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  3. Ubiquitin-specific proximity labeling for the identification of E3 ligase substrates

Ubiquitin-specific proximity labeling for the identification of E3 ligase substrates

  • Nat Chem Biol. 2024 Mar 21. doi: 10.1038/s41589-024-01590-9.
Hai-Tsang Huang 1 2 3,  Ryan J Lumpkin 4 5,  Ryan W Tsai 1,  Shuyao Su 1,  Xu Zhao 1,  Yuan Xiong 4 5,  James Chen 1,  Nada Mageed 4,  Katherine A Donovan 4 5,  Eric S Fischer 4 5,  William R Sellers 6 7 8
Affiliations

Affiliations

  • 1 Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3 Harvard Medical School, Boston, MA, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 6 Broad Institute of Harvard and MIT, Cambridge, MA, USA. wsellers@broadinstitute.org.
  • 7 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. wsellers@broadinstitute.org.
  • 8 Harvard Medical School, Boston, MA, USA. wsellers@broadinstitute.org.
PMID: 38514884 DOI: 10.1038/s41589-024-01590-9
Abstract

Protein ubiquitylation controls diverse processes within eukaryotic cells, including protein degradation, and is often dysregulated in disease. Moreover, small-molecule degraders that redirect ubiquitylation activities toward disease targets are an emerging and promising therapeutic class. Over 600 E3 ubiquitin ligases are expressed in humans, but their substrates remain largely elusive, necessitating the development of new methods for their discovery. Here we report the development of E3-substrate tagging by ubiquitin biotinylation (E-STUB), a ubiquitin-specific proximity labeling method that biotinylates ubiquitylated substrates in proximity to an E3 Ligase of interest. E-STUB accurately identifies the direct ubiquitylated targets of protein degraders, including collateral targets and ubiquitylation events that do not lead to substrate degradation. It also detects known substrates of E3 Ligase CRBN and VHL with high specificity. With the ability to elucidate proximal ubiquitylation events, E-STUB may facilitate the development of proximity-inducing therapeutics and act as a generalizable method for E3-substrate mapping.

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