| Autor: |
Jonathan D. Taylor, Nathalie Barrett, Sergio Martinez Cuesta, Katelyn Cassidy, Fiona Pachl, James Dodgson, Radhika Patel, Tuula M. Eriksson, Aidan Riley, Matthew Burrell, Christin Bauer, D. Gareth Rees, Raffaello Cimbro, Andrew X. Zhang, Ralph R. Minter, James Hunt, Sandrine Legg |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Communications Biology, Vol 7, Iss 1, Pp 1-17 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2399-3642 |
| DOI: |
10.1038/s42003-024-06803-4 |
| Popis: |
Abstract Proteins can be targeted for degradation by engineering biomolecules that direct them to the eukaryotic ubiquitination machinery. For instance, the fusion of an E3 ubiquitin ligase to a suitable target binding domain creates a ‘biological Proteolysis-Targeting Chimera’ (bioPROTAC). Here we employ an analogous approach where the target protein is recruited directly to a human E2 ubiquitin-conjugating enzyme via an attached target binding domain. Through rational design and screening we develop E2 bioPROTACs that induce the degradation of the human intracellular proteins SHP2 and KRAS. Using global proteomics, we characterise the target-specific and wider effects of E2 vs. VHL-based fusions. Taking SHP2 as a model target, we also employ a route to bioPROTAC discovery based on protein display libraries, yielding a degrader with comparatively weak affinity capable of suppressing SHP2-mediated signalling. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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