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  3. PROTAC-Based Proteomics Strategy Uncovers Arsenic-Binding Proteomes

PROTAC-Based Proteomics Strategy Uncovers Arsenic-Binding Proteomes

  • Anal Chem. 2026 Jun 9;98(22):16501-16511. doi: 10.1021/acs.analchem.6c01761.
Jiahui Liu 1,  Ling Fang 2,  Shijun Wen 3,  Na Zhao 4,  Yongshun Huang 4,  Hongtao Liu 2,  Baowei Chen 5 6,  Tiangang Luan 1 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
  • 2 Instrumental Analysis and Research Center, Sun Yat-Sen University, Guangzhou 510275, China.
  • 3 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
  • 4 Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510300, China.
  • 5 Southern Marine Science and Engineering Guangdong Laboratory, School of Marine Sciences, Sun Yat-Sen University, Zhuhai 519082, China.
  • 6 Guangdong Provincial Laboratory of Chemistry and Fine Chemical Engineering Jieyang Center, Jieyang 515200, China.
  • 7 School of Environmental and Chemical Engineering, Wuyi University, Jiangmen 529020, China.
PMID: 42212908 DOI: 10.1021/acs.analchem.6c01761
Abstract

Manipulating intracellular protein degradation systems provides extraordinary opportunities to find targeting proteins critical for drug discovery, as exemplified by proteolysis-targeting chimeras (PROTACs). Here, using trivalent arsenical-PROTAC (As(III)-PROTAC) probes, we developed an in situ proteolysis strategy to uncover the As-binding proteomes. Combined with proteomic analysis, this strategy identified 135 downregulated proteins in A549 human lung carcinoma cells, providing a candidate list for seeking As-binding proteins. Bioinformatics analysis revealed that they were involved in multiple pathways, such as the tricarboxylic acid cycle, DNA replication, and DNA repair. Karyopherin subunit α-2 (KPNA2) and cyclin-dependent kinase 1 (CDK1) could play core roles in the context of protein interactions. Western blotting confirmed the downregulation of embryonic ectoderm development (EED) and Phospholipase A-2-activating (PLAA) proteins after the probe treatment. A cellular thermal shift assay (CETSA) exhibited intracellular binding of iAsIII to EED and PLAA. This work demonstrates the development and application of PROTAC probes for screening of As-binding proteomes and establishes a methodological foundation for comprehending the biological effects induced by arsenicals.

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