Unravelling the pRotein Allosterome of Gene Expression

Projektinformationen

proteoRAGE

ID Finanzhilfevereinbarung: 948544

DOI

10.3030/948544

EK-Unterschriftsdatum 20 August 2020

Startdatum 1 Juli 2021

Enddatum 31 August 2027

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 684 594,00

EU-Beitrag

€ 1 684 594,00

Koordiniert durch

MAX DELBRUECK CENTRUM FUER MOLEKULARE MEDIZIN IN DER HELMHOLTZ-GEMEINSCHAFT (MDC)
Germany

Periodic Reporting for period 3 - proteoRAGE (Unravelling the pRotein Allosterome of Gene Expression)

Berichtszeitraum: 2024-07-01 bis 2025-12-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Proteins perform many of the chemical reactions essential to cell homeostasis, growth and proliferation. The most rapid and efficient mechanism to modulate protein activity is allosteric regulation, which depends on the direct binding between proteins and small-molecules. Since their intracellular concentration depends on environmental conditions, allosteric ligands can set responses of adaptation to the external environment independently on genetic factors. The lack of global streamlined methods to investigate allosteric mechanisms limits our current understanding of cellular physiology in health and disease. In this project we plan to elucidate how the complex network of interactions between small-molecules and proteins affects cellular responses. We will systematically measure protein structural changes produced by the binding of metabolites in the cell and which aspects of cellular activity they influence. This is important to understand the chemical reactions necessary for life and modulate them with drug molecules.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

In this project we set-up the methodological framework by showing that structural proteomics can be used to identify new drug targets in human cells. We also figured that analysis of global protein structural responses are more sensitive readouts than classical protein abundance measurements for interrogating activation of biological responses in cells and tissues (Mateus, et. al. MSB 2021). This establishes the methodological background for addressing the scientific questions proposed in this project.
We carried on highlighting the importance of small molecules in modulating intermolecular and intramolecular binding interfaces between multiple proteins (Ruwolt et. al. Current Opinion in structural biology 2023). We also investigated the contribution of post-translational gene regulation in explaining transcriptional memory in Saccharomyces cerevisiae. We showed that the protein subunits of the nuclear exosome (the TRAMP and the NNS complexes) are less active in primed conditions compared to naive conditions. This decrease in protein function is consistent with a relative increase in the expression of genes sensitive to the action of the nuclear exosome. Unexpectedly, there was also a relative decrease in factors involved in cytoplasmic decay. This suggests that changes in the cytoplasmic mRNA decay may contribute to modulate transcriptional memory in yeast (Li et. al. Nature Communications, 2023).
We have also presented a comprehensive workflow to perform structural proteomics experiments to discover proteins interacting with drugs or metabolite (Koudelka et. al. Molecular&Cellular Proteomics, 2025).

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

By the end of the project we will show how environmentally-driven interactions between proteins and metabolites are driving cell fate in homeostasis and during disease where protein translation and metabolic enzymes are involved.

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