Modulation of Phosphoprotein Activity by Phosphorylation Targeting Chimeras (PhosTACs)
| Autor: | Angela Gong, Elvira An, Ifunanya Okeke, Saul Jaime-Figueroa, Zhenyi Hu, Xuanmeng Luo, Craig M. Crews, Po-Han Chen, Sijin Zheng |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Phosphatase
Hyperphosphorylation Biochemistry Dephosphorylation Structure-Activity Relationship Catalytic Domain Humans Protein phosphorylation Phosphorylation biology Chimera Chemistry Kinase Forkhead Box Protein O3 Retinoblastoma protein RNA-Binding Proteins General Medicine Protein phosphatase 2 Phosphoproteins Cell biology Enzyme Activation biology.protein Molecular Medicine Protein Tyrosine Phosphatases Apoptosis Regulatory Proteins Holoenzymes HeLa Cells |
| Zdroj: | ACS Chemical Biology. 16:2808-2815 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.1c00693 |
| Popis: | Protein phosphorylation, which regulates many critical aspects of cell biology, is dynamically governed by kinases and phosphatases. Many diseases are associated with dysregulated hyperphosphorylation of critical proteins, such as retinoblastoma protein in cancer. Although kinase inhibitors have been widely applied in the clinic, growing evidence of off-target effects and increasing drug resistance prompts the need to develop a new generation of drugs. Here, we propose a proof-of-concept study of phosphorylation targeting chimeras (PhosTACs). Similar to PROTACs in their ability to induce ternary complexes, PhosTACs focus on recruiting a Ser/Thr phosphatase to a phosphosubstrate to mediate its dephosphorylation. However, distinct from PROTACs, PhosTACs can uniquely provide target gain-of-function opportunities to manipulate protein activity. In this study, we applied a chemical biology approach to evaluate the feasibility of PhosTACs by recruiting the scaffold and catalytic subunits of the PP2A holoenzyme to protein substrates such as PDCD4 and FOXO3a for targeted protein dephosphorylation. For FOXO3a, this dephosphorylation resulted in the transcriptional activation of a FOXO3a-responsive reporter gene. |
| Databáze: | OpenAIRE |
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