Descrizione del progetto
Il ruolo delle interazioni tra proteina e metabolita nell’espressione genica
I segnali ambientali quali piccole molecole e metaboliti orientano in larga misura la fisiologia cellulare. Le proteine avvertono tali segni ambientali interagendo direttamente con queste molecole, innescando rapide variazioni delle attività proteiche come risposta. Tali interazioni allosteriche sono oggetto di un’indagine del progetto proteoRAGE, finanziato dall’UE. Il gruppo scientifico è interessato a comprendere il modo in cui queste interazioni possono controllare l’espressione genica. Tramite un nuovo approccio proteomico, il team intende studiare l’esito funzionale di interazioni specifiche tra proteina e metabolita a livello genomico, della struttura proteica e del fenotipo, fornendo importanti informazioni sulla loro modulazione.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
13125 Berlin
Germania