Descripción del proyecto
El papel de las interacciones proteína-metabolito en la expresión genética
Las señales ambientales, como las moléculas y los metabolitos de pequeño tamaño, impulsan en gran medida la fisiología celular. Las proteínas perciben estas señales ambientales interactuando directamente con estas moléculas, y se desencadenan variaciones rápidas de la actividad de las proteínas como respuesta. El equipo científico del proyecto financiado con fondos europeos proteoRAGE, que se encarga de investigar estas interacciones alostéricas, está interesado en entender cómo dichas interacciones pueden controlar la expresión genética. A través de un novedoso enfoque proteómico, planea estudiar el resultado funcional de las interacciones específicas proteína-metabolito a nivel del genoma, la estructura de la proteína y el fenotipo, lo que proporcionará información importante sobre su modulación.
Objetivo
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.
Ámbito científico
Palabras clave
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
13125 Berlin
Alemania