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Identification of Functional Protein Regions Through Chimeric Protein Construction
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Disordered region of cereblon is required for efficient degradation by proteolysis-targeting chimera

Kidae Kim1,2, Dong Ho Lee3, Sungryul Park1,2

  • 1Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.

Scientific Reports
|December 25, 2019
PubMed

Insights

Intrinsically disordered regions in proteins are essential for efficient proteolysis targeting chimeras (PROTACs)-induced degradation. This finding provides a new criterion for selecting protein targets for PROTAC development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Proteolysis targeting chimeras (PROTACs) are a novel therapeutic strategy for targeted protein degradation.
  • Understanding the molecular determinants of PROTAC-mediated protein degradation is crucial for optimizing their efficacy.

Purpose of the Study:

  • To investigate the role of intrinsically disordered regions in protein degradability by PROTACs.
  • To identify new criteria for selecting suitable protein targets for PROTAC-based therapies.

Main Methods:

  • Development of von Hippel-Lindau-Cereblon (VHL-CRBN) heterodimerizing PROTACs.
  • Quantitative proteomic analysis to assess protein degradation.
  • Truncation and attachment of disordered regions in target proteins (CRBN and Androgen Receptor).

Main Results:

  • VHL-CRBN heterodimerizing PROTACs induced degradation of CRBN but not VHL or known IMiD neo-substrates (IKZF1, IKZF3).
  • Truncation of disordered regions attenuated PROTAC-induced degradation of CRBN and Androgen Receptor.
  • Attachment of disordered regions enhanced PROTAC-induced degradation of stable CRBN and Androgen Receptor variants.

Conclusions:

  • Intrinsically disordered regions are essential for efficient PROTAC-mediated protein degradation.
  • The presence of disordered regions can serve as a key criterion for selecting protein targets in PROTAC drug design.

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