Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizers
Preprint
Abstract
SUMMARY: Targeted protein degradation and stabilization are promising therapeutic modalities due to their potency and versatility. However, only few E3 ligases and deubiquitinases have been harnessed for this purpose. Moreover, there may be other protein classes that could be exploited for protein stabilization or degradation. Here, we used a proteome-scale platform to identify hundreds of human proteins that can promote the degradation or stabilization of a target protein in a proximity-dependent manner. This allowed us to comprehensively compare the activities of human E3s and deubiquitinases, characterize non-canonical protein degraders and stabilizers, and establish that effectors have vastly different activities against diverse targets. Notably, the top degraders were more potent against multiple therapeutically relevant targets than the currently used E3s CBRN and VHL. Our study provides a functional catalogue of effectors for targeted protein degradation and stabilization and highlights the potential of induced proximity screens for discovery of novel proximity-dependent protein modulators.Keywords
This publication has 138 references indexed in Scilit:
- Structural Basis for Cul3 Protein Assembly with the BTB-Kelch Family of E3 Ubiquitin LigasesJournal of Biological Chemistry, 2013
- The mechanism of OTUB1-mediated inhibition of ubiquitinationNature, 2012
- OTUB1 Co-opts Lys48-Linked Ubiquitin Recognition to Suppress E2 Enzyme FunctionMolecular Cell, 2012
- Global quantification of mammalian gene expression controlNature, 2011
- E3 ligase Rad18 promotes monoubiquitination rather than ubiquitin chain formation by E2 enzyme Rad6Proceedings of the National Academy of Sciences, 2011
- Single Domain Intracellular Antibodies from Diverse LibrariesJournal of Biological Chemistry, 2011
- Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14LJournal of Cell Biology, 2010
- Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2Proceedings of the National Academy of Sciences, 2010
- The E2 Ubiquitin-conjugating Enzymes Direct Polyubiquitination to Preferred LysinesJournal of Biological Chemistry, 2010
- Tumour prevention by a single antibody domain targeting the interaction of signal transduction proteins with RASThe EMBO Journal, 2007