Related Experiment Video
Updated: Sep 29, 2025

Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation
Dhanusha A Nalawansha1, Ke Li1, John Hines1
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States.
Abstract:
Targeted protein degradation (TPD) by PROTACs is a promising strategy to control disease-causing protein levels within the cell. While TPD is emerging as an innovative drug discovery paradigm, there are currently only a limited number of E3 ligase:ligand pairs that are employed to induce protein degradation. Herein, we report a novel approach to induce protein degradation by hijacking a methyl reader:E3 ligase complex. L3MBTL3 is a methyl-lysine reader protein that binds to the Cul4DCAF5 E3 ligase complex and targets methylated proteins for proteasomal degradation. By co-opting this natural mechanism, we report the design and biological evaluation of L3MBTL3-recruiting PROTACs and demonstrate nuclear-specific degradation of FKBP12 and BRD2. We envision this as a generalizable approach to utilize other reader protein-associated E3 ligase complexes in PROTAC design to expand the E3 ligase toolbox and explore the full potential of TPD.
More Related Videos
Related Concept Videos
Regulation of Nuclear Protein Sorting
Nuclear Export of mRNA
Nonsense-mediated mRNA Decay
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Nuclear Export
NES are of three types- the canonical 10-residue long leucine-rich signal and other...
Nuclear Protein Sorting
Proteins targeted to the nucleus carry nuclear localization signals or NLS recognized by import receptors in the cytosol. Similarly, proteins with nuclear export signals are recognized by export receptors. Import and export receptors are...
Export of Misfolded Proteins out of the ER

