Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes

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.

Authors

Institutions

Publication Details

Journal
Communications Biology
Published
2024-09-19
DOI
https://doi.org/10.1038/s42003-024-06803-4
Citations
14
Primary Topic
Protein Degradation and Inhibitors
Type
article
Field-Weighted Citation Impact
3.27

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes

Sergio Martínez Cuesta, Christin Bauer, Raffaello Cimbro, Tuula M Eriksson et al.
14 citations
Communications Biology
Protein Degradation and Inhibitors
3.27
article

Targeted protein degradation using chimeric human E2 ubiquitin-conjugating enzymes

Sergio Martínez Cuesta, Christin Bauer, Raffaello Cimbro, Tuula M Eriksson, Nathalie Barrett, Sandrine Legg, Fiona Pachl, James Hunt, Radhika Patel, Katelyn Cassidy, Ralph Minter, D. Gareth Rees, Jonathan D. Taylor, Matthew Burrell, James Dodgson, Aidan Riley, Andrew X Zhang
article en
14 citations

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.

Communications BiologyVol. 7(1)
AstraZeneca (United Kingdom) (GB), AstraZeneca (South Korea) (KR), AstraZeneca (Australia) (AU), AstraZeneca (Singapore) (SG), AstraZeneca (Poland) (PL), AstraZeneca (United States) (US), AstraZeneca (Germany) (DE)
AstraZeneca
Zero hunger
Openalex Percentile: Top 7%
Protein Degradation and Inhibitors
3.27
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.