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

Descripción del proyecto

Datos moleculares sobre la absorción celular de colina

La colina es un componente esencial de muchos fosfolípidos de las membranas celulares. La absorción de colina a través de la membrana en las células eucariotas requiere la participación de la familia de proteínas transportadoras de colina (CTL, por sus siglas en inglés), pero no está adecuadamente caracterizada. El principal objetivo del proyecto CTL, financiado con fondos europeos, es cerrar esta brecha científica e investigar la función de las proteínas CTL. Los científicos descifrarán el mecanismo molecular de la absorción celular de colina a través de una combinación de técnicas de caracterización estructural biológica y bioquímica. Dado que las proteínas CTL están involucradas en diferentes enfermedades, los resultados del proyecto sentarán las bases para futuros estudios farmacológicos.

Objetivo

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.

Régimen de financiación

MSCA-IF-EF-ST - Standard EF

Coordinador

AARHUS UNIVERSITET
Aportación neta de la UEn
€ 219 312,00
Dirección
NORDRE RINGGADE 1
8000 Aarhus C
Dinamarca

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Región
Danmark Midtjylland Østjylland
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 219 312,00