Description du projet
Mieux comprendre l’absorption cellulaire de la choline au niveau moléculaire
La choline est un constituant essentiel de nombreux phospholipides de la membrane cellulaire et de neurotransmetteurs comme l’acétylcholine. Dans les cellules eucaryotes, l’absorption transmembranaire de la choline fait intervenir la famille des protéines «semblables aux transporteurs de choline» (en anglais: choline transporter-like, CTL), mais elle est mal caractérisée. L’objectif principal du projet CTL, financé par l’UE, consiste à combler cette lacune scientifique et à étudier la fonction des protéines CTL. En combinant biologie structurelle et techniques de caractérisation biochimique, les scientifiques décrypteront le mécanisme moléculaire de l’absorption cellulaire de la choline. Étant donné que les protéines CTL sont impliquées dans diverses maladies, les résultats du projet prépareront le terrain pour de futures études pharmacologiques.
Objectif
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.
Champ scientifique
- natural sciencesearth and related environmental sciencesgeologymineralogycrystallography
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesmolecular biologystructural biology
Programme(s)
Régime de financement
MSCA-IF-EF-ST - Standard EFCoordinateur
8000 Aarhus C
Danemark