A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ
Abstract Understanding how small molecules bind to specific protein complexes in living cells is critical to understanding their mechanism-of-action. Unbiased chemical biology strategies for direct readout of protein interactome remodelling by small molecules would provide advantages over target-foc...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-43507-5 |
| _version_ | 1797397882796507136 |
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| author | Andrew J. Tao Jiewei Jiang Gillian E. Gadbois Pavitra Goyal Bridget T. Boyle Elizabeth J. Mumby Samuel A. Myers Justin G. English Fleur M. Ferguson |
| author_facet | Andrew J. Tao Jiewei Jiang Gillian E. Gadbois Pavitra Goyal Bridget T. Boyle Elizabeth J. Mumby Samuel A. Myers Justin G. English Fleur M. Ferguson |
| author_sort | Andrew J. Tao |
| collection | DOAJ |
| description | Abstract Understanding how small molecules bind to specific protein complexes in living cells is critical to understanding their mechanism-of-action. Unbiased chemical biology strategies for direct readout of protein interactome remodelling by small molecules would provide advantages over target-focused approaches, including the ability to detect previously unknown ligand targets and complexes. However, there are few current methods for unbiased profiling of small molecule interactomes. To address this, we envisioned a technology that would combine the sensitivity and live-cell compatibility of proximity labelling coupled to mass spectrometry, with the specificity and unbiased nature of chemoproteomics. In this manuscript, we describe the BioTAC system, a small-molecule guided proximity labelling platform that can rapidly identify both direct and complexed small molecule binding proteins. We benchmark the system against µMap, photoaffinity labelling, affinity purification coupled to mass spectrometry and proximity labelling coupled to mass spectrometry datasets. We also apply the BioTAC system to provide interactome maps of Trametinib and analogues. The BioTAC system overcomes a limitation of current approaches and supports identification of both inhibitor bound and molecular glue bound complexes. |
| first_indexed | 2024-03-09T01:17:40Z |
| format | Article |
| id | doaj.art-7e60e12c82e148d7ba52ad726511fade |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-09T01:17:40Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-7e60e12c82e148d7ba52ad726511fade2023-12-10T12:23:47ZengNature PortfolioNature Communications2041-17232023-12-0114111110.1038/s41467-023-43507-5A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situAndrew J. Tao0Jiewei Jiang1Gillian E. Gadbois2Pavitra Goyal3Bridget T. Boyle4Elizabeth J. Mumby5Samuel A. Myers6Justin G. English7Fleur M. Ferguson8Department of Chemistry and Biochemistry, University of California San DiegoDepartment of Chemistry and Biochemistry, University of California San DiegoDepartment of Chemistry and Biochemistry, University of California San DiegoDepartment of Chemistry and Biochemistry, University of California San DiegoDepartment of Chemistry and Biochemistry, University of California San DiegoDepartment of Biochemistry, University of Utah School of MedicineLaboratory for Immunochemical Circuits, La Jolla Institute for ImmunologyDepartment of Biochemistry, University of Utah School of MedicineDepartment of Chemistry and Biochemistry, University of California San DiegoAbstract Understanding how small molecules bind to specific protein complexes in living cells is critical to understanding their mechanism-of-action. Unbiased chemical biology strategies for direct readout of protein interactome remodelling by small molecules would provide advantages over target-focused approaches, including the ability to detect previously unknown ligand targets and complexes. However, there are few current methods for unbiased profiling of small molecule interactomes. To address this, we envisioned a technology that would combine the sensitivity and live-cell compatibility of proximity labelling coupled to mass spectrometry, with the specificity and unbiased nature of chemoproteomics. In this manuscript, we describe the BioTAC system, a small-molecule guided proximity labelling platform that can rapidly identify both direct and complexed small molecule binding proteins. We benchmark the system against µMap, photoaffinity labelling, affinity purification coupled to mass spectrometry and proximity labelling coupled to mass spectrometry datasets. We also apply the BioTAC system to provide interactome maps of Trametinib and analogues. The BioTAC system overcomes a limitation of current approaches and supports identification of both inhibitor bound and molecular glue bound complexes.https://doi.org/10.1038/s41467-023-43507-5 |
| spellingShingle | Andrew J. Tao Jiewei Jiang Gillian E. Gadbois Pavitra Goyal Bridget T. Boyle Elizabeth J. Mumby Samuel A. Myers Justin G. English Fleur M. Ferguson A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ Nature Communications |
| title | A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ |
| title_full | A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ |
| title_fullStr | A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ |
| title_full_unstemmed | A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ |
| title_short | A biotin targeting chimera (BioTAC) system to map small molecule interactomes in situ |
| title_sort | biotin targeting chimera biotac system to map small molecule interactomes in situ |
| url | https://doi.org/10.1038/s41467-023-43507-5 |
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