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USP14: Structure, Function, and Target Inhibition.

Feng Wang1, Shuo Ning1, Beiming Yu1

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|January 24, 2022
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Summary
This summary is machine-generated.

Ubiquitin-specific protease 14 (USP14) regulates protein degradation and is implicated in diseases. Inhibitors targeting USP14 are being developed, with structural studies guiding potent drug design for therapeutic applications.

Keywords:
diseasepathophysiological functionregulationsignaling pathwaystructuretarget inhibitionubiquitin-specific protease 14

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Area of Science:

  • Biochemistry and Molecular Biology
  • Enzymology
  • Proteostasis Regulation

Background:

  • Ubiquitin-specific protease 14 (USP14) is a deubiquitinating enzyme (DUB) crucial for proteasome-mediated protein degradation.
  • USP14 exhibits dual roles: protecting substrates from degradation and promoting degradation by activating the proteasome.
  • Dysregulation of USP14 is linked to cancer, neurodegenerative diseases, and immune responses.

Purpose of the Study:

  • To review the structure, regulation, and pathophysiological roles of USP14.
  • To summarize advancements in the development of selective USP14 inhibitors.
  • To highlight USP14 as a therapeutic target for various diseases.

Main Methods:

  • Analysis of structural studies on USP14, including its autoinhibited state and activation mechanisms.
  • Review of existing literature on USP14's involvement in cellular signaling pathways and disease.
  • Examination of inhibitor development strategies and structural insights from USP14-inhibitor complexes.

Main Results:

  • USP14 activity is tightly regulated, requiring conformational changes for deubiquitinating function.
  • Crystal structures of USP14 with inhibitors reveal allosteric mechanisms, aiding inhibitor design.
  • Significant progress has been made in identifying USP14 inhibitors, though selectivity and affinity remain challenges.

Conclusions:

  • USP14's complex roles in protein degradation and disease make it a promising therapeutic target.
  • Understanding USP14's structure and regulation is key to developing effective and selective inhibitors.
  • Continued research into USP14 inhibition holds potential for treating cancers and neurodegenerative disorders.