H2020Индивидуална стипендия2016–2018

MoTOR · Analysis of the “moonlighting” proteins in the mTOR-signalling pathway

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

Период: 2016-02-01 → 2018-01-31
Финансиране от ЕС: 171 461 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Протеините от пътя на mTOR регулират метаболизма, но някои от тях неочаквано се свързват и с РНК молекули. Разбирането на тази връзка помага при търсенето на нови мишени за лекарства срещу тумори, болест на Алцхаймер и метаболитни нарушения.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Analysis of the “moonlighting” proteins in the mTOR-signalling pathway

RNA is the language in which the genome talks. This smaller molecule carries pieces of messages to different effect places in the cell. The cell decorates the RNA molecules with numerous modifications and RNA binding proteins to regulate this information flow. The mTOR kinase is the control hub of metabolic regulation in the cell. The two complexes the mTOR kinase forms integrate the signal from the environment and inside the cell, make decisions, and communicate the decisions to other parts of the cell and thus influence a broad range of growth events. In general, the decisions that mTOR complexes take support cell growth and proliferation, and inhibit cell death. Impairment in these protein complexes is often observed in tumours, Alzheimer’s disease, and several metabolic disorders. Recent studies have shown that a series of mTOR related proteins were identified as non-canonical RNA binding proteins. This finding has shed light on the connection between the metabolic control hub mTOR kinase and the RNA molecules. What is striking though, unlike the classical RNA binding proteins, most of the proteins found here do not possess an RNA binding domain. Since the mechanism and biological function of this new interaction are unknown, these novel RNA binding proteins are named enigmRBPs (RNA binding proteins with enigmatic function). My project “MoTOR” aims to answer the question, why the mTOR related proteins bind to RNA and what is the biological function of this interaction. Every novel interaction provides new drug target, the results of this work could provide insights to discover or design new drugs. The first objective was to validate the candidate RNA binding proteins. The second objective was to study the confirmed RNA binding proteins and their function. The third objective was using the Next Generation Sequencing method to identify the interacting RNA of these candidates. The overall project has identified the ADP-ribosylation factor Arf1p and the FKBP12 homolog Fpr1p as bona fide RNA binding proteins. We further followed up Fpr1p and identified a point mutation in the protein that disrupts the interaction of Fpr1p to RNA. Interestingly, this mutation also displays various growth phenotype when the cell is treated with drugs. Using eCLIP, we could reveal that the species of RNA interacting Fpr1p is the transfer RNAs (tRNAs). Further functions of this protein will be studied in the future.

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

Цел на проекта

The mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase in eukaryotic organisms. mTOR is the catalytic subunit of two different complexes (mTORC1 and mTORC2), which differ by their subcellular localization and function. The mTORCs integrate the environmental and cellular signal and regulate a broad range of downstream growth events. Impaired regulation of mTOR was often observed in tumors, Alzheimer’s disease, several metabolic disorders, and is known to accelerate aging. Thus, the study of the mTOR pathway is of paramount importance for both fundamental biology and medicine. A tremendous amount of studies have been carried out to elucidate the regulatory role of mTOR in metabolism and diseases. Yet the detailed mechanism of the mTOR regulatory pathway remains to be completed. Recently, using the novel method “mRNA interactome capture”, the host laboratory identified proteins involved in the mTOR-signalling pathway that acts as RNA-binding proteins (RBPs) in yeast, mouse embryonic stem cells (mESC) and HeLa cells. This finding revealed a conserved and previously unrecognized function of the mTOR pathway with RNA being an important component of it. Here I propose a project aiming to unravel the biological function of RNAs and RBPs in the mTOR pathway. In this project, I will use the budding yeast Saccharomyces cerevisiae as a model system, and will identify the novel RNA binding domains (RBDs) of the RBPs. I will further investigate the network of the interacting RBPs and RNAs. This will elucidate the biological impact of the RNA-protein interactions in the mTOR pathway. I will carry out this interdisciplinary study using biochemical and genetic methods, as well as large-scale analysis. The datasets created in this study will open new perspectives on the mTOR regulatory pathway.

Оригинален текст от CORDIS (на английски).

Участници

EUROPEAN MOLECULAR BIOLOGY LABORATORY · HeidelbergКоординаторГермания