Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
19 Sep 2024
19 Sep 2024
Historique:
received:
08
03
2024
accepted:
29
08
2024
medline:
20
9
2024
pubmed:
20
9
2024
entrez:
19
9
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39300128
doi: 10.1038/s42003-024-06803-4
pii: 10.1038/s42003-024-06803-4
doi:
Substances chimiques
Ubiquitin-Conjugating Enzymes
EC 2.3.2.23
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
KRAS protein, human
0
PTPN11 protein, human
EC 3.1.3.48
Recombinant Fusion Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1179Informations de copyright
© 2024. The Author(s).
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