Molecular dynamics simulations on the Tre1 G protein-coupled receptor: Exploring the role of the arginine of the NRY motif in Tre1 structure

Abstract Background: The arginine of the D/E/NRY motif in Rhodopsin family G protein-coupled receptors (GPCRs) is conserved in 96% of these proteins. In some GPCRs, this arginine in transmembrane 3 can form a salt bridge with an aspartic acid or glutamic acid in transmembrane 6. The Drosophila melanogaster GPCR Trapped in endoderm-1 (Tre1) is required for normal primordial germ cell migration. In a mutant form of the protein, Tre1sctt, eight amino acids RYILIACH are missing, resulting in a severe disruption of primordial germ cell development. The impact of the loss of these amino acids on Tre1 structure is unknown. Since the missing amino acids in Tre1sctt include the arginine that is part of the D/E/NRY motif in Tre1, molecular dynamics simulations were performed to explore the hypothesis that these amino acids are involved in salt bridge formation and help maintain Tre1 structure. Results: Structural predictions of wild type Tre1 (Tre1+) and Tre1sctt were subjected to over 250 ns of molecular dynamics simulations. The ability of the model systems to form a salt bridge between the arginine of the D/E/NRY motif and an aspartic acid residue in transmembrane 6 was analyzed. The results indicate that a stable salt bridge can form in the Tre1+ systems and a weak salt bridge or no salt bridge, using an alternative arginine, is likely in the Tre1sctt systems. Conclusions: The weak salt bridge or lack of a salt bridge in the Tre1sctt systems could be one possible explanation for the disrupted function of Tre1sctt in primordial germ cell migration. These results provide a framework for studying the importance of the arginine of the D/E/NRY motif in the structure and function of other GPCRs that are involved in cell migration, such as CXCR4 in the mouse, zebrafish, and chicken

Structure-function analyses of the Tre1 G protein-coupled receptor

Cell migration is a process that is essential to animals during their entire lifetime and improper cell migration is implicated in diseased states such as cancer. Primordial germ cell migration in Drosophila melanogaster is an excellent model to study cell migration. The movements of Drosophila primordial germ cells are well documented and some of the molecules involved have been identified. The G protein-coupled receptor (GPCR) trapped in endoderm-1 (tre1) is one of the first genes involved in primordial germ cell migration. The work in this dissertation focuses on the GPCR Tre1, the roles of Tre1 in Drosophila germ cell migration, and how Tre1\u27s structure relates to its function. Chapter 2 describes the mutant allele of tre1, tre1sctt, and the molecular basis for its phenotype. Chapter 3 discusses the work done to dissect the similarity in phenotypes of tre1sctt mutant embryos and embryos lacking wunen and wunen2, two lipid phosphate phosphatases. Chapter 4 reports work done to investigate the structural differences between wild-type Tre1 and the mutant protein, Tre1sctt, to better understand the function of Tre1 in primordial germ cell migration

ICT-Systeme zur Verbesserung der Gesundheitsversorgung in den Gesundheitssystemen der afrikanischen Entwicklungsländer. : Fallstudien: Benin

Vergleicht man, die verschiedenen afrikanischen Gesundheitssysteme mit- und untereinander mit Hilfe der Case Study Forschungsmethodologie, so ergibt sich eine große Ähnlichkeit in vielen Bereichen, wie z. B. Alltagsprobleme, Struktur und Organisation des Sektors, etc. (Kapitel 3). Dieser Teil der vorliegenden Arbeit fokussiert auf die Struktur, die Organisation und die Alltagsprobleme im Gesundheitssystem in Benin (Kapitel 2). Insbesondere wurde die Gesundheitspolitik, deren Gesetze und Verordnungen, und die Finanzierung des Gesundheitssystems sowie der aktuelle Stand der Technik und der technischen Infrastruktur des Landes untersucht. Ferner ist der Nutzungsgrad von ICT-Systemen (engl. Information and Communication Technologies) ermittelt worden. Die Untersuchungsergebnisse werden ausführlich besprochen und analysiert, und es wird ein Fazit gezogen. Bei den Untersuchungen und der Analyse der verschiedenen Ergebnisse sind alle Akteure des Gesundheitssystems in Benin berücksichtigt worden. Die Alltagsprobleme sind je nach Akteur im System unterschiedlich, und sind deshalb unter verschiedenen Aspekten untersucht und analysiert worden