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Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation

Dhanusha A. Nalawansha, Ke Li, John Hines, Craig M. Crews
doi: https://doi.org/10.1101/2022.01.24.477424
Dhanusha A. Nalawansha
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States
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Ke Li
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States
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John Hines
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States
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Craig M. Crews
1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States
2Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States
3Department of Pharmacology, Yale University, New Haven, Connecticut 06511, United States
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  • For correspondence: craig.crews@yale.edu
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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.

Competing Interest Statement

C.M.C. is a shareholder in Arvinas, Inc. and in Halda, LLC, for which he consults and receives laboratory research support.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 27, 2022.
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Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation
Dhanusha A. Nalawansha, Ke Li, John Hines, Craig M. Crews
bioRxiv 2022.01.24.477424; doi: https://doi.org/10.1101/2022.01.24.477424
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Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation
Dhanusha A. Nalawansha, Ke Li, John Hines, Craig M. Crews
bioRxiv 2022.01.24.477424; doi: https://doi.org/10.1101/2022.01.24.477424

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