Designed allosteric protein logic
Abstract The regulation of protein function by external or internal signals is one of the key features of living organisms. The ability to directly control the function of a selected protein would represent a valuable tool for regulating biological processes. Here, we present a generally applicable...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Cell Discovery |
| Online Access: | https://doi.org/10.1038/s41421-023-00635-y |
| _version_ | 1797350135159586816 |
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| author | Tjaša Plaper Estera Merljak Tina Fink Tadej Satler Ajasja Ljubetič Duško Lainšček Vid Jazbec Mojca Benčina Sintija Stevanoska Sašo Džeroski Roman Jerala |
| author_facet | Tjaša Plaper Estera Merljak Tina Fink Tadej Satler Ajasja Ljubetič Duško Lainšček Vid Jazbec Mojca Benčina Sintija Stevanoska Sašo Džeroski Roman Jerala |
| author_sort | Tjaša Plaper |
| collection | DOAJ |
| description | Abstract The regulation of protein function by external or internal signals is one of the key features of living organisms. The ability to directly control the function of a selected protein would represent a valuable tool for regulating biological processes. Here, we present a generally applicable regulation of proteins called INSRTR, based on inserting a peptide into a loop of a target protein that retains its function. We demonstrate the versatility and robustness of coiled-coil-mediated regulation, which enables designs for either inactivation or activation of selected protein functions, and implementation of two-input logic functions with rapid response in mammalian cells. The selection of insertion positions in tested proteins was facilitated by using a predictive machine learning model. We showcase the robustness of the INSRTR strategy on proteins with diverse folds and biological functions, including enzymes, signaling mediators, DNA binders, transcriptional regulators, reporters, and antibody domains implemented as chimeric antigen receptors in T cells. Our findings highlight the potential of INSRTR as a powerful tool for precise control of protein function, advancing our understanding of biological processes and developing biotechnological and therapeutic interventions. |
| first_indexed | 2024-03-08T12:40:24Z |
| format | Article |
| id | doaj.art-710274972bba4f1d86afcb8ef980b686 |
| institution | Directory Open Access Journal |
| issn | 2056-5968 |
| language | English |
| last_indexed | 2024-03-08T12:40:24Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Discovery |
| spelling | doaj.art-710274972bba4f1d86afcb8ef980b6862024-01-21T12:10:20ZengNature Publishing GroupCell Discovery2056-59682024-01-0110111510.1038/s41421-023-00635-yDesigned allosteric protein logicTjaša Plaper0Estera Merljak1Tina Fink2Tadej Satler3Ajasja Ljubetič4Duško Lainšček5Vid Jazbec6Mojca Benčina7Sintija Stevanoska8Sašo Džeroski9Roman Jerala10Department of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of Synthetic Biology and Immunology, National Institute of ChemistryDepartment of knowledge technologies, Jožef Stefan InstituteDepartment of knowledge technologies, Jožef Stefan InstituteDepartment of Synthetic Biology and Immunology, National Institute of ChemistryAbstract The regulation of protein function by external or internal signals is one of the key features of living organisms. The ability to directly control the function of a selected protein would represent a valuable tool for regulating biological processes. Here, we present a generally applicable regulation of proteins called INSRTR, based on inserting a peptide into a loop of a target protein that retains its function. We demonstrate the versatility and robustness of coiled-coil-mediated regulation, which enables designs for either inactivation or activation of selected protein functions, and implementation of two-input logic functions with rapid response in mammalian cells. The selection of insertion positions in tested proteins was facilitated by using a predictive machine learning model. We showcase the robustness of the INSRTR strategy on proteins with diverse folds and biological functions, including enzymes, signaling mediators, DNA binders, transcriptional regulators, reporters, and antibody domains implemented as chimeric antigen receptors in T cells. Our findings highlight the potential of INSRTR as a powerful tool for precise control of protein function, advancing our understanding of biological processes and developing biotechnological and therapeutic interventions.https://doi.org/10.1038/s41421-023-00635-y |
| spellingShingle | Tjaša Plaper Estera Merljak Tina Fink Tadej Satler Ajasja Ljubetič Duško Lainšček Vid Jazbec Mojca Benčina Sintija Stevanoska Sašo Džeroski Roman Jerala Designed allosteric protein logic Cell Discovery |
| title | Designed allosteric protein logic |
| title_full | Designed allosteric protein logic |
| title_fullStr | Designed allosteric protein logic |
| title_full_unstemmed | Designed allosteric protein logic |
| title_short | Designed allosteric protein logic |
| title_sort | designed allosteric protein logic |
| url | https://doi.org/10.1038/s41421-023-00635-y |
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