H2020Индивидуална стипендия2020–2022

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

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-05-01 → 2022-04-30
Финансиране от ЕС: 219 312 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Протеините от семейството CTL транспортират холин – вещество, необходимо за изграждане на мозъка и нервната система. Разбирането на техните структура и функция помага да се разберат процеси при рак, стареене и болест на Алцхаймер.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

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

Choline is an essential nutrient for the human body with a critical importance for the fetal development of the brain, the nervous system and metabolism. It is a precursor in the synthesis of membrane phospholipids, the neurotransmitter acetylcholine and the methyl donor betaine. In order to be available for the human body it needs to be transported through the plasma membrane by specialized proteins, called membrane transporters. Transmembrane uptake of choline is the essential, but still enigmatic, first step in choline metabolism in the cell. Furthermore, uptake and cellular homeostasis of choline is affected in several diseases (e.g. Alzheimer, cardiovascular disease, fetal alcohol syndrome), brain ischemic events, aging and cancer; underlining its importance for human health. The choline transporter-like (CTL) family forms a unique class of membrane transporters with five family members, that facilitate the majority of choline uptake in all eukaryotes. With no direct homologies to other transporter families, protein structures, especially with bound substrate, are of utmost importance to understand how this enigmatic transporter class facilitates substrate transport. Therefore, the overall objectives of this project were the structural, functional and biochemical characterization of CTL proteins.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

AARHUS UNIVERSITET · Aarhus CКоординаторДания