H2020Индивидуална стипендия2021–2023

TFNup · Molecular, Structural, and Functional Studies of Leukemia-Associated Transcription Factor-Nucleoporin Fusion Proteins

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

Период: 2021-09-01 → 2023-08-31
Финансиране от ЕС: 174 806 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Безоформените протеини, като например NUP98, се изследват чрез нови методи за изображения, за да се разбере как се движат и групират в живите клетки. Това е важно, тъй като над 30% от човешките протеини са такива и влияят върху здравето и болестите.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Molecular, Structural, and Functional Studies of Leukemia-Associated Transcription Factor-Nucleoporin Fusion Proteins

The TFNup project aimed to tackle a fundamental challenge in biology—the study of intrinsically disordered proteins (IDPs). IDPs lack a fixed 3D structure, making them elusive subjects for scientific inquiry. However, their roles in cellular processes, particularly in health and disease, are of immense importance. The overarching goal was to develop innovative biochemical and biomolecular imaging tools that provide high-resolution insights into the plasticity of IDPs, particularly in living cells. In addition, the project aimed to shed light on the phase separation of IDPs that lead to the formation of larger protein assemblies often implicated in diseases. The project specifically focused on the molecular behaviors of an intrinsically disordered FG-rich nucleoporin (NUP98). Using the newly developed tools, the researchers measured the conformations and dynamics of NUP98 in live cells, even within functional nuclear pore complexes. This study pioneered the measurement of IDP conformations and dynamics in a nanosized object or biomolecular condensates inside cells. The project's significance lies in its potential to transform our understanding of molecular and cell biology. With over 30% of human proteins consisting of IDPs, this project has opened new avenues to unravel the complex relationships between disorder and function within cells.

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

Цел на проекта

Nup98 is a mobile nucleoporin that localizes both at the nuclear pore complex and within the nucleus. Nup98 is frequently rearranged to form leukemogenic Nup98-fusion proteins with various partners. Nup98-HoxA9 (NHA9), a fusion between phenylalanine-glycine-rich (FG-rich) region of Nup98 and the homeobox transcription factor (TF) HoxA9, is one of the most frequent Nup98-fusion associated with acute myeloid leukemia. The physiological role of NHA9 in hematopoietic development has been gradually established in the past decade at the cellular level. However, the plasticity and the phase separation behavior of such intrinsically disordered proteins (IDPs) largely hinder our understanding of their functions in gene regulation at the molecular level. In this project, I will develop platform technologies that combine chemical biology, microfluidics, and high-resolved molecular imaging to study the structure and biophysical function of NHA9 in vitro and in cells, and open up a new pathway to unravel its role in gene dysregulation from molecular perspective. Firstly, I will dual-label NHA9 at specific sites using the cutting-edge genetic code expansion technology developed by the host laboratory, and characterize the plasticity of NHA9 in live cells using Fluorescence lifetime imaging (FLIM) based Förster resonance energy transfer (FRET) platform. Next, I will use my strengths in microfluidics to design a new platform for tracking the phase separation behaviors of NHA9 with high temporal resolution in vitro. Finally, I will fuse NHA9 with proximity-dependent biotin identification (BioID) tags, and visualize the dynamic interaction networks of NHA9 using super-resolution microscopy (SRM) in live cells. By integrating those interdisciplinary approaches, the proposed research would make a conceptual breakthrough in understanding the molecular mechanism of NHA9-driven leukemogenesis and may provide a rationale for the search of potential therapeutic approaches in the future.

Оригинален текст от CORDIS (на английски).

Участници

JOHANNES GUTENBERG-UNIVERSITAT MAINZ · MainzКоординаторГермания