Description du projet
Le rôle des interactions entre les protéines et les métabolites dans l’expression génétique
Les indicateurs environnementaux, tels que les petites molécules et les métabolites, déterminent dans une large mesure la physiologie cellulaire. Les protéines détectent ces signaux environnementaux en interagissant directement avec ces molécules, ce qui déclenche des variations rapides des activités protéiques en tant que réponse. Ces interactions allostériques font l’objet des recherches du projet proteoRAGE, financé par l’UE. L’équipe scientifique a cherché à comprendre la manière dont ces interactions peuvent contrôler l’expression génétique. Grâce à une nouvelle approche protéomique, ils prévoient d’étudier les résultats fonctionnels d’interactions spécifiques entre les protéines et les métabolites à l’échelle du génome, de la structure protéique et du phénotype, ce qui apportera des informations significatives sur leur modulation.
Objectif
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.
Champ scientifique
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ERC-STG - Starting GrantInstitution d’accueil
13125 Berlin
Allemagne