SubsidieMeestersTranslation in cellular context: Elucidating function, organization and regulation with near-atomic models in whole cells
TransFORM aims to develop novel methods for in-cell structural biology to map ribosome dynamics and regulatory mechanisms in protein synthesis under various cellular conditions.
Projectdetails
Introduction
Translation – the fundamental process of protein synthesis catalyzed by ribosomes - has been extensively characterized from a biochemical, structural, and mechanistic perspective. However, how exactly the translation machinery operates as an interconnected system of millions of ribosomes in cells is poorly understood.
Ribosome Functionality
Within the cell, ribosomes associate with a multitude of regulatory proteins forming a variety of specialized complexes and distributing across cellular space in a manner that depends on cell state.
Key Questions
- What is the specific composition of those complexes, their significance, and their functional role?
- How are they defined and regulated by subcellular compartmentalization?
- How do they change in response to cellular stress?
TransFORM Synergy Team
Our TransFORM synergy team brings together experts in method development for in-cell structural biology and the biology of translation to allow us for the first time to attack these fundamental problems.
Method Development
Building on our prior achievements, we aim to synergistically develop novel methods of cryo-electron tomography with imaging across scales in conjunction with crosslinking mass spectrometry and integrative structural modeling for near-atomic structure determination directly in cells.
Research Objectives
TransFORM will determine the ribosome structural and functional states across the translation cycle in human cells, following distinct 40S, 80S, and disomal particles (80S+80S), in and out of polysomes and across different protein synthesis regimes.
Expected Outcomes
We will uncover structural and compositional changes and regulatory mechanisms across cellular space, in adaptation to perturbations by stressors and during viral infection. Our model systems will span from single cells to organoids.
Conclusion
TransFORM will provide a detailed and comprehensive in-cell map of the essential process of protein synthesis while delivering innovative methods for the next generation of in-cell structural biology.
Financiële details & Tijdlijn
Financiële details
| Subsidiebedrag | € 13.998.670 |
| Totale projectbegroting | € 13.998.670 |
Tijdlijn
| Startdatum | 1-2-2024 |
| Einddatum | 31-1-2030 |
| Subsidiejaar | 2024 |
Partners & Locaties
Projectpartners
- EUROPEAN MOLECULAR BIOLOGY LABORATORYpenvoerder
- JOHNS HOPKINS UNIVERSITY
- TECHNISCHE UNIVERSITAT BERLIN
Land(en)
Vergelijkbare projecten binnen European Research Council
| Project | Regeling | Bedrag | Jaar | Actie |
|---|---|---|---|---|
3-dimensional Organization and Functions of Translation in Organelle ProximityThis project aims to uncover the mechanisms linking translation regulation and organelle biogenesis using functional genomics and cryo-ET to map and understand proximal translation in eukaryotic cells. | ERC Starting... | € 1.999.838 | 2025 | Details |
Development of novel integrated sequencing methods to explore translation and its regulatory mechanisms in single cellsThis project aims to develop novel multi-omics approaches to quantify translation in single cells, integrating various regulatory mechanisms to enhance understanding of cellular heterogeneity. | ERC Advanced... | € 2.500.000 | 2023 | Details |
Stress-induced structural and organizational adaptations of the cellular translation machineryThis project aims to investigate how cellular strategies for maintaining protein homeostasis affect ribosome structure and organization under stress, using cryo-electron tomography for detailed insights relevant to neurodegenerative diseases. | ERC Starting... | € 1.498.832 | 2023 | Details |
Mechanisms of co-translational assembly of multi-protein complexesThis project aims to uncover the mechanisms of co-translational protein complex assembly using advanced techniques to enhance understanding of protein biogenesis and its implications for health and disease. | ERC Synergy ... | € 9.458.525 | 2023 | Details |
Deciphering co-translational protein folding, assembly and quality control pathways, in health and diseaseThis project aims to elucidate co-translational protein folding and degradation mechanisms to understand misfolding diseases and improve therapeutic strategies. | ERC Starting... | € 1.412.500 | 2022 | Details |
3-dimensional Organization and Functions of Translation in Organelle Proximity
This project aims to uncover the mechanisms linking translation regulation and organelle biogenesis using functional genomics and cryo-ET to map and understand proximal translation in eukaryotic cells.
Development of novel integrated sequencing methods to explore translation and its regulatory mechanisms in single cells
This project aims to develop novel multi-omics approaches to quantify translation in single cells, integrating various regulatory mechanisms to enhance understanding of cellular heterogeneity.
Stress-induced structural and organizational adaptations of the cellular translation machinery
This project aims to investigate how cellular strategies for maintaining protein homeostasis affect ribosome structure and organization under stress, using cryo-electron tomography for detailed insights relevant to neurodegenerative diseases.
Mechanisms of co-translational assembly of multi-protein complexes
This project aims to uncover the mechanisms of co-translational protein complex assembly using advanced techniques to enhance understanding of protein biogenesis and its implications for health and disease.
Deciphering co-translational protein folding, assembly and quality control pathways, in health and disease
This project aims to elucidate co-translational protein folding and degradation mechanisms to understand misfolding diseases and improve therapeutic strategies.