Projektbeschreibung
Molekularer Einblick in die Cholin-Aufnahme von Zellen
Cholin ist ein wichtiger Bestandteil vieler Zellmembran-Phospholipiden und Neurotransmitter wie zum Beispiel Acetylcholin. An der transmembranen Aufnahme von Cholin in eukaryotische Zellen ist die Cholin-Transporter-ähnliche Familie der Proteine beteiligt, sie ist aber schwach charakterisiert. Mit dem EU-finanzierten Projekt CTL soll in erster Linie diese wissenschaftliche Lücke geschlossen und die Funktion der Cholin-Transporter-ähnlichen Proteine untersucht werden. Mit einer Kombination aus Strukturbiologie und biochemischer Charakterisierungstechnik werden die Forschenden den molekularen Mechanismus der Cholin-Aufnahme von Zellen entschlüsseln. Angesichts der Tatsache, dass Cholin-Transporter-ähnliche Proteine bei verschiedenen Krankheiten eine Rolle spielen, werden die Ergebnisse des Projekts den Grundstein für zukünftige pharmakologische Studien legen.
Ziel
Choline is an essential nutrient necessary for the synthesis of the membrane lipids phosphatidylcholine and sphingomyelin that constitute over 50 % of the total lipid content in cellular membranes. It is the precursor for key metabolites such as the neurotransmitter acetylcholine and the osmolyte and methyl donor betaine. Transmembrane uptake of choline is the essential, but still enigmatic, first step in choline metabolism in the cell. Three groups of solute carriers have been identified in the transport of choline; CHT1, OCT and CTL (SLC5A7, SLC22, SLC44 in humans). While CHT1 and OCT perform specialized functions, the choline transporter-like (CTL) family facilitates the majority of choline uptake in all eukaryotes. Despite their clear physiological relevance, our knowledge of CTL family members is very limited, and there are no structures of choline transporters available. For this reason, knowledge on the molecular mechanism of cellular choline uptake is almost non-existent.
With this proposal, I will address this lack of data, and provide new and ground-breaking insights into the function of the CTL family members. I will elucidate the molecular mechanisms of substrate recognition and transport in the major eukaryotic choline uptake system through a combination of structural biology (X-ray crystallography and cryo-EM) and biochemical characterization. The project will focus on human CTL family members but will also include other eukaryotic CTL proteins. A structural framework on the CTL family will provide insight into a key metabolic uptake pathway present in all eukaryotes and will be a fundamental resource for further research. Furthermore, CTLs are implicated in several diseases, including cancer, and the proposed work on CTL proteins will allow for future pharmacological studies addressing these with great impact on society.
Wissenschaftliches Gebiet
- natural sciencesearth and related environmental sciencesgeologymineralogycrystallography
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesmolecular biologystructural biology
Programm/Programme
Thema/Themen
Aufforderung zur Vorschlagseinreichung
Andere Projekte für diesen Aufruf anzeigenFinanzierungsplan
MSCA-IF-EF-ST - Standard EFKoordinator
8000 Aarhus C
Dänemark