Proteomics

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Targeted protein degradation using E2 ubiquitin-conjugating enzymes


ABSTRACT: Proteins can be targeted for degradation by using engineered molecular conjugates to enhance their interaction with 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 report an analogous approach where the target is recruited directly to an E2 ubiquitin-conjugating enzyme via an attached target binding domain. We demonstrate that E2 bioPROTACs can induce the degradation of the human proteins SHP2, KRAS and Human Antigen R (HuR). Taking advantage of both rational and unbiased combinatorial screening, we identified novel SHP2 degraders that possess unusually weak affinity. Finally, we explored the proteomic impact of E2 vs. E3 bioPROTACs to inform on their wider impact on the cellular proteome.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Fiona Pachl  

LAB HEAD: Andrew Zhang

PROVIDER: PXD041225 | Pride | 2024-09-23

REPOSITORIES: Pride

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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  ...[more]

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