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Targeted Protein Localization by Covalent 14-3-3 Recruitment
Qian Shao1,2, Tuong Nghi Duong1,2, Inji Park1,2
1Departments of Chemistry and Molecular and Cell Biology, University of California, Berkeley, Berkeley, California 94720, United States.
Journal of the American Chemical Society
|August 28, 2024
Summary
Researchers developed a novel covalent ligand, EN171, acting as a 14-3-3 molecular glue. This enhances 14-3-3σ interactions with transcription factors like YAP and TAZ, enabling targeted protein sequestration.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- 14-3-3 proteins bind diverse phosphorylated substrates, regulating cellular signaling.
- Enhancing 14-3-3 interactions with transcription factors is therapeutically challenging.
- 14-3-3σ (SFN) has a reactive cysteine (C38) near its substrate-binding interface.
Purpose of the Study:
- To identify molecular glues that enhance 14-3-3σ interactions with transcription factors.
- To target both druggable (ERα) and intractable (YAP, TAZ) substrates.
- To explore covalent recruiters for sequestering nuclear neo-substrates.
Main Methods:
- Screening a synthetic cysteine-reactive covalent ligand library against 14-3-3σ.
- Utilizing a hit compound (EN171) to assess its effect on ERα, YAP, and TAZ binding.
- Testing EN171 in heterobifunctional molecules for nuclear neo-substrate sequestration.
Main Results:
- Identified EN171, a covalent ligand targeting 14-3-3σ C38 and C96.
- EN171 enhanced 14-3-3σ interactions with ERα, YAP, and TAZ, reducing their transcriptional activity.
- Demonstrated EN171's utility as a recruiter for sequestering BRD4 and BLC6 into the cytosol.
Conclusions:
- EN171 is a novel covalent 14-3-3 molecular glue for challenging transcription factors.
- Covalent 14-3-3 glues can be engineered into heterobifunctional molecules.
- Targeted sequestration of nuclear proteins to the cytosol is achievable for therapeutic applications.
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