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Characterization of the molecular mechanism behind CTL - the major choline uptake system in eukaryotes

Descrizione del progetto

Informazioni molecolari sull’assorbimento cellulare della colina

La colina è un componente chiave di molti fosfolipidi della membrana cellulare e neurotrasmettitori quali l’acetilcolina. L’assorbimento transmembrana della colina nelle cellule eucariotiche coinvolge la famiglia di proteine simili al trasportatore di colina (CTL, Choline Transporter-Like) ma è scarsamente caratterizzata. L’obiettivo chiave del progetto CTL, finanziato dall’UE, è quello di colmare questo divario scientifico e studiare la funzione delle proteine CTL. Attraverso una combinazione di biologia strutturale e tecniche di caratterizzazione biochimica, gli scienziati decifreranno il meccanismo molecolare dell’assorbimento di colina cellulare. Considerando che le proteine CTL sono implicate in varie malattie, i risultati del progetto porranno le basi per futuri studi farmacologici.

Obiettivo

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.

Meccanismo di finanziamento

MSCA-IF-EF-ST - Standard EF

Coordinatore

AARHUS UNIVERSITET
Contribution nette de l'UE
€ 219 312,00
Indirizzo
NORDRE RINGGADE 1
8000 Aarhus C
Danimarca

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Regione
Danmark Midtjylland Østjylland
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 219 312,00