Summary
While advanced molecular biology approaches provide insight on the role of proteins in cellular processes, their ability to freely modify proteins and control their functions when desired is limited, hindering the achievement of a detailed understanding of the cellular functions of numerous proteins. At the same time, chemical synthesis of proteins allows for unlimited protein design, enabling the preparation of unique protein analogues that are otherwise difficult or impossible to obtain. However, effective methods to introduce these designed proteins into cells are for the most part limited to simple systems. To monitor proteins cellular functions and fates in real time, and in order to answer currently unanswerable fundamental questions about the cellular roles of proteins, the fields of protein synthesis and cellular protein manipulation must be bridged by significant advances in methods for protein delivery and real-time activation. Here, we propose to develop a general approach for enabling considerably more detailed in-cell study of uniquely modified proteins by preparing proteins having the following features: 1) traceless cell delivery unit(s), 2) an activation unit for on-demand activation of protein function in the cell, and 3) a fluorescence probe for monitoring the state and the fate of the protein.
We will adopt this approach to shed light on the processes of ubiquitination and deubiquitination, which are critical cellular signals for many biological processes. We will employ our approach to study 1) the effect of inhibition of deubiquitinases in cancer. 2) Examining effect of phosphorylation on proteasomal degradation and on ubiquitin chain elongation. 3) Examining effect of covalent attachment of a known ligase ligand to a target protein on its degradation Moreover, which could trigger the development of new methods to modify the desired protein in cell by selective chemistries and so rationally promote their degradation.
We will adopt this approach to shed light on the processes of ubiquitination and deubiquitination, which are critical cellular signals for many biological processes. We will employ our approach to study 1) the effect of inhibition of deubiquitinases in cancer. 2) Examining effect of phosphorylation on proteasomal degradation and on ubiquitin chain elongation. 3) Examining effect of covalent attachment of a known ligase ligand to a target protein on its degradation Moreover, which could trigger the development of new methods to modify the desired protein in cell by selective chemistries and so rationally promote their degradation.
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| Web resources: | https://cordis.europa.eu/project/id/831783 |
| Start date: | 01-10-2019 |
| End date: | 30-09-2025 |
| Total budget - Public funding: | 2 500 000,00 Euro - 2 500 000,00 Euro |
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Original description
While advanced molecular biology approaches provide insight on the role of proteins in cellular processes, their ability to freely modify proteins and control their functions when desired is limited, hindering the achievement of a detailed understanding of the cellular functions of numerous proteins. At the same time, chemical synthesis of proteins allows for unlimited protein design, enabling the preparation of unique protein analogues that are otherwise difficult or impossible to obtain. However, effective methods to introduce these designed proteins into cells are for the most part limited to simple systems. To monitor proteins cellular functions and fates in real time, and in order to answer currently unanswerable fundamental questions about the cellular roles of proteins, the fields of protein synthesis and cellular protein manipulation must be bridged by significant advances in methods for protein delivery and real-time activation. Here, we propose to develop a general approach for enabling considerably more detailed in-cell study of uniquely modified proteins by preparing proteins having the following features: 1) traceless cell delivery unit(s), 2) an activation unit for on-demand activation of protein function in the cell, and 3) a fluorescence probe for monitoring the state and the fate of the protein.We will adopt this approach to shed light on the processes of ubiquitination and deubiquitination, which are critical cellular signals for many biological processes. We will employ our approach to study 1) the effect of inhibition of deubiquitinases in cancer. 2) Examining effect of phosphorylation on proteasomal degradation and on ubiquitin chain elongation. 3) Examining effect of covalent attachment of a known ligase ligand to a target protein on its degradation Moreover, which could trigger the development of new methods to modify the desired protein in cell by selective chemistries and so rationally promote their degradation.
Status
SIGNEDCall topic
ERC-2018-ADGUpdate Date
27-04-2024
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