Target protein localization and its impact on PROTAC-mediated degradation.
Cell Chem Biol
; 29(10): 1482-1504.e7, 2022 Oct 20.
Article
in En
| MEDLINE
| ID: mdl-36075213
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Tacrolimus Binding Protein 1A
/
Ubiquitin-Protein Ligases
Language:
En
Journal:
Cell Chem Biol
Year:
2022
Document type:
Article
Affiliation country:
United kingdom