_N and/or ADH_zinc_N) and takes part in an oxidation-reduction process, often with NAD or NADP as cofactor. Many of the proteins contain zinc and are expressed in liver tissue. Conclusions: A python based tool for automatic annotation has been created to annotate the different MDR member families. The tool is easily extendable to be used with new databases and much of the results agrees with information found in literature. The utility and necessity of this system, as well as the quality of its produced results, are expected to only increase over time, even if no additional extensions are produced, as the system itself is able to make further and more detailed inferences as more and more data become available.
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Rezvoy, Clément. "Large Scale Parallel Inference of Protein and Protein Domain families." Phd thesis, Ecole normale supérieure de lyon - ENS LYON, 2011. http://tel.archives-ouvertes.fr/tel-00682495.
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Protein domains are recurring independent segment of proteins. The combinatorial arrangement of domains is at the root of the functional and structural diversity of proteins. Several methods have been developed to infer protein domain decomposition and domain family clustering from sequence information alone. MkDom2 is one of those methods. Mkdom2 infers domain families in a greedy fashion. Families are inferred one after the other in order to create a delineation of domains on proteins and a clustering of those domains in families. MkDom2 is instrumental in the building of the ProDom database. The exponential growth of the number of sequences to process as rendered MkDom2 obsolete, it would now take several years to compute a newrelease of ProDom. We present a nous algorithm, MPI_MkDom2, allowing computation of several families at once across a distributed computing platform. MPI_MkDom2 is an asynchronous distributed algorithm managing load balancing to ensure efficient platform usage; it ensures the creation of a non-overlapping partitioning of the whole protein set. A new proximity measure is defined to assess the effect of the parallel computation on the result. We also Propose a second algorithm, MPI_mkDom3, allowing the simultaneous computation of a clustering of protein domains as well as full protein sharing the same domain decomposition.
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Stamler, Robin Jacob. "Structural biology of two proteins from two eye-related protein families : ABCR and TSP36." Thesis, Birkbeck (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.414721.
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Sonnhammer, Erik Leonard Laage. "Classification of protein domain families for genomic sequence analysis." Thesis, Open University, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336799.
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Kunin, Victor. "Evolution and function of protein families in complete genomes." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.616101.
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Hill, E. E. "Evolution of protein families : genome sequences and three dimensional structures." Thesis, University of Cambridge, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604054.
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The aim here is to investigate the relationship between sequence and structure for families of structurally related proteins with low sequence identity in order to determine any conserved positions and define them. We do this in two main ways: (i) Evolution of Three Dimensional Structures The members of the 4-helical cytokine superfamily of proteins have no significant sequence identity. Despite this superfamilies' low to non-existent sequence similarity their homology is inferred by their common structural and functions. We carry out an in depth analysis of the long and short chain families both separately and together to determine the conserved structural regions. From an examination of the residues that occur at equivalent sites within these regions we identified the only positions at which there is any conservation. We then determined the structural role of these conserved sites so as to understand how the members of this family can maintain similar structures but have very different sequences. (ii) Evolution of Sequences Within Genomes For the cadherin superfamily, we use automated methods and hand analysis (incorporating information gathered previously on the structurally important residues) in order to identify all cadherin domains in their respective proteins within two sequenced eukaryotic genomes, Caenorhabditis elegans and Drosophila melanogaster. Identification of the entire cadherin protein repertoires within the two eukaryotic genomes allowed us to carry out a comparative analysis. This allows that the cadherin repertoires in the two organisms are surprisingly different. The ability to identify all genes within an organism that encode certain structural domains is certainly a huge achievement, and must be part of the way towards understanding an organism in its entirety.
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Bonneau, Richard A. "Gene annotation using Ab initio protein structure prediction : method development and application to major protein families /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/9241.
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Daniels, Jan Peter. "Nuclear architecture and gene expression-associated protein families in trypanosoma brucei." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509914.
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Yan, Yongpan. "Computational analyses of microbial genomes operons, protein families and lateral gene transfer /." College Park, Md. : University of Maryland, 2005. http://hdl.handle.net/1903/2596.
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Thesis (Ph. D.) -- University of Maryland, College Park, 2005.Thesis research directed by: Cell Biology & Molecular Genetics. Title from t.p. of PDF. Includes bibliographical references. Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
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Gamblin, Richard James. "Molecular recognition mechanisms in DNA binding protein families, using molecular modelling techniques." Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.436398.
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Yahashiri, Atsushi. "Comparative investigations of H-transfer in dihydrofolate reductases from different families." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/763.
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This thesis presents an effort to understand the C-H-C transfer in enzymatic reactions from the comparison of different variants of enzymes that have unrelated protein sequences and structures, but catalyze the same chemical transformation. I evaluated the kinetic isotope effects (KIEs) and their temperature dependences and interpreted the findings in accordance with Marcus-like models. The enzyme system studied is dihydrofolate reductase (DHFR), which catalyzes the reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) using reduced β-nicotinamide adenine dinucleotide 2' phosphate (NADPH) as a reducing agent. H-transfer reactions in typical enzymes from three genetically unrelated families, E. coli chromosomal DHFR (cDHFR, FolA), plasmid coded R67 DHFR (FolB), and pteridine reductase 1 (PTR1, FolM) were comparatively investigated. Chapter I provides a brief introduction to the thesis. Chapter II presents optimized procedures for a one-pot, enzymatic microscale synthesis of several NADPH isotopologues used in KIE experiments. Chapter III focuses on the application of novel competitive primary H/D KIE determinations. Chapter IV compares the H-transfer reactions between primitive R67 DHFR and the chromosomal DHFR, and Chapter V describes the investigation of H-transfer reactions at high and low ionic strengths with theoretical and experimental approaches in order to understand the unusual enhancement in H-transfer rate of R67 DHFR with increasing ionic strength. Chapter VI discusses an improved PTR1 purification procedure and comparisons of steady state kinetic parameters using PTR1 and cDHFR with H2F and dihydrobiopterin (H2B) substrates. Thus, the investigation of the H-transfer reaction catalyzed by cDHFR with an unnatural substrate, H2B is described. Finally, a summary is provided and future directions are discussed in Chapter VII.
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Bresell, Anders. "Characterization of protein families, sequence patterns, and functional annotations in large data sets." Doctoral thesis, Linköping : Department of Physics, Chemistry and Biology, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-10565.
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Reeves, Gabrielle Anne. "Evolutionary analysis of protein structural families to assist comparative modelling of genome sequences." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405922.
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Foight, Glenna Wink. "Determinants of protein-peptide interaction specificity in the Bcl-2 and TRAF families." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/101350.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, September 2015.Cataloged from PDF version of thesis. "September 2015."
Includes bibliographical references.
Protein-peptide interactions have important roles in the majority of cellular processes. There are many families of peptide recognition domains in which homologous members display differential binding preferences for peptide sequence features. Peptide binding specificity is critical for the functional roles played by each family member, which can be overlapping or distinct. The two peptide recognition domain families discussed in this work, Bcl-2 and TRAF proteins, have roles in cellular processes including apoptosis, inflammation, and immunity. Aberrant function of these proteins has been linked to a variety of diseases. There is great interest in understanding the mechanistic basis of protein-peptide binding specificity in these families and others. An improved understanding will enable models of binding preferences for interactome prediction and design of specific peptide reagents for the inhibition and study of protein-peptide interactions. The anti-apoptotic Bcl-2 family members bind [alpha]-helical Bcl-2-homology 3 (BH3) motifs in pro-apoptotic Bcl-2 family members to prevent apoptosis. Kaposi Sarcoma herpesvirus and Epstein Barr herpesvirus express viral homologs of the anti-apoptotic Bcl-2 proteins, KSBcl-2 and BHRF 1, respectively, during viral replication to prevent host cell death. Because human Bel- 2 proteins are important in preventing apoptosis in cancers, there is interest in targeting the viral homologs, as they may also have a role in herpesvirus-associated malignancies. I designed and screened libraries of BH3 peptide variants for binding specificity to KSBcl-2 and BHRF 1. From library screening and additional rational mutagenesis, I developed peptides that showed specific binding to KSBcl-2, BHRF 1, or the human homolog Ml- 1, and displayed large margins of specificity over the other human Bel-2 homologs. TRAF proteins bind sequences in the unstructured regions of cell surface receptors and other adapter proteins in order to mediate downstream signaling events. TRAF-peptide binding preferences are relatively uncharacterized. I adapted a bacterial surface display system for screening peptides for TRAF binding. Using this system, I explored the binding preferences of TRAFs 2, 3, and 5 to single and double mutant libraries of two peptide interaction partners from CD40 and TANK. Comparison of the enriched peptide sequences reveals a surprising degree of difference between these three close TRAF homologs, yielding hypotheses relevant to TRAF function and inhibition.
by Glenna Wink Foight.
Ph. D.
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Prikryl, Jana 1976. "Functions of organelle-specific nucleic acid binding protein families in chloroplast gene expression." Thesis, University of Oregon, 2009. http://hdl.handle.net/1794/10614.
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xii, 83 p. : ill. A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number.My dissertation research has centered on understanding how nuclear encoded proteins affect chloroplast gene expression in higher plants. I investigated the functions of three proteins that belong to families whose members function solely or primarily in mitochondrial and chloroplast gene expression; the Whirly family (ZmWHY1) and the pentatricopeptide repeat (PPR) family (ZmPPR5 and ZmPPR10). The Whirly family is a plant specific protein family whose members have been described as nuclear DNA-binding proteins involved in transcription and telomere maintenance. I have shown that ZmWHY1 is localized to the chloroplast where it binds nonspecifically to DNA and also binds specifically to the atpF group II intron RNA. Why1 mutants show reduced atpF intron splicing suggesting that WHY1 is directly involved in atpF RNA maturation. Why1 mutants also have aberrant 23S rRNA metabolism resulting in a lack of plastid ribosomes. The PPR protein family is found in all eukaryotes but is greatly expanded in land plants. Most PPR proteins are predicted to localize to the mitochondria or chloroplasts where they are involved in many RNA-related processes including splicing, cleavage, editing, stabilization and translational control. Our results with PPR5 and PPR10 suggest that most of these activities may result directly from the unusually long RNA binding surface predicted for PPR proteins, which we have shown imparts two biochemical properties: site-specific protection of RNA from other proteins and site-specific RNA unfolding activity. I narrowed down the binding site for PPR5 and PPR10 to ∼45 nt and 19 nt, respectively. I showed that PPR5 contributes to the splicing of its group II intron ligand by restructuring sequences that are important for splicing. I used in vitro assays with purified PPR10 to confirm that PPR10 can block exonucleolytic RNA decay from both the 5' and 3' directions, as predicted by prior in vivo data. I also present evidence that PPR10 promotes translation by restructuring its RNA ligand to allow access to the ribosome. These findings illustrate how the unusually long RNA interaction surface predicted for PPR proteins can have diverse effects on RNA metabolism. This dissertation includes both previously published and unpublished co-authored material.
Committee in charge: Eric Selker, Chairperson, Biology; Alice Barkan, Advisor, Biology; Victoria Herman, Member, Biology; Karen Guillemin, Member, Biology; J. Andrew Berglund, Outside Member, Chemistry
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Addou, Sarah. "Evolutionary and Functional Analyses of Protein Structural Families to Improve the Functional Annotation of Genomes." Thesis, University College London (University of London), 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498050.
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Timberlake, David S. "Associations between polymorphisms of the G protein-coupled receptors and intermediate phenotypes in hypertensive families /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2003. http://wwwlib.umi.com/cr/ucsd/fullcit?p3091353.
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Mendillo, Marc Laurence. "The MutS and MutL protein families and their role in the initiation of DNA mismatch repair." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3273476.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed April 9, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Briedis, Kristine Mary. "The distribution and evolution of protein kinase and phosphatase families in the three superkingdoms of life." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3307357.
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Thesis (Ph. D.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed July 22, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 171-195).
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Neumann, Sindy [Verfasser], Dimitri Akademischer Betreuer] Frischmann, and Dieter [Akademischer Betreuer] [Langosch. "Structure-function relationships in membrane protein families / Sindy Neumann. Gutachter: Dimitri Frischmann ; Dieter Langosch. Betreuer: Dimitri Frischmann." München : Universitätsbibliothek der TU München, 2012. http://d-nb.info/1024354946/34.
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Page, S. P. "The clinical characteristics of families with hypertrophic cardiomyopathy associated with mutations of cardiac myosin binding protein C." Thesis, University College London (University of London), 2010. http://discovery.ucl.ac.uk/20245/.
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Introduction: Mutations in cardiac myosin binding protein-C (MYBPC3), the most common genetic cause of hypertrophic cardiomyopathy (HCM), have been reported to cause a comparatively benign and late-onset form of the disease with incomplete penetrance. Based upon selected families with small numbers of mutations, these early reports may be misleading however. This study aimed to redefine the clinical characteristics of HCM related to MYBPC3 by evaluating a large cohort of unselected patients and their families, in whom an MYBPC3 mutation had been identified. Methods: Index cases and their families underwent history, physical examination, electrocardiogram (ECG), transthoracic echocardiography, ambulatory ECG monitoring, metabolic exercise testing and mutation analysis. Long-term follow up data was collected where available. Results: 44 MYBPC3 mutations were identified in 59 index cases. 26 of 59 (44%) were missense with 11 (19%) insertions/deletions, 11 (19%) intronic, and 5 (8%) nonsense mutations. A further 6 (10%) had complex genetic status with two different sequence variations identified. Nine families shared the R502W missense mutation and haplotype analysis confirmed a common founder, the first to be described in a UK cohort. A further 111 mutation carriers were identified, of which 39 were clinically affected - disease penetrance was therefore incomplete (58%) and related to age and gender but not mutation type. Mean age at diagnosis was 40.1 +/- 15.9 years with a wide range (5-76); 91.8% of affected mutation carriers were diagnosed over the age of 20 years. Most had asymmetric septal hypertrophy (86.4%) and mean maximal wall thickness was 20 +/- 5.8mm. Families sharing identical mutations showed significant variability in disease penetrance, age at diagnosis and risk of sudden death, suggesting that modifying factors play a significant role in disease development. No clinically useful markers of early disease expression were apparent from tissue Doppler studies in unaffected genotyped relatives. During long term follow up (mean 7.9 +/- 4.5 years) 1 individual developed hypertrophy as an adult, 5 individuals died (3 suddenly) and overall survival was 94%. Discussion: The broad spectrum of mutations, disease severity and natural history of disease suggests that earlier reports of late-onset, benign disease related to MYBPC3 mutations were premature. In this study disease expression is broadly similar to non-genotyped HCM cohorts with disease severity ranging from mild to severe, risk of sudden death ranging from low to high and clinical disease being diagnosed in all decades of life. Such variance is not adequately explained by the sarcomeric protein gene or specific mutation per se and other genetic and environmental factors influence disease penetrance, severity and prognosis. The next generation of genotype-phenotype studies require a shift in focus from single gene analysis to include other genetic and environmental variables and an international collaborative database is recommended.
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De, Lazzari Eleonora. "Gene families distributions across bacterial genomes : from models to evolutionary genomics data." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066406/document.
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La génomique comparative est un sujet essentiel pour éclaircir la biologie évolutionnaire. La première étape pour dépasser une connaissance seulement descriptive est de développer une méthode pour représenter le contenu du génome. Nous avons choisi la représentation modulaire des génomes pour étudier les lois quantitatives qui réglementent leur composition en unités élémentaires de type fonctionnel ou évolutif. La première partie de la thèse se fonde sur l'observation que le nombre de domaines ayant la même fonction est lié à la taille du génome par une loi de puissance. Puisque les catégories fonctionnelles sont des agrégats de familles de domaines, on se demande comment le nombre de domaines dans la même catégorie fonctionnelle est lié à l'évolution des familles. Le résultat est que les familles suivent également une loi de puissance. Le deuxième partie présente un modèle positif qui construit une réalisation à partir des composants liés dans un réseau de dépendance. L'ensemble de toutes les réalisations reproduit la distribution des composants partagés et la relation entre le nombre de familles distinctes et la taille du génome. Le dernier chapitre étend l'approche modulaire aux écosystèmes microbiens. Sur la base des constatations que nous avons faites sur les lois de puissance pour les familles de domaines, nous avons analysé comment le nombre de familles dans un metagénome en est influencé. Par conséquence, nous avons défini une nouvelle observable dont la forme fonctionnelle comprend des informations quantitatives sur la composition originelle du metagénomeComparative genomics is as a fundamental discipline to unravel evolutionary biology. To overcome a mere descriptive knowledge of it the first challenge is to develop a higher-level description of the content of a genome. Therefore we used the modular representation of genomes to explore quantitative laws that regulate how genomes are built from elementary functional and evolutionary ingredients. The first part sets off from the observation that the number of domains sharing the same function increases as a power law of the genome size. Since functional categories are aggregates of domain families, we asked how the abundance of domains performing a specific function emerges from evolutionary moves at the family level. We found that domain families are also characterized by family-dependent scaling laws. The second chapter provides a theoretical framework for the emergence of shared components from dependency in empirical component systems with non-binary abundances. We defined a positive model that builds a realization from a set of components linked in a dependency network. The ensemble of resulting realizations reproduces both the distribution of shared components and the law for the growth of the number of distinct families with genome size. The last chapter extends the component systems approach to microbial ecosystems. Using our findings about families scaling laws, we analyzed how the abundance of domain families in a metagenome is affected by the constraint of power-law scaling of family abundance in individual genomes. The result is the definition of an observable, whose functional form contains quantitative information on the original composition of the metagenome
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Ammunet, Tea. "Evolution and diversification of secreted protein effectors in the order Legionellales." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-357800.
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The evolution of a large, diverse group of intracellular bacteria was previously very difficult to study. Recent advancements in both metagenomic methods and bioinformatics has made it possible. This thesis investigates the evolution of the order Legionellales. The study concentrates on a group of proteins essential for pathogenesis and host manipulation in the order, called effector proteins. The role of effectors in host adaptation, evolutionary history and the diversification of the order were investigated using a multitude of bioinformatics methods. First, the abundance and distribution of the known effector proteins in the orderwas found to cover newly discovered clades. There was a clear distinction between the proteins present in Legionellales and the outgoup, indicating the important role of the effectors in the order. Further, the effectors with known functions found in the new clades, particularly in Berkiella, revealed potential modes of host manipulation of this group. Secondly, the evolution of the effector gene content in the order shed light on theevolution of the order, as well as on the potential evolutionary differences between Legionellaceae and Coxiellaceae. In general, most of the effectors were gained early in the last common ancestor of Legionellales and Legionellaceae, as further indication of their role in the diversification of the order. New effector genes were acquired in the Legionellaceae even up to recent speciation events, whereas Coxiellacea have lost more protein coding genes with time. These differences may be due to horizontal gene transfer in the case of gene gains in Legionellaceae and loss of selection in the case of gene losses in Coxiellaceae. Third, the early evolution of core gained effector proteins for the order was studied.Two of the eight investigated core effectors seem to have a connection to eukaryotes, the rest to other bacteria, indicating both inter-domain and within bacteria horizontal gene transfer. In particular, one effector protein with eukaryotic motif gained at the last common ancestor of Legionellales, was found in all the clades and is therefore an important evolutionary link that may have allowed Legionellales to utilize eukaryotic hosts.
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Marles-Wright, Jon. "Structural studies on determinants of receptor/ligand binding in the tumour necrosis factor and T cell receptor protein families." Thesis, University of Oxford, 2005. http://ora.ox.ac.uk/objects/uuid:1f6d480a-a641-4778-9ff0-ece1b2d38d5c.
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Protein-protein recognition plays a central role in the surveillance of self and non-self in the mammalian immune system and ultimately in cellular survival within the organism. Two systems of fundamental importance to the immune system are the Tumour Necrosis Factor (TNF) and the T cell receptor (TCR) families. High-throughput methods developed within the Oxford Protein Production Facility have been successfully applied to the production of members of the TNF receptor and ligand superfamilies for structural characterisation. The TNF receptor DR6 was successfully refolded from E.coli inclusion bodies using a rapid-dilution technique and yielded diffraction quality crystals. Data collected from these crystals will be used to obtain an x-ray crystallographic model of DR6. Vascular Endothelial Growth Inhibitor (VEGI) was produced as a soluble recombinant protein in E.coli, and formed a number of poorly diffracting crystals, it is hoped that further trials and optimization of conditions will lead to improved data quality. Lymphotoxin β receptor was produced in a Eukaryotic system. This has shed light on the complications posed by signal peptide cleavage and glycosylation on the production of protein for crystallization trials. TNF superfamily proteins are ideal targets for the design of novel therapeutic agents due to their involvement in a number of disease pathologies. Various methods of molecular docking and small molecule design were applied to the search for potential inhibitors of receptor binding for the TNF ligand proteins TRAIL and BAFF. A number of potential drug leads were identified from the National Cancer Institute drug database. The Natural Killer (NK) T cell restricted TCRs recognise CD1d-presented glycolipid. Determination of the crystal structures of the invariant NK TCR and the NK restricted TCRs 5E and 5B shows that these proteins adopt the canonical structures of class I MHC restricted TCRs. This suggests that the binding of CD1d-glycolipid by these receptors will conform to the same model of binding seen for the class I MHC restricted TCRs.
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Mikryukov, Alexander. "Studies on the functions of the misshapen and e-syt protein families in wnt and fgf signalling during early xenopus development." Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/28888/28888.pdf.
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Les voies de signalisation Wnt et FGF sont parmi les plus importantes dans les communications inter-cellulaires qui régissent le développement et l’homéostase des tissus embryonnaires ou adultes. Bien que l’on connaisse énormément de choses sur ces voies et les protéines qui les composent, plusieurs questions persistent quant à leur régulation. Notre travail fait usage du modèle amphibien Xenopus laevis dans l’étude du rôle de deux MAP4K kinases de la famille Misshapen: xTNIK et xMINK dans la balance entre les branches «canonique» et «non-canonique» de la signalisation Wnt, ainsi que dans l’étude d’une nouvelle protéine adaptatrice de l’endocytose: E-Syt2 et de son rôle dans la régulation de la signalisation FGF. La voie signalétique Wnt est principalement traduite par la famille des récepteurs serpentins Frizzled vers deux voies distinctes : la voie dite «canonique» régulant la β-catenine nucléaire, et la voie dite «non-canonique» qui active les petites GTPases Rac et RhoA ainsi que la MAP-kinase JNK et les PKCs. Nous montrons ici que TNIK (Traf2 and Nck-interacting kinase) et xMINK (Misshapen/NIKs-related kinase) sont des composantes essentielles de ces deux voies de réponse. xTNIK et xMINK interagissent ensemble in vivo et subissent un clivage protéolytique libérant des domaines Kinase et Citron-NIK-Homology (CNH) respectivement activateur et suppresseur du signal. Les deux kinases interviennent dans la voie «non-canonique» cependant, alors que xTNIK est également un médiateur de la voie «canonique», xMINK y joue un rôle antagoniste et ces effets dépendent de leurs activités catalytiques. Nous apportons enfin la preuve qu’une régulation spécifique du clivage protéolytique des deux pro-enzymes dans les différents tissus embryonnaires régule leur activité de façon différentielle et suggérons qu’il s’agit là d’un mode d’aiguillage de la réponse Wnt entre les voies «canonique» et «non-canonique» in vivo. Enfin, nous montrons que la protéine membranaire de type synaptotagmine E-Syt2 est essentielle dans la phase précoce de l’endocytose du récepteur aux FGF activé, elle-même nécessaire à l’activation de ERK et à l’induction du mésoderme. E-Syt2 interagit spécifiquement avec le récepteur aux FGF activé ainsi qu’avec l’Adaptin-2. Il est en outre requis en amont de Ras dans l’activation de ERK et nos données identifient donc E-Syt2 comme un adaptateur endocytique de la voie de la clathrine.The Wnt and FGF pathways are among the most critical inter-cellular signalling pathways controlling embryo development and the homeostasis of adult tissues. Although much is known about the signal transduction routes and proteins constituting these pathways, many questions concerning their regulation remain to be answered. The present work uses the Xenopus laevis model system to study the role of two kinases of the Misshapen family of MAP4K signalling kinases, xTNIK and xMINK, in the balance between canonical and non-canonical branches of Wnt signalling, and the role of a new endocytic adapter protein, E-Syt2, in regulation of FGF signalling by endocytosis. Wnt signals are predominantly transduced via the Frizzled family of serpentine receptors to two distinct pathways, the canonical pathway regulating nuclear -catenin and a non-canonical pathway that activates the small GTPases Rac and RhoA, the JNK MAP-kinase and PKC. My work shows that xTNIK (Traf2 and Nck-interacting kinase) and xMINK (Misshapen/NIKs-related kinase) are essential and indeed integral components of both the canonical and non-canonical Wnt pathways. xTNIK and xMINK interact with each other and are proteolytically cleaved in vivo to generate Kinase domain fragments that are active in signal transduction, and Citron-NIK-Homology domain (CNH) fragments that are suppressive. The Kinase domain fragments of xTNIK mediate both canonical and non-canonical signalling, whereas those derived from xMINK mediate non-canonical signalling but strongly antagonize canonical signalling. This work suggests that tissue specific regulation of the proteolytic cleavage of xTNIK and xMINK controls the balance between canonical and non-canonical Wnt signalling. The synaptotagmin-related membrane protein E-Syt2 was found to be essential for an early phase of activated FGF receptor endocytosis that is necessary for functional ERK activation and mesoderm induction. E-Syt2 interacts selectively with the activated FGF receptor and with Adaptin-2, and is required upstream of Ras for ERK activation. Together these data identified E-Syt2 as an endocytic adapter for the Clathrin-dependent pathway.
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Bassard, Jean-Etienne. "Study of protein-protein and protein-membrane interactions leading to the channeling of metabolic fluxes in phenylpropanoid metabolism in Arabidopsis thaliana, involving cytochromes P450 from CYP73A and CYP98A families : Functional analysis of CYP98As and CYP73As paralogues in Nicotiana tabacum." Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/BASSARD_Jean-Etienne_2010.pdf.
Full textAbstract:
Les métabolons sont des complexes supramoléculaires constitués d’éléments structuraux et d’enzymes consécutives d’une voie de biosynthèse. De telles structures offrent de nombreux avantages pour l’organisation et l’efficacité des voies métaboliques et du métabolisme dans son ensemble. La formation de métabolons dans la voie de biosynthèse des phénylpropanoïdes est envisagée depuis de longues années. L’association/dissociation de ces derniers assurerait la canalisation des flux métaboliques entre les différentes branches constituant cette voie de biosynthèse. Deux cytochromes P450 membranaires, CYP73A5 et CYP98A3, ainsi que deux enzymes solubles, la p-coumaroyl :CoA ligase 1 (4CL-1) et l’hydroxycinnamoyl-CoA :shikimate hydroxycinnamoyl transférase (HCT), sont des éléments clé dans la formation du métabolon spécifique de la voie de biosynthèse de la lignine. Ce métabolon a été étudié in vitro par reconstitution sur nanodisques lipidiques, ainsi que par imagerie confocale sur des cellules épidermiques de Nicotiana benthamiana exprimant transitoirement des protéines de fusion fluorescentes. Ce travail a révélé des propriétés non décrites des enzymes cibles, comme le mouvement rapide des P450 ancrés au réticulum endoplasmique (RE), ou l’interaction de 4CL-1 et HCT avec les membranes artificielles ou cellulaires. In vivo, une relocalisation vers le RE des enzymes solubles a été observée en présence des P450s. Des interactions protéine-protéine ont été mises en évidence entre protéines membranaires et solubles, et furent accrues lors de la co-expression de l’ensemble des partenaires du métabolon. Ce travail a également permis de démontrer une homo- et une hétéro-oligomérisation des CYP73A5 et CYP98A3. CYP98A3 semble jouer un rôle déterminant pour la formation du métabolon. Ce travail souligne le caractère extrêmement dynamique du métabolon. En parallèle, une analyse fonctionnelle des familles CYP98 et CYP73 a été réalisée chez N. Tabacum. Une caractérisation fonctionnelle précise des divers membres de ces familles n’a pas pu être réalisée en raison de leur faible expression en système recombinant. En revanche, les patrons d’expression des différents membres de ces familles chez le tabac sain ou stressé indiquent une spécialisation fonctionnelle des différents paraloguesMetabolons are supramolecular complexes of sequential metabolic enzymes and cellular structural elements. This organization of metabolic pathways at the molecular level is expected to have several advantages on the metabolism efficiency. The existence of metabolons in the phenylpropanoid pathway was proposed many years ago. Metabolons association and dissociation was proposed to coordinate fluxes in the different branches of this complex pathway. Two membrane-anchored cytochromes P450, CYP73A5 and CYP98A3, and two soluble enzymes, the p-coumaroyl:CoA ligase 1 (4CL-1) and the hydroxycinnamoyl-CoA:shikimate hydroxycinnamoyl transferase (HCT), are expected to play essential roles in the lignin branch metabolon. The formation of this lignin metabolon has been investigated by in vitro reconstruction on lipid nanodiscs, and by confocal microscopy on N. Benthamiana epidermal cells after transient expression of fluorescent fusion proteins. This work revealed unexpected features of the target enzymes, including fast movement of the P450 enzymes with the plant endoplasmic reticulum (ER) and membrane binding of 4CL and HCT, independent from the presence of the P450 proteins. It also indicated membrane relocalization of soluble enzymes in vivo in the presence of their partner proteins and demonstrated direct protein/protein interactions that were enhanced when CYP73A5, CYP98A3 and their two soluble partners were co-expressed in the same cells. This work also revealed P450 homo- and hetero-oligomerization and suggests that CYP98A3 plays an essential role in the formation of the lignin metabolon. These data underscore a very dynamic model for plant metabolon. In parallel, functional investigations on the members of the CYP98 and CYP73 families in Nicotiana tabacum have been carried out. Enzyme functions could not be precisely described due to their low expression in the recombinant system. The different expression patterns of the paralogues in healthy or stressed tobacco plants were, however, clearly indicative of their subfunctionalization
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Foret, Sylvain, and sylvain foret@anu edu au. "Function and Evolution of Putative Odorant Carriers in the Honey Bee (Apis mellifera)." The Australian National University. Research School of Biological Sciences, 2007. http://thesis.anu.edu.au./public/adt-ANU20070613.144745.
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The remarkable olfactory power of insect species is thought to be generated by a combinatorial action of G-protein-coupled olfactory receptors (ORs) and olfactory carriers. Two such carrier gene families are found in insects: the odorant binding proteins (OBPs) and the chemosensory proteins (CSPs). In olfactory sensilla, OBPs and CSPs are believed to deliver hydrophobic air-borne molecules to ORs, but their expression in non-olfactory tissues suggests that they also may function as general carriers in other developmental and physiological processes.
¶
Bioinformatics and experimental approaches were used to characterise the OBP and CSP gene families in a highly social insect, the western honey bee (Apis mellifera). Comparison with other insects reveals that the honey bee has the smallest set of these genes, consisting of only 21 OBPs and 6 CSPs. These numbers stand in stark contrast to the 66 OBPs and 7 CSPs in the mosquito Anopheles gambiae and the 46 OBPs and 20 CSPs in the beetle Tribolium castaneum. The genes belonging to both families are often organised in clusters, and evolve by lineage specic expansions. Positive selection has been found to play a role in generating a greater sequence diversication in the OBP family in contrast to the CSP gene family that is more conserved, especially in the binding pocket. Expression proling under a wide range of conditions shows that, in the honey, bee only a minority of these genes are antenna-specic. The remaining genes are expressed either ubiquitously, or are tightly regulated in specialized tissues or during development. These findings support the view that OBPs and CSPs are not restricted to olfaction, and are likely to be involved in broader physiological functions.
¶
Finally, the detailed expression study and the functional characterization of a member of the CSP family, uth (unable-to-hatch), is reported. This gene is expressed in a maternal-zygotic fashion, and is restricted to the egg and embryo. Blocking the zygotic expression of uth with double-stranded RNA causes abnormalities in all body parts where this gene is highly expressed.
The treated embryos are `unable-to-hatch' and cannot progress to the larval stages. Our ndings reveal a novel, essential role for this gene family and suggest that uth is an ectodermal gene involved in embryonic cuticle formation.
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Yang, Yang. "Crystallographic and Modeling Studies Suggest that the SKICH Domains from Different Protein Families Share a Common Ig-like Fold but harbor substantial Structural Variations." OpenSIUC, 2014. https://opensiuc.lib.siu.edu/dissertations/981.
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TAX1BP1 is a pleiotropic multi-domain protein involved in many important biological processes such as signal transduction, cell growth and apoptosis, transcriptional coactivation, membrane trafficking, neurotransmission and autophagy. The N-terminus of TAX1BP1 contains a SKICH domain implicated in autophagy. SKICH domains are also present in four other proteins including NDP52, CALCOCO1, SKIP and PIPP. The SKICH domains of SKIP and PIPP mediate plasma membrane localization. The functions of the SKICH domains of NDP52 and CALCOCO1 are not known. We solved the crystal structure of the TAX1BP1 SKICH domain, which has an Ig-like fold similar to the NDP52 SKICH domain. Extensive pairwise and clustered aromatic π-stacking interactions are present in the TAX1BP1 SKICH domain. The aromatic residues mediating these interactions can be classified into four groups with varying degrees of conservation among different protein families. The interactions mediated by highly conserved residues are found in the interior and one outward face of the Ig-like β-barrel, representing common structural features of the SKICH domains. Three TAX1BP1-specific pairwise interactions locate in the loop regions, each augmented by a proline-aromatic interaction. The three proline-aromatic clusters are linked together by more generic hydrophobic interactions, forming a unique hydrophobic surface at one end of the TAX1BP1 SKICH domain. The structures and homologous models of SKICH domains from different proteins reveal substantial differences in electrostatic surface properties of the domains. Together with existing biochemical data, results from the structural study suggest that an intact SKICH domain is required for the autophagy function of TAX1BP1.
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Yerardi, Jason T. "The Implementation and Evaluation of Bioinformatics Algorithms for the Classification of Arabinogalactan-Proteins in Arabidopsis thaliana." Ohio University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1301069861.
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Сhurbanov, Alexander Y., Tatiana M. Karafet, Igor V. Morozov, Valeriia Yu Mikhalskaia, Marina V. Zytsar, Alexander A. Bondar, and Olga L. Posukh. "Whole Exome Sequencing Reveals Homozygous Mutations in RAI1, OTOF, and SLC26A4 Genes Associated with Nonsyndromic Hearing Loss in Altaian Families (South Siberia)." Public Library of Science, 2016. http://hdl.handle.net/10150/614680.
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Hearing loss (HL) is one of the most common sensorineural disorders and several dozen genes contribute to its pathogenesis. Establishing a genetic diagnosis of HL is of great importance for clinical evaluation of deaf patients and for estimating recurrence risks for their families. Efforts to identify genes responsible for HL have been challenged by high genetic heterogeneity and different ethnic-specific prevalence of inherited deafness. Here we present the utility of whole exome sequencing (WES) for identifying candidate causal variants for previously unexplained nonsyndromic HL of seven patients from four unrelated Altaian families (the Altai Republic, South Siberia). The WES analysis revealed homozygous missense mutations in three genes associated with HL. Mutation c.2168A>G (SLC26A4) was found in one family, a novel mutation c.1111G>C (OTOF) was revealed in another family, and mutation c.5254G>A (RAI1) was found in two families. Sanger sequencing was applied for screening of identified variants in an ethnically diverse cohort of other patients with HL (n = 116) and in Altaian controls (n = 120). Identified variants were found only in patients of Altaian ethnicity (n = 93). Several lines of evidences support the association of homozygosity for discovered variants c.5254G>A (RAI1), c.1111C>G (OTOF), and c.2168A>G (SLC26A4) with HL in Altaian patients. Local prevalence of identified variants implies possible founder effect in significant number of HL cases in indigenous population of the Altai region. Notably, this is the first reported instance of patients with RAI1 missense mutation whose HL is not accompanied by specific traits typical for Smith-Magenis syndrome. Presumed association of RAI1 gene variant c.5254G>A with isolated HL needs to be proved by further experimental studies.
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Shahzad, Zaigham. "Molecular study of Metal Tolerance Protein 1(MTP1) and Plant Defensins Type I (PDF1) gene sub-families : inference on their role in evolution of zinc hypertolerance in Arabidopsis halleri." Thesis, Montpellier, SupAgro, 2010. http://www.theses.fr/2010NSAM0014.
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A. halleri, est une espèce modèle pour l'étude des mécanismes moléculaires liés à l'évolution des caractères d'hypertolérance au zinc et d'hyperaccumulation de ce métal, car elle est phylogénétiquement proche d'A. thaliana qui est sensible au zinc et non-accumulatrice. Dans ce travail, nous avons caractérisé comparativement chez A. thaliana et chez A. halleri, deux sous-familles de gènes liés à l'homéostasie du zinc et ou à sa tolérance: Metal Tolérance Protein 1 (MTP1) et Plant Defensin type I (PDF1). Notre analyse génomique montre que le nombre de ces gènes est plus élevé chez A. halleri que chez A. thaliana confortant l'hypothèse actuelle reliant les duplications de gènes chez A. halleri à l'acquisition de son caractère d'hypertolérance. Mais, les résultats de nos études fonctionnelles ne vont pas dans ce sens, car ils montrent que, par exemple, certaines protéines AhMTP1 et AhPDF1 induisent une tolérance au zinc faible voire nulle lorsqu'elles sont testées dans la levure. Mais le résultat le plus marquant est que les transcrits de plusieurs gènes AhMTP1 et AhPDF1 ne sont pas détectables ou bien sont faiblement accumulés dans la plante. Nos résultats montrent donc que les gènes de ces sous-familles ne sont pas équivalents en ce qui concerne leur fonction dans la tolérance au zinc suggérant ainsi qu'ils sont le sujet de devenirs évolutifs différents. En dehors de leur contribution à la compréhension des mécanismes moléculaires qui sous-tendent l'évolution de la tolérance au zinc chez A. halleri, nos travaux sont également porteurs de développements biotechnologiques appliqués au zinc dans les domaines de la phytoremédiation et de la biofortificationA. halleri, is a model species to study molecular evolutionary mechanisms related to zinc hypertolerance and hyperaccumulation, due to its close relatedness with A. thaliana which is zinc sensitive and non-accumulator. Here, we comparatively characterised in both species, two zinc homeostasis and/or zinc tolerance related genes sub-families: the Metal Tolerance Protein 1 (MTP1) and the Plant defensins type I (PDF1). Genomic analyses revealed that the copy number of these genes is increased in A. halleri compared to A. thaliana. It was thus tempting to relate the acquisition of zinc hypertolerance in A. halleri to these gene duplications. However, the assumption was invalidated by functional analyses. For instance, some of the AhMTP1 or AhPDF1 proteins induced weak or no zinc tolerance to yeast. More importantly, transcripts of many AhMTP1 or AhPDF1 genes were either not accumulated or were very poorly expressed in A. halleri. These results indicate that different members of these gene sub-families are not equally functional. It is thus expected that these gene duplicates are undergoing different evolutionary fates regarding zinc tolerance. Besides helping to understand the molecular evolutionary mechanisms, studying zinc-related genes in A. halleri may also help developing strategies like phytoremediation and biofortification
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Oliveira, Juliana Ferreira de. "Estudos estruturais e funcionais de proteinas da familia SBDS com enfase nas ortologas de Trypanosoma cruzi e humana." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314721.
Full textAbstract:
Orientadores: Ana Carolina de Mattos Zeri, Nilson Ivo Tonin ZanchinTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Proteínas da família SBOS (Shwachman-Bodian-Diamond Syndrome) ocorrem largamente na natureza e s.ão bastante conservadas, apresentando ortólogas em Archaea e eucariotos. Estudos de análises genômica e biofísica tem relacionado a SBOS com o metabolismo de RNA e biosíntese de ribossomos. O gene ortólogo da SBOS de Archaea está localizado em um operon conservado que contém genes do processamento de RNA; estudos de perfil de expressão gênica tem agrupado o gene da proteína SBOS de Saccharomyces cerevisiae, Sdo1p, com fatores do processamento de rRNA e estudos de análise proteômica identificaram a interação da proteína Sdo1p com fatores da biossíntese de ribossomos; ortólogas de planta contém um C-terminal estendido apresentando motivo de ligação a RNA. Mutações identificadas no gene SBDS tem sido relacionadas com a síndrome Shwachman-Oiamond (80S), uma doença caracterizada por insuficiência exócrina pancreática e disfunção na medula óssea, cujos pacientes apresentam grandes chances de desenvolver leucemia. SOS representa, portanto, um importante modelo para entender os processos envolvidos no desenvolvimento da leucemia. O objetivo principal desse trabalho consistiu na caracterização estrutural e funcional de proteínas da família SBOS. Foram realizados ensaios de cristalização com ortólogas ; da SBOS de Archaea, levedura, tripanossoma e humana. A SBOS de Pyrococcus abyssi foi cristalizada, porém os cristais difrataram a baixa resolução (3,50 A). A ' caracterização da SBOS ortóloga de Trypanosoma cruzi (TcSBOS) mostrou que esta, proteína contém uma região C-terminal estendida. Ensaios de proteólise limitada,' dicroismo circular e espectroscopia por Ressonância Magnética Nuclear (RMN) indicaram que a região adicional da TcSBOS se comporta como um fragmento de proteína intrinsicamente desenovelado, responsável pela interação da TcSBOS com RNA, verificada por ensaios de Electrophoretic Mobility Shift Assay (EMSA). Também foi realizada a determinação da estrutura da ortóloga humana (HsSBOS) em solução por espectroscopia de RMN. A proteína HsSBOS é composta de três domínios bem estruturados, apresentando mobilidade conformacional entre os domínios N-terminal e central. Experimentos de titulação de RNA, novamente utilizando-se RMN, possibilitaram a confirmação da interação direta da SBOS humana com RNA. A região de ligação ao RNA foi identificada no N-terminal da proteína, região bastante conservada na família e considerada o principal alvo das mutações relacionadas à doença SDS
Abstract: The Shwachman-Bodian-Oiamond syndrome (SBOS) protein family occurs widely in nature and is highly conserved, with orthologues in Archaea and eukaryotes. Genomic and biophysical studies have suggested involvement of this protein in RNA metabolism and in ribosome biogenesis. Archaeal SBOS orthologue genes are located within highly conserved operons that include RNA-processing genes; transcriptional profiling analysis has clustered the yeast ortholog protein Sdo 1 p with rRNA processing factors and proteomic analysis have identified potential interactions between Sd01 p and ribosome biogenesis factors; several plant SBOS orthologues contain extended C-terminal region with putative RNA binding motif. Mutations in the SBDS gene are associated to the Shwachman-Oiamond syndrome (SOS), arare multisystem disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, and an increased risk of acute myeloid leukemia. SOS therefore represents an extremely useful model for understanding leukaemogenesis. The objective of the present work was the structural and functional characterization of the SBOS protein family. SBOS orthologues from Archaea, yeast, trypanosomatid and human were assayed for crystallization. The Archaeal SBOS orthologue, PaUPF0023 in Pyrococcus abyssi, was crystallized, but the crystals 'diffracted to a relatively low resolution (3.50 A). Characterization of the Trypanosoma cruzi SBOS ortholog (TcSBOS) by using limited proteolysis, circular dichroism and NMR analyses indicated that the C-terminal additional region of TcSBOS behaves as a natively unfolded protein segment, responsible for TcSBOS-RNA interaction activity in electrophoretic mobility shift assays. We have also determined the solution structure and backbone dynamics of the human SBOS protein using NMR spectroscopy. The overall structure of human SBOS comprises three well-folded domains with conformational exchange in the linker between the N-terminal and the central domains. RNA titration experiments using NMR spectroscopy provide evidence that human SBOS interacts with RNA via the N-terminal domain, a conserved region in the SBOS family and the most frequent target for SOSassociated mutations
Doutorado
Bioquimica
Doutor em Biologia Funcional e Molecular
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Scapin, Sandra Mara Naressi. "Analises estruturais de GTPases da familia RAB e mecanismo de regulção de MAFB pela proteina TIPRL." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317183.
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Orientadores: Nilson Ivo Tonin Zanchin, Beatriz Gomes GuimaraesTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: As GTPases da família Rab regulam o transporte intracelular de vesículas em eucariotos. Cada Rab atua em uma via de transporte específica e seu mecanismo de ação se dá através da realização de um ciclo de ligação e hidrólise de GTP. Neste trabalho, foi determinada a estrutura cristalográfica das formas inativa (ligada a GDP) e ativa (ligada a GppNHp) da GTPase Rab11b, um membro da subfamília Rab11 que está envolvida na reciclagem de proteínas dos endossomos para a membrana plasmática, no tráfego de vesículas da rede trans-Golgi para a membrana plasmática e na fagocitose. Os resultados foram confrontados com os dados estruturais da Rab11a descritos anteriormente. A Rab11b inativa cristalizou como um monômero, o que gera conflitos a respeito da formação de dímeros funcionais pela Rab11a. A Rab11b e a Rab11a ativas divergiram em relação à posição e à interação da serina 20, que é importante na hidrólise de GTP, mas apresentaram taxas hidrolíticas semelhantes in vitro. Visando uma investigação mais ampla da família Rab, a GTPase Rab21 também foi cristalizada, mas os cristais difrataram até 2.90 Å de resolução. Ensaios de desnaturação térmica revelaram que a Rab21 é estruturalmente mais instável do que a Rab11, talvez pela presença de cisteínas que estão susceptíveis à oxidação, contribuindo para a agregação e precipitação da proteína. A Rab11 é bastante estável, e possivelmente forma estruturas do tipo beta-amilóide em altas temperaturas. Este trabalho envolveu também o estudo funcional da interação entre a proteína TIP41 humana (TIPRL) e o fator de transcrição MafB. A TIPRL é uma proteína conservada que foi identificada como uma ativadora de MAP quinases enquanto sua homóloga em levedura foi caracterizada como um antagonista da via de sinalização da quinase TOR que regula o crescimento celular. A MafB está envolvida no controle transcricional em diversos processos de desenvolvimento, mas seus reguladores ainda não estão bem estabelecidos. A interação direta entre a TIPRL e a MafB inteira, ou seu domínio bZIP isolado, foi confirmada através de ensaios de ligação in vitro. As proteínas co-localizaram no núcleo de células HEK293 e nossos resultados preliminares mostram que a TIPRL inibe a atividade transcricional da MafB in vivo, embora apenas interfira na ligação in vitro do domínio bZIP da MafB ao seu DNA-alvo mediante a estabilização do complexo TIPRL-bZIP. A TIPRL pode, portanto, constituir um novo regulador da atividade de MafB
Abstract: GTPases of the Rab family are responsible for the intracellular transport of vesicles. Each family member acts on a specific transport pathway and their function is regulated by GTP binding and hydrolysis, cycling between inactive (GDP-bound) and active (GTP-bound) forms. In this work, we describe the crystal structure of inactive and active forms of the GTPase Rab11b, a member of the Rab11 subfamily which is involved in recycling of proteins from endosomes to the plasma membrane, in polarized transport in epithelial cells, in the transport of molecules of the trans-Golgi network to the plasma membrane and in phagocytosis. The Rab11b structure showed several differences from the Rab11a isoform previously described. Inactive Rab11b crystallized as a monomer, contradicting the hypothesis about functional dimers formed by Rab11a. Active Rab11b differ from Rab11a relative to the position of the serine 20 sidechain, which is involved in GTP hydrolysis, although both GTPases show similar GTP hydrolysis rates in vitro. In order to obtain structural information on Rab GTPases, Rab21 was also crystallized, but the crystals diffracted to a relatively low resolution (2.90 Å). Rab21 is a cysteine rich protein, showing a higher instability relative to Rab11b. Thermal unfolding followed by circular dicroism confirmed this hypothesis. Both Rab11b and Rab11a show a relatively high thermal stability and circular dicroism analysis indicate that they undergo conversion to structures rich in beta-strands upon thermal denaturation. This work includes also studies on the function of TIPRL in regard to its interaction with the transcription factor MafB. TIPRL is a conserved human protein identified as an activator of MAP kinases whereas its yeast counterpart Tip41 functions as an antagonist of the TOR kinase pathway. MafB is a large member of the Maf family of bZIP transcription factors controlling developmental processes in vertebrates. Regulation of MafB is critical, for example, during erythroid differentiation. A direct interaction between TIPRL and full length MafB and the bZIP domain of MafB was confirmed by in vitro interaction assays. TIPRL is localized throughout the whole cell and overlaps with MafB in the nucleus of HEK293 cells. Preliminary assays showed that TIPRL inhibits transcriptional activation mediated by MafB in HEK293 cells, although MafB shows a higher binding affinity to its target DNA relative to TIPRL in vitro. This evidence indicates that TIPRL may control MafB activity in vivo
Doutorado
Genetica Animal e Evolução
Doutor em Genetica e Biologia Molecular
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Hanschen, Erik R., Tara N. Marriage, Patrick J. Ferris, Takashi Hamaji, Atsushi Toyoda, Asao Fujiyama, Rafik Neme, et al. "The Gonium pectorale genome demonstrates co-option of cell cycle regulation during the evolution of multicellularity." NATURE PUBLISHING GROUP, 2016. http://hdl.handle.net/10150/614763.
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The transition to multicellularity has occurred numerous times in all domains of life, yet its initial steps are poorly understood. The volvocine green algae are a tractable system for understanding the genetic basis of multicellularity including the initial formation of cooperative cell groups. Here we report the genome sequence of the undifferentiated colonial alga, Gonium pectorale, where group formation evolved by co-option of the retinoblastoma cell cycle regulatory pathway. Significantly, expression of the Gonium retinoblastoma cell cycle regulator in unicellular Chlamydomonas causes it to become colonial. The presence of these changes in undifferentiated Gonium indicates extensive group-level adaptation during the initial step in the evolution of multicellularity. These results emphasize an early and formative step in the evolution of multicellularity, the evolution of cell cycle regulation, one that may shed light on the evolutionary history of other multicellular innovations and evolutionary transitions.
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Muhammad, Sayyed Auwn. "Probabilistic Modelling of Domain and Gene Evolution." Doctoral thesis, KTH, Beräkningsvetenskap och beräkningsteknik (CST), 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-191352.
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Phylogenetic inference relies heavily on statistical models that have been extended and refined over the past years into complex hierarchical models to capture the intricacies of evolutionary processes. The wealth of information in the form of fully sequenced genomes has led to the development of methods that are used to reconstruct the gene and species evolutionary histories in greater and more accurate detail. However, genes are composed of evolutionary conserved sequence segments called domains, and domains can also be affected by duplications, losses, and bifurcations implied by gene or species evolution. This thesis proposes an extension of evolutionary models, such as duplication-loss, rate, and substitution, that have previously been used to model gene evolution, to model the domain evolution. In this thesis, I am proposing DomainDLRS: a comprehensive, hierarchical Bayesian method, based on the DLRS model by Åkerborg et al., 2009, that models domain evolution as occurring inside the gene and species tree. The method incorporates a birth-death process to model the domain duplications and losses along with a domain sequence evolution model with a relaxed molecular clock assumption. The method employs a variant of Markov Chain Monte Carlo technique called, Grouped Independence Metropolis-Hastings for the estimation of posterior distribution over domain and gene trees. By using this method, we performed analyses of Zinc-Finger and PRDM9 gene families, which provides an interesting insight of domain evolution. Finally, a synteny-aware approach for gene homology inference, called GenFamClust, is proposed that uses similarity and gene neighbourhood conservation to improve the homology inference. We evaluated the accuracy of our method on synthetic and two biological datasets consisting of Eukaryotes and Fungal species. Our results show that the use of synteny with similarity is providing a significant improvement in homology inference.QC 20160904
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Wiley, Jesse Carey. "Familial Alzheimer's disease mutations decrease gamma-secretase processing of beta amyloid precurson [sic] protein /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/4985.
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Häusler, Lars Christian. "Aktivierung von GTPasen der Rho-Familie." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972269673.
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Simmonds, Rachel Elizabeth. "Protein S deficiency and familial thrombophilia." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267993.
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Kemen, Ariane Christiane. "RTP1p, eine neue Familie amyloid-ähnlicher Proteine." [S.l. : s.n.], 2006. http://nbn-resolving.de/urn:nbn:de:bsz:352-opus-31486.
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Reid, A. J. "Exploring the function and evolution of proteins using domain families." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/16310/.
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Proteins are frequently composed of multiple domains which fold independently. These are often evolutionarily distinct units which can be adapted and reused in other proteins. The classification of protein domains into evolutionary families facilitates the study of their evolution and function. In this thesis such classifications are used firstly to examine methods for identifying evolutionary relationships (homology) between protein domains. Secondly a specific approach for predicting their function is developed. Lastly they are used in studying the evolution of protein complexes. Tools for identifying evolutionary relationships between proteins are central to computational biology. They aid in classifying families of proteins, giving clues about the function of proteins and the study of molecular evolution. The first chapter of this thesis concerns the effectiveness of cutting edge methods in identifying evolutionary relationships between protein domains. The identification of evolutionary relationships between proteins can give clues as to their function. The second chapter of this thesis concerns the development of a method to identify proteins involved in the same biological process. This method is based on the concept of domain fusion whereby pairs of proteins from one organism with a concerted function are sometimes found fused into single proteins in a different organism. Using protein domain classifications it is possible to identify these relationships. Most proteins do not act in isolation but carry out their function by binding to other proteins in complexes; little is understood about the evolution of such complexes. In the third chapter of this thesis the evolution of complexes is examined in two representative model organisms using protein domain families. In this work, protein domain superfamilies allow distantly related parts of complexes to be identified in order to determine how homologous units are reused.
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Fauré, Julien. "Régulation des GTPases de la famille RHO par RHO-GDI." Université Joseph Fourier (Grenoble), 1999. http://www.theses.fr/1999GRE10006.
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Les membres de la famille RHO de GTPpases monomériques sont des interrupteurs moléculaires impliqués dans la transduction de nombreux signaux aboutissant notamment à la motilité cellulaire et à la transcription de gènes. Notre travail a porté sur le complexe formé entre la protéine G RHO et RHO-GDI, son régulateur naturel. Les deux protéines sont associées dans le cytosol mais il est nécessaire qu'elles soient séparées pour que RHO puisse exercer sa fonction. Nous nous sommes intéressés aux stimuli permettant d'activer leur protéine G à partir de son complexe avec RHO-GDI. Nous avons d'abord mis au point dans un système d'expression eucaryote la production de complexes formés in vivo entre les GTPases de la famille RHO et RHO-GDI. La purification de ces complexes a abouti à la production de cristaux et devrait permettre l'étude de leurs structures tridimensionnelles. Nous avons utilisé ces complexes pour étudier l'effet des phosphoïnositides sur l'état d'association de RHO avec RHO-GDI. Nous avons montré que ces lipides induisaient une conformation pré-activée du complexe, sans toutefois dissocier les deux partenaires. La méthode double-hybride nous a permis de cloner par interaction avec RHO-GDI l'ensemble des membres de la famille RHO ainsi que plusieurs régulateurs potentiels. Cette methode a ensuite servi à étudier les zones de RHO susceptibles d'interagir avec RHO-GDI grâce à la production de mutants de RHOA. L'interaction entre la GTPase RHO et RHO-GDI met en oeuvre un résidu isoprène lié à l'extrémité c-terminale de RHO. Les mutants de RHOA ne portant pas ce résidu sont cependant toujours capables d'interagir avec RHO-GDI, vraissemblablement grâce à la zone d'insertion de RHO. Enfin, une technique d'overlay a été utilisée pour mettre en évidence des partenaires membranaires du complexe RHO/RHO-GDI activé par les phosphoïnositides. Une protéine de 32kda, lâchement attachée à la membrane, a ainsi été isolée comme régulateur potentiel du complexe RHO/RHO-GDI.
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Ritter, Brigitte. "Isolierung neuer PACSIN-Isoformen und funktionale Charakterisierung der Protein-Familie." [S.l. : s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=962715360.
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Möhrlen, Frank. "Analyse der Struktur, Funktion und Evolution der Astacin-Protein-Familie." [S.l. : s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=965165582.
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Hajjar, Christine. "Etude fonctionnelle du coeur catalytique membranaire d'enzymes de la famille NOX : Identification de la première NADPH oxydase procaryote." Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENV032.
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La famille des NADPH oxydases est constituée de complexes multi protéiques, dont un des composants est la sous unité catalytique NOX. Il s'agit de protéine transmembranaire qui assure le transport des électrons à travers la membrane, à partir d'un donneur d'électrons, le NADPH, à un accepteur final, l'oxygène moléculaire. Il en résulte la production de superoxydes, précurseur d'espèces réactives de l'oxygène. Les NOX sont impliquées dans divers processus physiologiques et pathologiques qui les ont placés au rang des cibles thérapeutiques à forte valeur ajoutée.Les NOX sont reportées comme des protéines membranaires propres aux eucaryotes supérieures. Ainsi toutes les données fonctionnelles disponibles pour cette famille d'enzyme, ont été le fruit des études structure-fonction et de données putatives indirectes. D'où l'idée et l'intérêt d'identifier chez les procaryotes des candidats homologues aux Nox eucaryotes et susceptibles d'être de bons modèles pour des études structurales. En se servant d'outils bio-informatiques, nous avons définis des signatures de séquences propres aux NOX et avons identifié chez les procaryotes des centaines de séquences homologues. SpNox de chez Streptococcus Pneumoniae, a été sélectionnée et surexprimée chez E. Coli. SpNox a été purifiée et a fait l'objet d'une caractérisation fonctionnelle et biochimique approfondie. Au vue des résultats obtenus, SpNox se rapproche de part ses propriétés structurales et mechanistiques des NOX eucaryotes. Ainsi elle se présente comme le premier modèle procaryote de protéine NOX. Les premiers cristaux de cette famille de protéines ont été obtenus et son rôle in vivo reste à exploiter.En parallèle à l'approche procaryote, nous avons mené une étude structure-fonction sur la protéine NOX2 des neutrophiles PLB-985. Deux arginines conservées chez toutes les NOX eucaryotes ont été sélectionnées et leur rôle a été étudié par mutagenèse dirigée. Apres évaluation des propriétés enzymatiques des mutants NOX2, nous avons pu identifier l'arginine 513 comme étant impliquée dans la spécificité de NOX2 vis a vis du NADPH. Ces résultats nous ont permis de proposer une nouvelle orientation du NADPH dans son site d'ancrage à la protéine NOX2The NADPH oxidase complex was the first identified example of a system that generates reactive oxygen species in a dedicated manner. NOX are proteins involved in the transmembrane transfer of electrons to the molecular oxygen, resulting in the production of superoxides. In addition to ROS related damages, deregulation of Nox-dependant ROS production induces pathological consequences. Accordingly, the Nox family became a potential drug target, making the understanding of their function at molecular basis crucial.In the literature, it has always been reported that Nox proteins exist only in eukaryotes. Since eukaryotic membrane proteins have proven to be difficult to study, all the data available on Nox enzymes are obtained from putative assignments or structure-function studies.In our project, to overcome the difficulty of working on eukaryotic membrane proteins, we used an original approach based on bioinformatics tools. Through using specific filters and a novel program, we were able to identify hundreds of prokaryotic candidates. Among them, we selected SpNox, as a prokaryotic model from Streptococcus Pneumoniae. We have developed its expression in E. Coli as well as a multistep purification scheme. We also conducted an extensive enzymatic and mechanistic characterization of the purified enzyme. Our data support a strong structural and functional homology with known NOX enzymes. Finally, crystallization trials are performed leading to first crystals ever obtained for this family of protein. The understanding of Nox's physiological function in bacteria remains to investigate.In parallel to the prokaryotic approach, a structure-function study was conducted on the human model NOX2 in the PLB-985 neutrophils. Conserved arginines among eukaryotic Nox sequences were selected. Site directed mutagenesis followed by activity tests, lead us to identify a crucial role for arginine 513. It is implicated in the specificity towards NADPH as an electron donor for NOX2. With these data, we were able to suggest a new orientation of the NADPH, notably the phosphate moiety, in the binding site
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Burhenne, Nicole. "Protein-Protein-Wechselwirkungen innerhalb der T1R-Familie der Umami- und Süss-Rezeptoren aus Rattus norvegicus (Berkenhout, 1769)." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=96962025X.
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Fleming, James Frederick. "Concerning the evolution of opsin proteins, and the relationships between the families therein." Thesis, University of Bristol, 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.761215.
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Goers, Emily Sarah Marie 1981. "The muscleblind protein family's RNA sequence elements, structural elements and novel binding sites defined through SELEX." Thesis, University of Oregon, 2008. http://hdl.handle.net/1794/9173.
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xv, 106 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number.Myotonic Dystrophy type I (DM1) is caused by muscleblind protein sequestration to aberrantly expanded CUG repeats. When muscleblind is sequestered it can no longer fulfill its role as an alternative splicing regulator, leading to mis-splicing events in both humans and Drosophila . The muscleblind protein family's RNA binding specificity has been minimally characterized. Only one pre-mRNA target in humans, cardiac troponin T (cTNT), has a known MBNL1 binding site. In order to understand muscleblind's RNA binding specificity and identify a consensus binding motif, systematic evolution of ligands by exponential enrichment (SELEX) was performed on both the Drosophila muscleblind protein, Mbl, and the human ortholog, MBNL1. Drosophila has provided a useful model for studying the disease mechanism of DM1. Studies of Mbl's RNA binding specificity to CUG repeats concluded that replacing the U-U mismatches with different pyrimidine-pyrimidine mismatches was tolerated, but no other mutations were. To understand Mbl's RNA binding specificity, SELEX was performed. After 6 rounds, several sequences were identified that bound with high affinity, all containing the 5'-AGUCU-3' consensus motif. One sequence, SELEX RNA 20 was analyzed further. In addition to the guanosine in the consensus motif of SELEX RNA 20, two other guanosines were shown to be protected by Mbl in a footprinting assay, indicating that Mbl has a strong preference for binding guanosine. Also, two "tail" regions of SELEX RNA 20 were shown to be single stranded and required for binding by Mbl. These results indicate that Mbl is a highly specific RNA binding protein with preference for both single and double stranded guanosine-rich regions. A doped SELEX was performed on MBNL1's binding site from the cTNT pre-mRNA to determine which sequences and structural aspects were important for recognition by MBNL1. Pool 5 RNA sequences bound with high affinity, and the motif 5'-YGCUU-3' was selected. This motif was then used to identify new MBNL1 binding sites in pre-mRNAs regulated by MBNL1, SERCA1 and MBNL1. The identification of this motif and two new MBNL1 sites provide insight into MBNL1-mediated alternative splicing. This dissertation includes both my previously published co-authored material and my unpublished co-authored material.
Adviser: J. Andrew Berglund
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Schuch, Ilaine. "Perfil socioeconomico e alimentar das familias indigenas Kaingang de Guarita-RS." [s.n.], 2001. http://repositorio.unicamp.br/jspui/handle/REPOSIP/254937.
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Orientador: Maria Antonia Martins GaleazziDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia de Alimentos
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Resumo: Este trabalho teve como objetivo caracterizar a situação alimentar de uma amostra de famílias da reserva indígena de Guarita no estado do Rio Grande do Sul. Utilizou-se a metodologia desenvolvida por Galeazzi para inquérito de consumo familiar de alimentos. Adicionalmente, fez-se um levantamento de dados socioeconômicos, demográficos, da infra-estrutura e do saneamento básico bem como a situação quanto à utilização de políticas da área da alimentação e nutrição em uma amostra de 92 famílias. Após análise descritiva das variáveis, selecionou-se aquelas que melhor poderiam explicar as diferenças entre as famílias com menor ou maior consumo de calorias, utilizando-se para tanto o teste Pearson Chi-Square, sendo que o nível de significância determinado foi de 5%. Os resultados mostram que as famílias são numerosas, formadas majoritariamente por pessoas jovens. A maioria das pessoas ocupadas desenvolvem atividades na agricultura. A Cesta Básica de alimentos não atende as necessidades nutricionais. A atividade agrícola concentra-se nos seguintes produtos: milho, feijão, mandioca e batata-doce. A análise do consumo revelou que a média de calorias consumidas é de 2.115,55. No entanto 30,4% das famílias não atingem 80% do consumo de calorias em relação às necessidades, estando estas em situação de risco nutricional. A contribuição relativa da proteína no consumo calórico total é de 10,6%, sendo esta em maior parte de origem vegetal. Quanto ao consumo de vitaminas e sais minerais, mais de 90% das famílias pesquisadas não atingem 80% de adequação em relação as necessidades de cálcio e vitamina A, sendo também insuficientes para maioria das famílias o consumo de ferro, tiamina, riboflavina, niacina e vitamina C. O consumo de sal teve uma associação significativa com a hipertensão auto-referida (significância ao nível de 1%)
Abstract: This study aimed to characterize the nutritional situation of a sample of households in the Indian reservation of Guarita in the state of Rio Grande do Sul The method was developed by Galeazzi for investigation of household consumption of food. Additionally, it was a survey of socioeconomic data, demographic, infrastructure and sanitation and the state policies on the use of the area of food and nutrition in a sample of 92 families. After descriptive analysis of the variables selected to be those that could better explain the differences between families with lower or higher consumption of calories, using the test for both Pearson Chi-Square, where the level of significance was determined by 5% . The results show that families are numerous, trained mainly by young people. Most people are employed in farming activities. The basic basket of food does not meet the nutritional needs. The agricultural activity is concentrated in the following products: corn, beans, cassava and sweet potatoes. The analysis showed that the average consumption of calories consumed is to 2115.55. However 30.4% of households do not reach 80% of the consumption of calories in relation to needs, these are at nutritional risk. The relative contribution of the protein in total calorie intake is 10.6%, being in most of plant origin. As for the consumption of vitamins and minerals, over 90% of households surveyed did not reach 80% of suitability for the needs of calcium and vitamin A, is also insufficient for most families the consumption of iron, thiamine, riboflavin, niacin and vitamin C. The consumption of salt has had a significant association with self-reported hypertension (significance at 1%)
Mestrado
Nutrição Aplicada a Tecnologia de Alimentos
Mestre em Alimentos e Nutrição