Project description
The role of protein–metabolite interactions in gene expression
Environmental signals such as small molecules and metabolites drive to a large extent cellular physiology. Proteins sense these environmental cues by directly interacting with these molecules, triggering rapid variations of protein activities as a response. These allosteric interactions are the subject of investigation of the EU-funded proteoRAGE project. The scientific team is interested to understand how these interactions may control gene expression. Through a novel proteomics approach, they plan to study the functional outcome of specific protein–metabolite interactions at the genome, protein structure and phenotype level, providing significant insight into their modulation.
Objective
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.
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Funding Scheme
ERC-STG - Starting GrantHost institution
13125 Berlin
Germany