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Structural and functional characterization of USP47 reveals a hot spot for inhibitor design

Sang Chul Shin1,2, Jinyoung Park1,3, Kyung Hee Kim1

  • 1Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.

Communications Biology
|September 22, 2023
PubMed

Insights

Ubiquitin-specific protease 47 (USP47) regulates cancer cell growth via p53. Its structure reveals how USP47 binds ubiquitin, offering potential drug targets for cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Ubiquitin-specific protease 47 (USP47) plays a role in tumor development and metastasis.
  • USP47 also regulates inflammatory responses, myocardial infarction, and neuronal development.

Purpose of the Study:

  • To investigate the functional and biochemical properties of USP47.
  • To elucidate the molecular mechanisms underlying USP47's activity and substrate recognition.

Main Methods:

  • Depletion of USP47 in cancer cells.
  • Biochemical assays to measure deubiquitinase activity.
  • Crystal structure determination of USP47 catalytic domain (free and ubiquitin-bound states).

Main Results:

  • USP47 depletion inhibited cancer cell growth in a p53-dependent manner, enhanced by USP7 knockdown.
  • Full-length USP47 exhibited higher deubiquitinase activity than its catalytic domain.
  • Crystal structures revealed ubiquitin-induced catalytic triad alignment in USP47, similar to USP7.
  • Differences in BL1, BL2, and BL3 regions contribute to USP47's selectivity.

Conclusions:

  • USP47's activity is regulated by ubiquitin binding, with structural features dictating substrate selectivity.
  • Understanding USP47's molecular regulation provides insights into cancer development.
  • USP47 represents a potential target for novel cancer drug discovery.

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