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CORDIS

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

Project description

Molecular insight into cellular uptake of choline

Choline is a key constituent of many cell membrane phospholipids and neurotransmitters such as acetylcholine. Transmembrane uptake of choline into eukaryotic cells involves the choline transporter-like (CTL) family of proteins, but it is poorly characterised. The key objective of the EU-funded CTL project is to bridge this scientific gap and investigate the function of CTL proteins. Through a combination of structural biology and biochemical characterisation techniques, scientists will decipher the molecular mechanism of cellular choline uptake. Given that CTL proteins are implicated in various diseases, the project's results will lay the foundation for future pharmacological studies.

Objective

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.

Coordinator

AARHUS UNIVERSITET
Net EU contribution
€ 219 312,00
Address
NORDRE RINGGADE 1
8000 Aarhus C
Denmark

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Region
Danmark Midtjylland Østjylland
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 219 312,00