4.5 Review

Proteomic approaches for the profiling of ubiquitylation events and their applications in drug discovery

Journal

JOURNAL OF PROTEOMICS
Volume 231, Issue -, Pages -

Publisher

ELSEVIER
DOI: 10.1016/j.jprot.2020.103996

Keywords

Ubiquitylation; Anti-diGly antibody; Affinity purification; Proteomics; TUBE; Drug discovery

Funding

  1. National Key R&D Program of China [2019YFA0802400]
  2. National Natural Science Foundation of China [31971353, 31700722]
  3. State Key Laboratory of Proteomics [SKLP-O201905]
  4. Suzhou Bureau of Science and Technology (Basic Research in Medical and Health Sciences) [SYS201718]
  5. Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX17_2040]
  6. Hui-Chun Chin and Tsung-Dao Lee Chinese Undergraduate Research Endowment (CURE)
  7. Jiangsu Key Laboratory of Neuropsychiatric Diseases [BM2013003]
  8. National Center for International Research [2017B01012]
  9. Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions

Ask authors/readers for more resources

Protein ubiquitylation plays critical roles in regulating various biological processes in eukaryotic cells with dysregulation leading to the onset of diseases; Identifying ubiquitylation sites is crucial for uncovering key ubiquitylation events associated with diseases and specific signaling pathways, and for understanding the biological functions of specific ubiquitylation events.
Protein ubiquitylation regulates almost all aspects of the biological processes including gene expression, DNA repair, cell proliferation and apoptosis in eukaryotic cells. Dysregulation of protein ubiquitylation caused by abnormal expression of enzymes in the ubiquitin system results in the onset of many diseases including cancer, neurodegenerative diseases, and metabolic syndromes. Therefore, targeting the ubiquitin system becomes a promising research area in drug discovery. Identification of protein ubiquitylation sites is critical for revealing the key ubiquitylation events associated with diseases and specific signaling pathways and for elucidating the biological functions of the specific ubiquitylation events. Many approaches that enrich for the ubiquitylated proteins and ubiquitylated peptides at the protein and peptide levels have been developed to facilitate their identification by MS. In this paper, we will review the proteomic approaches available for the identification of ubiquitylation events at the proteome scale and discuss their advantages and limitations. We will also brief the application of the profiling of ubiquitylation events in drug target discovery and in target validation for proteolysis-targeting chimera (PROTAC). Possible future research directions in this field will also be discussed. Significance: Ubiquitylation plays critical roles in regulating many biological processes in eukaryotic cells. Identification of ubiquitylation sites can provide the essential information for the functional study of the specific modified substrates. Since ubiquitylated proteins have much lower abundance than non-ubiquitylated proteins, enrichment of ubiquitylated proteins or peptides is critical for their identification by MS. This review focuses on different enrichment approaches that facilitate their isolation and identification by MS and discusses the advantages and drawbacks of these approaches. The application of the profiling of ubiquitylation events in drug target discovery and future research directions will be beneficial to the research community.

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