Projektbeschreibung
Einfluss von Protein-Metabolit-Interaktionen auf die Genexpression
Umgebungssignale, die von kleinen Molekülen und Metaboliten generiert werden, sind wichtige Voraussetzungen für zellphysiologische Prozesse. Diese Signale werden von Proteinen erfasst, die direkt mit den Molekülen interagieren, sodass eine umgehende Anpassung von Proteinaktivitäten initiiert werden kann. Diese sogenannten allosterischen Interaktionen sind nun Forschungsthema des EU-finanzierten Projekts proteoRAGE, das sich mit möglichen Einflüssen solcher Wechselwirkungen auf die Genexpression befasst. Mit einem innovativen proteomischen Ansatz soll das funktionelle Ergebnis spezifischer Protein-Metabolit-Interaktionen auf Genom-, struktureller Protein- und Phänotypebene untersucht werden, um wichtige Einblicke in ihre Modulation zu gewinnen.
Ziel
Understanding how different environmental cues influence cellular physiology is critical but challenging. Small molecule metabolites such as nutrients and signalling molecules carry information about the external and internal state of the cell. Proteins sense these environmental signals through direct physical interactions with metabolites that trigger rapid variations of protein activities as response. Those events where protein and metabolites interact leading to functional consequences are called allosteric interactions. Allosteric interactions are classically studied in the context of enzymatic reactions, but much less is known regarding their potential ability to control gene expression. I propose to test the hypothesis that metabolites can, in some cases, bypass classical signaling pathways and act directly on gene expression. To address this question, I will study systematically the proteins that regulate gene expression (i.e. transcription and translation) and that can be directly activated (or inhibited) by interactions with metabolites. Building on my previous work studying metabolite-protein interactions using limited proteolysis, I will apply novel mass spectrometry-based proteomics approaches to investigate the gene expression allosterome. I will couple the measurement of structural changes caused by protein-metabolite interactions with their direct effects on chromatin accessibility and mRNA-protein associations. By measuring those effects in vivo, I will link allosteric interactions with gene expression activity. Finally, I will validate their functional role by integrating structural information with deep mutagenesis and cellular phenotyping in multiple environments. In summary, my research aims to establish a novel interdisciplinary approach to functionally characterize the complexity of the allosterome, to identify novel entry points for its modulation using small molecules and to refine our understanding of gene expression.
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
13125 Berlin
Deutschland