Target protein localization and its impact on PROTAC-mediated degradation

Luke M. Simpson, Lorraine Glennie, Abigail Brewer, Jin-Feng Zhao, Jennifer Crooks, Natalia Shpiro, Gopal P. Sapkota (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)
122 Downloads (Pure)


Proteolysis-targeting chimeras (PROTACs) bring a protein of interest (POI) into spatial proximity of an E3 ubiquitin ligase, promoting POI ubiquitylation and proteasomal degradation. PROTACs rely on endogenous cellular machinery to mediate POI degradation, therefore the subcellular location of the POI and access to the E3 ligase being recruited potentially impacts PROTAC efficacy. To interrogate whether the subcellular context of the POI influences PROTAC-mediated degradation, we expressed either Halo or FKBP12F36V (dTAG) constructs consisting of varying localization signals and tested the efficacy of their degradation by von Hippel-Lindau (VHL)- or cereblon (CRBN)-recruiting PROTACs targeting either Halo or dTAG. POIs were localized to the nucleus, cytoplasm, outer mitochondrial membrane, endoplasmic reticulum, Golgi, peroxisome or lysosome. Differentially localized Halo or FKBP12F36V proteins displayed varying levels of degradation using the same respective PROTACs, suggesting therefore that the subcellular context of the POI can influence the efficacy of PROTAC-mediated POI degradation.

Original languageEnglish
Pages (from-to)1482-1504.e7
Number of pages23
JournalCell Chemical Biology
Issue number10
Early online date7 Sept 2022
Publication statusPublished - Oct 2022


  • proteolysis-targeting chimera (PROTAC)
  • Targeted protein degradation (TPD)
  • protein localization
  • degrader
  • dTAG
  • Halo
  • VHL
  • cereblon
  • CRBN
  • E3
  • HiBiT
  • targeted protein degradation (TPD)

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmacology


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