Site-specific combinatorial ubiquitination drives the targeted degradation of plasma membrane proteins
Olsson, N.; Gaun, A.; Villa, S.; Jackson, K.; Fitzgerald, M. E.; McAllister, F. E.; Stokoe, D.; Nile, A. H.; Bersuker, K.
Show abstract
Cullin-RING E3 ligases (CRLs) ubiquitinate their substrates by recruiting them to complexes containing ubiquitin-conjugating enzymes (UCEs). Ubiquitination proceeds through the transfer of ubiquitin from UCEs to substrate lysines, but the specificity of lysine ubiquitination has not been widely investigated in cells. In this study, we use global ubiquitination profiling to identify sites in the kinase domains of receptor tyrosine kinases (RTKs), EGFR and Her2, that undergo CRL-mediated ubiquitination in cells treated with heterobifunctional degrader molecules. We find that VHL- and Cereblon-dependent degraders trigger the ubiquitination of a common subset of accessible lysines. Using mutagenesis, we show that the number of available ubiquitination sites specifies the extent of RTK degradation. Furthermore, introduction of non-native sites mostly fails to rescue clearance of lysine-deficient RTK mutants. These results highlight the specificity with which UCEs ubiquitinate their substrates and suggest that the ubiquitination of multiple sites governs the efficacy of degraders targeting plasma membrane proteins.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation 95%
- Chemoproteomics reveals immunogenic and tumor-associated cell surface substrates of ectokinase CK2α 95%
- A Strategy to Assess the Cellular Activity of E3 Ligases against Neo-Substrates using Electrophilic Probes 94%
Similar papers in this journal
Similar papers in this journal
Similar papers in this journal
- Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions 95%
- Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger Cyclin K degradation 95%
- Identification of a conserved neutralizing epitope present on spike proteins from all highly pathogenic coronaviruses 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.